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Sample records for retinitis pigmentosa due

  1. Retinitis Pigmentosa

    MedlinePlus

    ... Action You are here Home › Retinal Diseases Listen Retinitis Pigmentosa What is retinitis pigmentosa? What are the symptoms? ... available? Are there any related diseases? What is retinitis pigmentosa? Retinitis pigmentosa (RP) refers to a group of ...

  2. Retinitis Pigmentosa.

    ERIC Educational Resources Information Center

    Carr, Ronald E.

    1979-01-01

    The author describes the etiology of retinitis pigmentosa, a visual dysfunction which results from progressive loss of the retinal photoreceptors. Sections address signs and symptoms, ancillary findings, heredity, clinical diagnosis, therapy, and research. (SBH)

  3. Genetics Home Reference: retinitis pigmentosa

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions retinitis pigmentosa retinitis pigmentosa Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Retinitis pigmentosa is a group of related eye disorders that ...

  4. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci

    SciTech Connect

    Kajiwara, K.; Berson, E.L.; Dryja, T.P. )

    1994-06-10

    In spite of recent advances in identifying genes causing monogenic human disease, very little is known about the genes involved in polygenic disease. Three families were identified with mutations in the unlinked photoreceptor-specific genes ROM 1 and peripherin/RDS, in which only double heterozygotes develop retinitis pigmentosa (RP). These findings indicate that the allelic and nonallelic heterogeneity known to be a feature of monogenic RP is complicated further by interactions between unlinked mutations causing digenic RP. Recognition of the inheritance pattern exemplified by these three families might facilitate the identification of other examples of digenic inheritance in human disease.

  5. Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay

    PubMed Central

    Rio Frio, Thomas; Wade, Nicholas M.; Ransijn, Adriana; Berson, Eliot L.; Beckmann, Jacques S.; Rivolta, Carlo

    2008-01-01

    Dominant mutations in the gene encoding the mRNA splicing factor PRPF31 cause retinitis pigmentosa, a hereditary form of retinal degeneration. Most of these mutations are characterized by DNA changes that lead to premature termination codons. We investigated 6 different PRPF31 mutations, represented by single-base substitutions or microdeletions, in cell lines derived from 9 patients with dominant retinitis pigmentosa. Five of these mutations lead to premature termination codons, and 1 leads to the skipping of exon 2. Allele-specific measurement of PRPF31 transcripts revealed a strong reduction in the expression of mutant alleles. As a consequence, total PRPF31 protein abundance was decreased, and no truncated proteins were detected. Subnuclear localization of the full-length PRPF31 that was present remained unaffected. Blocking nonsense-mediated mRNA decay significantly restored the amount of mutant PRPF31 mRNA but did not restore the synthesis of mutant proteins, even in conjunction with inhibitors of protein degradation pathways. Our results indicate that most PRPF31 mutations ultimately result in null alleles through the activation of surveillance mechanisms that inactivate mutant mRNA and, possibly, proteins. Furthermore, these data provide compelling evidence that the pathogenic effect of PRPF31 mutations is likely due to haploinsufficiency rather than to gain of function. PMID:18317597

  6. Retinitis Pigmentosa and Education Issues

    ERIC Educational Resources Information Center

    Brown, Thomas J.

    2005-01-01

    Retinitis Pigmentosa includes a number of inherited diseases which usually result in blindness. The disease is progressive in nature and begins with the deterioration of cells in the eye responsible for peripheral vision. As the condition worsens there is a gradual loss of peripheral vision and night blindness. Proper educational planning requires…

  7. Molecular genetics of retinitis pigmentosa.

    PubMed Central

    Farber, D. B.; Heckenlively, J. R.; Sparkes, R. S.; Bateman, J. B.

    1991-01-01

    Retinitis pigmentosa is a model for the study of genetic diseases. Its genetic heterogeneity is reflected in the different forms of inheritance (autosomal dominant, autosomal recessive, or X-linked) and, in a few families, in the presence of mutations in the visual pigment rhodopsin. Clinical and molecular genetic studies of these disorders are discussed. Animal models of retinal degeneration have been investigated for many years with the hope of gaining insight into the cause of photoreceptor cell death. Recently, the genes responsible for two of these animal disorders, the rds and rd mouse genes, have been isolated and characterized. The retinal degeneration of the rd mouse is presented in detail. The possible involvement of human analogues of these mouse genes in human retinal diseases is being investigated. Images PMID:1771877

  8. Retinitis pigmentosa in southern Africa.

    PubMed

    Greenberg, J; Bartmann, L; Ramesar, R; Beighton, P

    1993-11-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders which are a common cause of genetic blindness. The relative frequencies of the different forms of RP in South Africa, as determined from the register at the DNA banking centre for RP at the Department of Human Genetics, University of Cape Town, are presented and discussed. Of the 125 families analysed, 29 (23%) showed autosomal dominant, 33 (27%) autosomal recessive and 3 (3%) X-linked inheritance. In 10 families the pedigree data were insufficient to allow accurate genetic subtyping and a further 50 patients were sporadic without a family history of RP or other syndromic features which would allow categorization. PMID:8313621

  9. Low Vision Rehabilitation of Retinitis Pigmentosa. Practice Report

    ERIC Educational Resources Information Center

    Rundquist, John

    2004-01-01

    Retinitis pigmentosa is a rod-cone dystrophy, commonly genetic in nature. Approximately 60-80% of those with retinitis pigmentosa inherit it by an autosomal recessive transmission (Brilliant, 1999). There have been some reported cases with no known family history. The symptoms of retinitis pigmentosa are decreased acuity, photophobia, night…

  10. Halting progressive neurodegeneration in advanced retinitis pigmentosa

    PubMed Central

    Koch, Susanne F.; Tsai, Yi-Ting; Duong, Jimmy K.; Wu, Wen-Hsuan; Hsu, Chun-Wei; Wu, Wei-Pu; Bonet-Ponce, Luis; Lin, Chyuan-Sheng; Tsang, Stephen H.

    2015-01-01

    Hereditary retinal degenerative diseases, such as retinitis pigmentosa (RP), are characterized by the progressive loss of rod photoreceptors followed by loss of cones. While retinal gene therapy clinical trials demonstrated temporary improvement in visual function, this approach has yet to achieve sustained functional and anatomical rescue after disease onset in patients. The lack of sustained benefit could be due to insufficient transduction efficiency of viral vectors (“too little”) and/or because the disease is too advanced (“too late”) at the time therapy is initiated. Here, we tested the latter hypothesis and developed a mouse RP model that permits restoration of the mutant gene in all diseased photoreceptor cells, thereby ensuring sufficient transduction efficiency. We then treated mice at early, mid, or late disease stages. At all 3 time points, degeneration was halted and function was rescued for at least 1 year. Not only do our results demonstrate that gene therapy effectively preserves function after the onset of degeneration, our study also demonstrates that there is a broad therapeutic time window. Moreover, these results suggest that RP patients are treatable, despite most being diagnosed after substantial photoreceptor loss, and that gene therapy research must focus on improving transduction efficiency to maximize clinical impact. PMID:26301813

  11. A Psychophysical Test for Retinitis Pigmentosa.

    ERIC Educational Resources Information Center

    Corwin, Thomas R; Mancini, Michael

    A new test designed to detect an hereditary eye disease called retinitis pigmentosa (RP) is described. This condition is revealed by pigmentation in the retina, but early diagnosis is difficult because the symptoms are subtle, and since it is genetically recessive it frequently occurs in families with no history of early blindness. In many cases…

  12. The Retinitis Pigmentosa Student: Selected Aspects.

    ERIC Educational Resources Information Center

    Sullivan, Franklin N.

    1984-01-01

    The characteristic features of RP (retinitis pigmentosa-an untreatable conditions usually resulting in night blindness) are discussed and functioning considerations in the classroom (including the use of protective devices and mobility aids) are noted. Classroom modifications such as darklined paper and black pens are suggested. (CL)

  13. Sildenafil alters retinal function in mouse carriers of retinitis pigmentosa.

    PubMed

    Nivison-Smith, Lisa; Zhu, Yuan; Whatham, Andrew; Bui, Bang V; Fletcher, Erica L; Acosta, Monica L; Kalloniatis, Michael

    2014-11-01

    Sildenafil, the active ingredient in Viagra, has been reported to cause transient visual disturbance from inhibition of phosphodiesterase 6 (PDE6), a key enzyme in the visual phototransduction pathway. This study investigated the effects of sildenafil on the rd1(+/-) mouse, a model for carriers of Retinitis Pigmentosa which exhibit normal vision but may have a lower threshold for cellular stress caused by sildenafil due to a heterozygous mutation in PDE6. Sildenafil caused a dose-dependent decrease in electroretinogram (ERG) responses of normal mice which mostly recovered two days post administration. In contrast, rd1(+/-) mice exhibited a significantly reduced photoreceptor and a supernormal bipolar cell response to sildenafil within 1 h of treatment. Carrier mice retinae took two weeks to return to baseline levels suggesting sildenafil has direct effects on both the inner and outer retina and these effects differ significantly between normal and carrier mice. Anatomically, an increase in expression of the early apoptotic marker, cytochrome C in rd1(+/-) mice indicated that the effects of sildenafil on visual function may lead to degeneration. The results of this study are significant considering approximately 1 in 50 people are likely to be carriers of recessive traits leading to retinal degeneration. PMID:25239397

  14. Case report: retinitis pigmentosa following cytotoxic chemotherapy in Usher's syndrome.

    PubMed

    Blanchet, P; Wellemeyer, M L; Burton, G V

    1992-05-01

    Ocular toxicity is an uncommon complication of cytotoxic chemotherapy. Retinitis pigmentosa complicating cancer chemotherapy has not been reported. A patient with probable Usher's syndrome (congenital sensorineural deafness) had apparent acceleration of retinitis pigmentosa with blindness following cytotoxic chemotherapy for non-Hodgkin's lymphoma. Retinitis pigmentosa, a feature of Usher's syndrome, usually develops as a slowly progressive process. The rapid acceleration of retinopathy following tumor therapy suggests a possible relationship to the cytotoxic chemotherapy. Lymphocytes and fibroblasts from patients with Usher's syndrome are hypersensitive to the x-ray type of DNA-damaging agents. The DNA-damaging effects of chemotherapy may have accelerated the progression of retinitis pigmentosa in this patient. PMID:1580321

  15. A Qualitative Self-Study of Retinitis Pigmentosa

    ERIC Educational Resources Information Center

    Fourie, Robert James

    2007-01-01

    Retinitis Pigmentosa (RP) is a retinal degenerative disease causing progressive blindness. Most research on RP is biomedical, and mostly from an observer perspective, therefore poorly reflecting the lived experience of having RP. Accordingly, the researcher conducted a retrospective qualitative self-study, to analyze reflections on his own…

  16. Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations*♦

    PubMed Central

    Sakami, Sanae; Maeda, Tadao; Bereta, Grzegorz; Okano, Kiichiro; Golczak, Marcin; Sumaroka, Alexander; Roman, Alejandro J.; Cideciyan, Artur V.; Jacobson, Samuel G.; Palczewski, Krzysztof

    2011-01-01

    Rhodopsin, the visual pigment mediating vision under dim light, is composed of the apoprotein opsin and the chromophore ligand 11-cis-retinal. A P23H mutation in the opsin gene is one of the most prevalent causes of the human blinding disease, autosomal dominant retinitis pigmentosa. Although P23H cultured cell and transgenic animal models have been developed, there remains controversy over whether they fully mimic the human phenotype; and the exact mechanism by which this mutation leads to photoreceptor cell degeneration remains unknown. By generating P23H opsin knock-in mice, we found that the P23H protein was inadequately glycosylated with levels 1–10% that of wild type opsin. Moreover, the P23H protein failed to accumulate in rod photoreceptor cell endoplasmic reticulum but instead disrupted rod photoreceptor disks. Genetically engineered P23H mice lacking the chromophore showed accelerated photoreceptor cell degeneration. These results indicate that most synthesized P23H protein is degraded, and its retinal cytotoxicity is enhanced by lack of the 11-cis-retinal chromophore during rod outer segment development. PMID:21224384

  17. On the heredity of retinitis pigmentosa.

    PubMed Central

    Jay, M.

    1982-01-01

    The aims of this study are: (1) to determine the frequencies of the various genetic forms of retinitis pigmentosa; and (2) to perform segregation analysis on autosomal dominant, autosomal recessive, and X-linked families. The families studied consisted of 2 series of patients at Moorfields Eye Hospital: (1) 426 families seen in the Genetic Clinic; and (2) 289 families seen in the Electrodiagnostic Department. Comparison between the 2 series identified biases of ascertainment, and it was estimated that the combined series included 53% of simplex cases and a minimum of 15% of X-linked families. Segregation analysis of the Genetic Clinic series showed good agreement with expectation in autosomal dominant and X-linked families, but indicated that no more than 70% of all simplex cases were autosomal recessive. The rest of the simplex cases were mildly affected and may represent fresh autosomal dominant mutations, autosomal dominant transmission with reduced penetrance, the heterozygous state of X-linked disease in some of the females, and phenocopies. PMID:7093178

  18. Eye Motility Alterations in Retinitis Pigmentosa

    PubMed Central

    Galeoto, Giovanni; Fratipietro, Manuela

    2015-01-01

    Purpose. We evaluated a sample of individuals with retinitis pigmentosa (RP) with the aim of assessing the presence or absence of ocular motility (OM) disorders. Materials and Methods. We included 23 out of the 25 individuals from the sample (9 females and 14 males) with an average visual acuity of 6/10. Results. The cover test about the vertical deviation in near distance showed an r/l in 3.45% and an l/r in 6.9%. The assessment of OM showed that 39.1% of the sample had a severe hyperfunction of the IO of the right eye and a severe hyperfunction (34.5%) of the SO of the left eye; 21.8% had a moderate hypofunction of right SO with a moderate percentage of hypofunction of 17.5% for the SO of the left eye; 30.5%, however, showed a serious hypofunction of the SR of both eyes; 21.7% of the sample showed a hyperfunction in both eyes of the IR. Conclusion. This alteration, however, is not attributable to either a high refractive defect (medium-low myopia: −1 diopter ±3 SD) or to a severely impaired binocular vision (visual acuity, motor fusion, and stereopsis are normal or within a range of values commonly accepted). Therefore, the disorders of OM lead to a genetic origin. PMID:26124957

  19. A case of CRB1-negative Coats-like retinitis pigmentosa.

    PubMed

    Sarao, Valentina; Veritti, Daniele; Prosperi, Raffaele; Pignatto, Silvia; Lanzetta, Paolo

    2013-08-01

    Retinitis pigmentosa is a heterogeneous group of ocular diseases that causes progressive degeneration of the photoreceptor cells mainly affecting the rods of the peripheral retina. The association between retinitis pigmentosa and exudative retinopathy was first described in 1956 and has been called "Coats-like retinitis pigmentosa." Mutations in the Crumbs homolog 1 (CRB1) gene have been reported as a risk factor for developing Coats-like changes in patients with autosomal recessive retinitis pigmentosa. We report the case of a 15-year-old girl affected by CRB1 gene-negative retinitis pigmentosa and Coats-like exudative vasculopathy who was successfully treated with laser photocoagulation. PMID:23871396

  20. Evidence for further genetic heterogeneity in autosomal dominant retinitis pigmentosa

    SciTech Connect

    Kumar-Singh, R.; Kenna, P.F.; Farrar, G.J.; Humphries, P. )

    1993-01-01

    We have investigated the possible involvement of further genetic heterogeneity in autosomal dominant retinitis pigmentosa using a previously unreported large Irish family with the disease. We have utilized polymorphic microsatellite markers to exclude the disease gene segregating in this family from 3q, 6p, and the pericentric region of 8, that is, each of the three chromosomal regions to which adRP loci are known to map. Hence, we provide definitive evidence for the involvement of a fourth locus in autosomal dominant retinitis pigmentosa. 25 refs., 2 figs.

  1. Detection of Retinitis Pigmentosa by Differential Interference Contrast Microscopy

    PubMed Central

    Kim, Yu Jeong; Lee, Hyunho; Cho, Joon Hyong; Cho, Young Ho; Kim, Chul-Ki; Lee, Taik Jin; Lee, Seok; Park, Ki Ho; Yu, Hyeong Gon; Lee, Hyuk-jae; Jun, Seong Chan; Kim, Jae Hun

    2014-01-01

    Differential interference contrast microscopy is designed to image unstained and transparent specimens by enhancing the contrast resulting from the Nomarski prism-effected optical path difference. Retinitis pigmentosa, one of the most common inherited retinal diseases, is characterized by progressive loss of photoreceptors. In this study, Differential interference contrast microscopy was evaluated as a new and simple application for observation of the retinal photoreceptor layer and retinitis pigmentosa diagnostics and monitoring. Retinal tissues of Royal College of Surgeons rats and retinal-degeneration mice, both well-established animal models for the disease, were prepared as flatmounts and histological sections representing different elapsed times since the occurrence of the disease. Under the microscopy, the retinal flatmounts showed that the mosaic pattern of the photoreceptor layer was irregular and partly collapsed at the early stage of retinitis pigmentosa, and, by the advanced stage, amorphous. The histological sections, similarly, showed thinning of the photoreceptor layer at the early stage and loss of the outer nuclear layer by the advanced stage. To count and compare the number of photoreceptors in the normal and early-retinitis pigmentosa-stage tissues, an automated cell-counting program designed with MATLAB, a numerical computing language, using a morphological reconstruction method, was applied to the differential interference contrast microscopic images. The number of cells significantly decreased, on average, from 282 to 143 cells for the Royal College of Surgeons rats and from 255 to 170 for the retinal-degeneration mouse. We successfully demonstrated the potential of the differential interference contrast microscopy technique’s application to the diagnosis and monitoring of RP. PMID:24810005

  2. Targeting the Proteostasis Network in Rhodopsin Retinitis Pigmentosa.

    PubMed

    Parfitt, David A; Cheetham, Michael E

    2016-01-01

    Mutations in rhodopsin are one of the most common causes of retinitis pigmentosa (RP). Misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis. There is currently no available treatment for RP. In this review, we discuss the different approaches currently being investigated for treatment of rhodopsin RP, focusing on the potential of manipulation of the proteostasis network as a therapeutic approach to combat retinal degeneration. PMID:26427449

  3. Workplace-Based Management of Retinitis Pigmentosa: A Case Report.

    ERIC Educational Resources Information Center

    Herse, Peter; Yapp, Michael

    1999-01-01

    Discusses the workplace-based accommodations that allowed a 45-year-old Southeast Asian woman with a moderate hearing deficit, who was diagnosed with retinitis pigmentosa, to continue to perform her duties as a checkout operator. Emphasizes the importance of conducting workplace evaluations before providers offer advice on vocational matters. (CR)

  4. Politics and Human Welfare: Retinitis Pigmentosa Patients in South Africa.

    ERIC Educational Resources Information Center

    McKendrick, B. W.; Leketi, M.

    1990-01-01

    The study found that apartheid impacted the sociopsychological and physical circumstances of 12 African and 11 White people with retinitis pigmentosa in South Africa. Findings are discussed in terms of onset of condition, effects on subjects' lives, knowledge of social services, and needs unmet by existing services. (JDD)

  5. Successful Vocational Rehabilitation of Clients with Retinitis Pigmentosa.

    ERIC Educational Resources Information Center

    Taheri-Araghi, M.; Hendren, G.

    1994-01-01

    Statistical analysis of 10 personal (client) variables and four program variables related to 76 people who became blind from retinitis pigmentosa revealed that 6 variables predicted clients' rehabilitation outcomes: age, gender, race, work status, amount of case-service money spent on the client's behalf, and number of changes in career objectives…

  6. Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT)

    PubMed Central

    Haer-Wigman, Lonneke; Newman, Hadas; Leibu, Rina; Bax, Nathalie M.; Baris, Hagit N; Rizel, Leah; Banin, Eyal; Massarweh, Amir; Roosing, Susanne; Lefeber, Dirk J.; Zonneveld-Vrieling, Marijke N.; Isakov, Ofer; Shomron, Noam; Sharon, Dror; Den Hollander, Anneke I.; Hoyng, Carel B.; Cremers, Frans P.M.; Ben-Yosef, Tamar

    2015-01-01

    Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is clinically and genetically heterogeneous and can appear as syndromic or non-syndromic. Mucopolysaccharidosis type IIIC (MPS IIIC) is a lethal disorder, caused by mutations in the heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) gene and characterized by progressive neurological deterioration, with retinal degeneration as a prominent feature. We identified HGSNAT mutations in six patients with non-syndromic RP. Whole exome sequencing (WES) in an Ashkenazi Jewish Israeli RP patient revealed a novel homozygous HGSNAT variant, c.370A>T, which leads to partial skipping of exon 3. Screening of 66 Ashkenazi RP index cases revealed an additional family with two siblings homozygous for c.370A>T. WES in three Dutch siblings with RP revealed a complex HGSNAT variant, c.[398G>C; 1843G>A] on one allele, and c.1843G>A on the other allele. HGSNAT activity levels in blood leukocytes of patients were reduced compared with healthy controls, but usually higher than those in MPS IIIC patients. All patients were diagnosed with non-syndromic RP and did not exhibit neurological deterioration, or any phenotypic features consistent with MPS IIIC. Furthermore, four of the patients were over 60 years old, exceeding by far the life expectancy of MPS IIIC patients. HGSNAT is highly expressed in the mouse retina, and we hypothesize that the retina requires higher HGSNAT activity to maintain proper function, compared with other tissues associated with MPS IIIC, such as the brain. This report broadens the spectrum of phenotypes associated with HGSNAT mutations and highlights the critical function of HGSNAT in the human retina. PMID:25859010

  7. X-linked dominant retinitis pigmentosa in an American family

    SciTech Connect

    McGuire, R.E.; Daiger, S.P.; Blanton, S.H.

    1994-09-01

    Retinitis pigmentosa is a genetically heterogeneous disease with autosomal dominant (adRP), autosomal recessive and X-linked forms. At least 3 forms of X-linked retinitis pigmentosa have been reported: RP2 which maps to Xp11.4-p 11.23, RP3 which maps to Xp21.1 and RP6, which maps to Xp21.3-p21.1. The X-linked forms of retinitis pigmentosa are generally considered to be recessive as female carriers are not affected or are much less affected than males. Here we report a five generation American family with X-linked retinitis pigmentosa in which both males and females are significantly affected. The disease locus in this family appears to be distinct from RP2 and RP3. The American family (UTAD054) presents with early-onset retinitis pigmentosa. The family appeared to fit an autosomal dominant pattern; however, linkage testing excluded all known adRP loci. Absence of male-to-male transmission in the pedigree suggested the possibility of X-linked dominant inheritance. Thus we tested six microsatellite markers that map to Xp (DXS987, DXS989, DXS993, DXS999, DXS1003 and DXS1110). Of these, DXS989 showed tight linkage with one allele (199) showing a 100% concordance with disease status. The odds favoring an X-linked dominant mode of inheritance in this family, versus autosomal dominant, are 10{sup 5}:1. In addition, recombinations for DXS999, and dXS1110, the two markers flanking DXS989, were observed in affected individuals. These data map the disease locus in this family to a 9 mb region on the X chromosome between Xp22.11 and Xp21.41. In addition, the recombinant individuals exclude close linkage to RP2 and RP3. The observance of high penetrance in females indicates that this family has X-linked dominant retinitis pigmentosa. We suggest that this mode of inheritance should be considered in other families with dominant retinitis pigmentosa but an absence of male-to-male transmission.

  8. Therapeutic Margins in a Novel Preclinical Model of Retinitis Pigmentosa

    PubMed Central

    Davis, Richard J.; Hsu, Chun-Wei; Tsai, Yi-Ting; Wert, Katherine J.; Sancho-Pelluz, Javier

    2013-01-01

    The third-most common cause of autosomal recessive retinitis pigmentosa (RP) is due to defective cGMP phosphodiesterase-6 (PDE6). Previous work using viral gene therapy on PDE6-mutant mouse models demonstrated photoreceptors can be rescued if administered before degeneration. However, whether visual function can be rescued after degeneration onset has not been addressed. This is a clinically important question, as newly diagnosed patients exhibit considerable loss of rods and cones in their peripheral retinas. We have generated and characterized a tamoxifen inducible Cre-loxP rescue allele, Pde6bStop, which allows us to temporally correct PDE6-deficiency. Whereas untreated mutants exhibit degeneration, activation of Cre-loxP recombination in early embryogenesis produced stable long-term rescue. Reversal at later time-points showed partial long-term or short-lived rescue. Our results suggest stable restoration of retinal function by gene therapy can be achieved if a sufficient number of rods are treated. Because patients are generally diagnosed after extensive loss of rods, the success of clinical trials may depend on identifying patients as early as possible to maximize the number of treatable rods. PMID:23946405

  9. Therapeutic margins in a novel preclinical model of retinitis pigmentosa.

    PubMed

    Davis, Richard J; Hsu, Chun-Wei; Tsai, Yi-Ting; Wert, Katherine J; Sancho-Pelluz, Javier; Lin, Chyuan-Sheng; Tsang, Stephen H

    2013-08-14

    The third-most common cause of autosomal recessive retinitis pigmentosa (RP) is due to defective cGMP phosphodiesterase-6 (PDE6). Previous work using viral gene therapy on PDE6-mutant mouse models demonstrated photoreceptors can be rescued if administered before degeneration. However, whether visual function can be rescued after degeneration onset has not been addressed. This is a clinically important question, as newly diagnosed patients exhibit considerable loss of rods and cones in their peripheral retinas. We have generated and characterized a tamoxifen inducible Cre-loxP rescue allele, Pde6b(Stop), which allows us to temporally correct PDE6-deficiency. Whereas untreated mutants exhibit degeneration, activation of Cre-loxP recombination in early embryogenesis produced stable long-term rescue. Reversal at later time-points showed partial long-term or short-lived rescue. Our results suggest stable restoration of retinal function by gene therapy can be achieved if a sufficient number of rods are treated. Because patients are generally diagnosed after extensive loss of rods, the success of clinical trials may depend on identifying patients as early as possible to maximize the number of treatable rods. PMID:23946405

  10. Psychological and Educational Recommendations for Working with Young People with Retinitis Pigmentosa

    ERIC Educational Resources Information Center

    Chacón-López, Helena; López-Justicia, Maria D.; Vervloed, Mathijs P. J.

    2014-01-01

    This article reviews the consequences of Retinitis Pigmentosa, a retinal degenerative disease with progressive reduction of the visual field, visual acuity, contrast sensitivity, and night blindness. Retinitis Pigmentosa is addressed from both a psychological and an educational standpoint, focusing on the impact on learning, emotional well-being,…

  11. Severe manifestations in carrier females in X linked retinitis pigmentosa.

    PubMed Central

    Souied, E; Segues, B; Ghazi, I; Rozet, J M; Chatelin, S; Gerber, S; Perrault, I; Michel-Awad, A; Briard, M L; Plessis, G; Dufier, J L; Munnich, A; Kaplan, J

    1997-01-01

    Retinitis pigmentosa (RP) is a group of progressive hereditary disorders of the retina in which various modes of inheritance have been described. Here, we report on X linked RP in nine families with constant and severe expression in carrier females. In our series, however, the phenotype was milder and delayed in carrier females compared to hemizygous males. This form of X linked RP could be regarded therefore as partially dominant. The disease gene maps to chromosome Xp2.1 in the genetic interval encompassing the RP3 locus (Zmax=13.71 at the DXS1100 locus). Single strand conformation polymorphism and direct sequence analysis of the retinitis pigmentosa GTPase regulator (RPGR) gene, which accounts for RP3, failed to detect any mutation in our families. Future advances in the identification of X linked RP genes will hopefully help to elucidate the molecular basis of this X linked dominant RP. Images PMID:9350809

  12. Retinitis pigmentosa with concomitant essential iris atrophy and glaucoma – case report

    PubMed Central

    Meirelles, Sérgio Henrique Sampaio; Barreto, Aline Sá; Buscacio, Eduardo Scaldini; Shinzato, Elke; Patrão, Lia Florim; de Oliveira Silva, Mauro Sérgio

    2015-01-01

    Purpose To report a case of a young patient with retinitis pigmentosa (RP), essential iris atrophy, and glaucoma. Case report This report presents a case of a 22-year-old female patient with unilateral glaucoma, increased intraocular pressure, increased cup–disc ratio, iris atrophy, peripheral anterior synechiae, and bilateral RP. Discussion The patient presented glaucoma due to the iridocorneal endothelial syndrome, despite low age. RP is a bilateral disorder that may be associated with angle-closure glaucoma. PMID:26648683

  13. ADIPOR1 Is Mutated in Syndromic Retinitis Pigmentosa.

    PubMed

    Xu, Mingchu; Eblimit, Aiden; Wang, Jing; Li, Jianli; Wang, Feng; Zhao, Li; Wang, Xia; Xiao, Ningna; Li, Yumei; Wong, Lee-Jun C; Lewis, Richard A; Chen, Rui

    2016-03-01

    Retinitis pigmentosa (RP) is a genetically heterogeneous retinal disorder. Despite the numerous genes associated with RP already identified, the genetic basis remains unknown in a substantial number of patients and families. In this study, we performed whole-exome sequencing to investigate the molecular basis of a syndromic RP case that cannot be solved by mutations in known disease-causing genes. After applying a series of variant filtering strategies, we identified an apparently homozygous frameshift mutation, c.31delC (p.Q11Rfs*24) in the ADIPOR1 gene. The reported phenotypes of Adipor1-null mice contain retinal dystrophy, obesity, and behavioral abnormalities, which highly mimic those in the syndromic RP patient. We further confirmed ADIPOR1 retina expression by immunohistochemistry. Our results established ADIPOR1 as a novel disease-causing gene for syndromic RP and highlight the importance of fatty acid transport in the retina. PMID:26662040

  14. Retinal Prosthesis System for Advanced Retinitis Pigmentosa: A Health Technology Assessment

    PubMed Central

    2016-01-01

    Background Retinitis pigmentosa is a group of genetic disorders that involves the breakdown and loss of photoreceptors in the retina, resulting in progressive retinal degeneration and eventual blindness. The Argus II Retinal Prosthesis System is the only currently available surgical implantable device approved by Health Canada. It has been shown to improve visual function in patients with severe visual loss from advanced retinitis pigmentosa. The objective of this analysis was to examine the clinical effectiveness, cost-effectiveness, budget impact, and safety of the Argus II system in improving visual function, as well as exploring patient experiences with the system. Methods We performed a systematic search of the literature for studies examining the effects of the Argus II retinal prosthesis system in patients with advanced retinitis pigmentosa, and appraised the evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria, focusing on visual function, functional outcomes, quality of life, and adverse events. We developed a Markov decision-analytic model to assess the cost-effectiveness of the Argus II system compared with standard care over a 10-year time horizon. We also conducted a 5-year budget impact analysis. We used a qualitative design and an interview methodology to examine patients’ lived experience, and we used a modified grounded theory methodology to analyze information from interviews. Transcripts were coded, and themes were compared against one another. Results One multicentre international study and one single-centre study were included in the clinical review. In both studies, patients showed improved visual function with the Argus II system. However, the sight-threatening surgical complication rate was substantial. In the base-case analysis, the Argus II system was cost-effective compared with standard care only if willingness-to-pay was more than $207,616 per quality-adjusted life

  15. Nonallelic heterogeneity in autosomal dominant retinitis pigmentosa with incomplete penetrance

    SciTech Connect

    Kim, S.K.; Berson, E.L.; Dryja, T.P.

    1994-08-01

    Retinitis pigmentosa is a group of retinal diseases in which photoreceptor cells throughout the retina degenerate. Although there is considerable genetic heterogeneity (autosomal dominant, autosomal recessive, and X-linked forms exist), there is a possibility that some clinically defined subtypes of the disease may be the result of mutations at the same locus. One possible clinically defined subtype is that of autosomal dominant retinitis pigmentosa (ADRP) with incomplete penetrance. Whereas in most families with ADRP, carriers can be clearly identified because of visual loss, ophthalmological findings, or abnormal electroretinograms (ERGs), in occasional families some obligate carriers are asymptomatic and have normal or nearly normal ERGs even late in life. A recent paper reported the mapping of the diseases locus in one pedigree (designated adRP7) with ADRP with incomplete penetrance to chromosome 7p. To test the idea that ADRP with incomplete penetrance may be genetically homogeneous, we have evaluated whether a different family with incomplete penetrance also has a disease gene linked to the same region. 4 refs., 1 fig., 1 tab.

  16. Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT)

    PubMed Central

    Wen, Yuquan; Fishman, Gerald A.; van den Born, L. Ingeborgh; Bittner, Ava; Bowles, Kristen; Fletcher, Emily C.; Collison, Frederick T.; Dagnelie, Gislin; Degli Eposti, Simona; Michaelides, Michel; Saperstein, David A.; Schuchard, Ronald A.; Barnes, Claire; Zein, Wadih; Zobor, Ditta; Birch, David G.; Mendola, Janine D.; Zrenner, Eberhart

    2015-01-01

    Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44%) showed a ≥20% increase and 4 of 18 (22%) showed a ≥40% increase in functional retinal area determined from Goldmann visual fields; 12 (67%) and 5 (28%) of 18 patients showed a ≥5 and ≥10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 ± 4.8 μm, mean ± 95% CI) than non-responders (3.5 ± 1.2 μm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity. Trial Registration ClinicalTrials.gov NCT01014052 PMID:26656277

  17. Mistrafficking of prenylated proteins causes retinitis pigmentosa 2

    PubMed Central

    Zhang, Houbin; Hanke-Gogokhia, Christin; Jiang, Li; Li, Xiaobo; Wang, Pu; Gerstner, Cecilia D.; Frederick, Jeanne M.; Yang, Zhenglin; Baehr, Wolfgang

    2015-01-01

    The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Δ (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The Rp2h−/− mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. Rp2h−/− scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the Rp2h−/− outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly “closed” conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.—Zhang, H., Hanke-Gogokhia, C., Jiang, L., Li, X., Wang, P., Gerstner, C. D., Frederick, J. M., Yang, Z., Baehr, W. Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. PMID:25422369

  18. A Family of Congenital Hepatic Fibrosis and Atypical Retinitis Pigmentosa

    PubMed Central

    Zanwar, Vinay; Mohite, Ashok; Surude, Ravindra; Rathi, Pravin; Balasubramani, Meenakshi

    2015-01-01

    Congenital hepatic fibrosis is a rare cause of portal hypertension and esophageal varices in children. We report cases of siblings with biopsy proven congenital hepatic fibrosis and with atypical retinitis pigmentosa. They presented with repeated episodes of jaundice along with progressive decrease of vision in night. They had hepatosplenomegaly and portal hypertension with esophageal varices. One of the siblings had a large regenerating nodule replacing the entire right lobe of the liver and other one developed repeated hematemesis. This constellation of diagnosis belongs to the ciliopathy group of disorders. The spectrum of ciliopathy disorders has been evolving, and it varies from mild to severe manifestations. PMID:26918098

  19. A Family of Congenital Hepatic Fibrosis and Atypical Retinitis Pigmentosa.

    PubMed

    Pawar, Sunil; Zanwar, Vinay; Mohite, Ashok; Surude, Ravindra; Rathi, Pravin; Balasubramani, Meenakshi

    2015-11-01

    Congenital hepatic fibrosis is a rare cause of portal hypertension and esophageal varices in children. We report cases of siblings with biopsy proven congenital hepatic fibrosis and with atypical retinitis pigmentosa. They presented with repeated episodes of jaundice along with progressive decrease of vision in night. They had hepatosplenomegaly and portal hypertension with esophageal varices. One of the siblings had a large regenerating nodule replacing the entire right lobe of the liver and other one developed repeated hematemesis. This constellation of diagnosis belongs to the ciliopathy group of disorders. The spectrum of ciliopathy disorders has been evolving, and it varies from mild to severe manifestations. PMID:26918098

  20. Progress in gene targeting and gene therapy for retinitis pigmentosa

    SciTech Connect

    Farrar, G.J.; Humphries, M.M.; Erven, A.

    1994-09-01

    Previously, we localized disease genes involved in retinitis pigmentosa (RP), an inherited retinal degeneration, close to the rhodopsin and peripherin genes on 3q and 6p. Subsequently, we and others identified mutations in these genes in RP patients. Currently animal models for human retinopathies are being generated using gene targeting by homologous recombination in embryonic stem (ES) cells. Genomic clones for retinal genes including rhodopsin and peripherin have been obtained from a phage library carrying mouse DNA isogenic with the ES cell line (CC1.2). The peripherin clone has been sequenced to establish the genomic structure of the mouse gene. Targeting vectors for rhodopsin and peripherin including a neomycin cassette for positive selection and thymidine kinase genes enabling selection against random intergrants are under construction. Progress in vector construction will be presented. Simultaneously we are developing systems for delivery of gene therapies to retinal tissues utilizing replication-deficient adenovirus (Ad5). Efficacy of infection subsequent to various methods of intraocular injection and with varying viral titers is being assayed using an adenovirus construct containing a CMV promoter LacZ fusion as reporter and the range of tissues infected and the level of duration of LacZ expression monitored. Viral constructs with the LacZ reporter gene under the control of retinal specific promoters such as rhodopsin and IRBP cloned into pXCJL.1 are under construction. An update on developments in photoreceptor cell-directed expression of virally delivered genes will be presented.

  1. Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa.

    PubMed

    Wang, Wei; Lee, Sang Joon; Scott, Patrick A; Lu, Xiaoqin; Emery, Douglas; Liu, Yongqin; Ezashi, Toshihiko; Roberts, Michael R; Ross, Jason W; Kaplan, Henry J; Dean, Douglas C

    2016-04-12

    Most retinitis pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nighttime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE) and, thus, is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment-rich outer segments (OSs), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis. PMID:27050517

  2. Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa

    PubMed Central

    Wang, Wei; Lee, Sang Joon; Scott, Patrick A.; Lu, Xiaoqin; Emery, Douglas; Liu, Yongqin; Ezashi, Toshihiko; Roberts, Michael R.; Ross, Jason W.; Kaplan, Henry J.; Dean, Douglas C.

    2016-01-01

    Most Retinitis Pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nightime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE), and thus is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment -rich outer segments (OS), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis. PMID:27050517

  3. Personalized therapeutic strategies for patients with retinitis pigmentosa

    PubMed Central

    Zheng, Andrew; Li, Yao

    2015-01-01

    Introduction Retinitis pigmentosa (RP) encompasses many different hereditary retinal degenerations that are caused by a vast array of different gene mutations and have highly variable disease presentations and severities. This heterogeneity poses a significant therapeutic challenge, although an answer may eventually be found through two recent innovations: induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genome editing. Areas covered This review discusses the wide-ranging applications of iPSCs and CRISPR–including disease modelling, diagnostics and therapeutics – with an ultimate view towards understanding how these two technologies can come together to address disease heterogeneity and orphan genes in a novel personalized medicine platform. An extensive literature search was conducted in PubMed and Google Scholar, with a particular focus on high-impact research published within the last 1 – 2 years and centered broadly on the subjects of retinal gene therapy, iPSC-derived outer retina cells, stem cell transplantation and CRISPR/Cas gene editing. Expert opinion For the retinal pigment epithelium, autologous transplantation of gene-corrected grafts derived from iPSCs may well be technically feasible in the near future. Photoreceptor transplantation faces more significant unresolved technical challenges but remains an achievable, if more distant, goal given the rapid pace of advancements in the field. PMID:25613576

  4. Genomic DNA nanoparticles rescue rhodopsin-associated retinitis pigmentosa phenotype

    PubMed Central

    Han, Zongchao; Banworth, Marcellus J.; Makkia, Rasha; Conley, Shannon M.; Al-Ubaidi, Muayyad R.; Cooper, Mark J.; Naash, Muna I.

    2015-01-01

    Mutations in the rhodopsin gene cause retinal degeneration and clinical phenotypes including retinitis pigmentosa (RP) and congenital stationary night blindness. Effective gene therapies have been difficult to develop, however, because generating precise levels of rhodopsin expression is critical; overexpression causes toxicity, and underexpression would result in incomplete rescue. Current gene delivery strategies routinely use cDNA-based vectors for gene targeting; however, inclusion of noncoding components of genomic DNA (gDNA) such as introns may help promote more endogenous regulation of gene expression. Here we test the hypothesis that inclusion of genomic sequences from the rhodopsin gene can improve the efficacy of rhodopsin gene therapy in the rhodopsin knockout (RKO) mouse model of RP. We utilize our compacted DNA nanoparticles (NPs), which have the ability to transfer larger and more complex genetic constructs, to deliver murine rhodopsin cDNA or gDNA. We show functional and structural improvements in RKO eyes for up to 8 months after NP-mediated gDNA but not cDNA delivery. Importantly, in addition to improvements in rod function, we observe significant preservation of cone function at time points when cones in the RKO model are degenerated. These results suggest that inclusion of native expression elements, such as introns, can significantly enhance gene expression and therapeutic efficacy and may become an essential option in the array of available gene delivery tools.— Han, Z., Banworth, M. J., Makkia, R., Conley, S. M., Al-Ubaidi, M. R., Cooper, M. J., Naash, M. I. Genomic DNA nanoparticles rescue rhodopsin-associated retinitis pigmentosa phenotype. PMID:25713057

  5. Genetic linkage studies in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Mansfield, D.C.; Teague, P.W.; Barber, A.

    1994-09-01

    Autosomal recessive retinitis pigmentosa (arRP) is a severe retinal dystrophy characterized by night blindness, progressive constriction of the visual fields and loss of central vision in the fourth or fifth decades. The frequency of this form of retinitis pigmentosa (RP) varies in different populations. Mutations within the rhodopsin, cyclic GMP phosphodiesterase-{beta} subunit and cGMP-gated channel genes have been reported in some arRP families. The genetic loci responsible for the majority of cases have yet to be identified. Genetic heterogeneity is likely to be extensive. In order to minimize the amount of genetic heterogenity, a set of arRP families was ascertained within the South-Central Sardinian population, in which 81% of families with a known mode of inheritance show an autosomal recessive form of RP. The Sardinian population is an ethnic {open_quotes}outlier{close_quotes}, having remained relatively isolated from mainland and other cultures. Genetic linkage data has been obtained in a set of 11 Sardinian arRP kindreds containing 26 affected members. Under the assumption of genetic homogeneity, no evidence of linkage was found in the arRP kindreds using 195 markers, which excluded 62% of the genome (Z<-2). Positive lod scores were obtained with D14S80 which showed no recombination in a subset of 5 families. Heterogeneity testing using D14S80 and arRP showed no significant evidence of heterogeneity (p=0.18) but evidence of linkage ({chi}{sup 2}=3.64, p=0.028). We are currently screening the neural retina-specific leucine zipper gene (NRL) in 14q11 for mutations as a candidate locus.

  6. CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa.

    PubMed

    Lipinski, Daniel M; Barnard, Alun R; Singh, Mandeep S; Martin, Chris; Lee, Edward J; Davies, Wayne I L; MacLaren, Robert E

    2015-08-01

    The long-term outcome of neuroprotection as a therapeutic strategy for preventing cell death in neurodegenerative disorders remains unknown, primarily due to slow disease progression and the inherent difficulty of assessing neuronal survival in vivo. Employing a murine model of retinal disease, we demonstrate that ciliary neurotrophic factor (CNTF) confers life-long protection against photoreceptor degeneration. Repetitive retinal imaging allowed the survival of intrinsically fluorescent cone photoreceptors to be quantified in vivo. Imaging of the visual cortex and assessment of visually-evoked behavioral responses demonstrated that surviving cones retain function and signal correctly to the brain. The mechanisms underlying CNTF-mediated neuroprotection were explored through transcriptome analysis, revealing widespread upregulation of proteolysis inhibitors, which may prevent cellular/extracellular matrix degradation and complement activation in neurodegenerative diseases. These findings provide insights into potential novel therapeutic avenues for diseases such as retinitis pigmentosa and amyotrophic lateral sclerosis, for which CNTF has been evaluated unsuccessfully in clinical trials. PMID:25896245

  7. Bifurcation analysis of a photoreceptor interaction model for Retinitis Pigmentosa

    NASA Astrophysics Data System (ADS)

    Camacho, Erika T.; Radulescu, Anca; Wirkus, Stephen

    2016-09-01

    Retinitis Pigmentosa (RP) is the term used to describe a diverse set of degenerative eye diseases affecting the photoreceptors (rods and cones) in the retina. This work builds on an existing mathematical model of RP that focused on the interaction of the rods and cones. We non-dimensionalize the model and examine the stability of the equilibria. We then numerically investigate other stable modes that are present in the system for various parameter values and relate these modes to the original problem. Our results show that stable modes exist for a wider range of parameter values than the stability of the equilibrium solutions alone, suggesting that additional approaches to preventing cone death may exist.

  8. Retinitis pigmentosa and allied conditions today: a paradigm of translational research

    PubMed Central

    2010-01-01

    Monogenic human retinal dystrophies are a group of disorders characterized by progressive loss of photoreceptor cells leading to visual handicap. Retinitis pigmentosa is a type of retinal dystrophy where degeneration of rod photoreceptors occurs at the early stages. At present, there are no available effective therapies to maintain or improve vision in patients affected with retinitis pigmentosa, but post-genomic studies are allowing the development of potential therapeutic approaches. This review summarizes current knowledge on genes that have been identified to be responsible for retinitis pigmentosa, the involvement of these genes in the different forms of the disorder, the role of the proteins encoded by these genes in retinal function, the utility of genotyping, and current efforts to develop novel therapies. PMID:20519033

  9. The Role of the Endothelin System in the Vascular Dysregulation Involved in Retinitis Pigmentosa

    PubMed Central

    Sorrentino, Francesco Saverio; Bonifazzi, Claudio; Perri, Paolo

    2015-01-01

    Retinitis pigmentosa is a clinical and genetic group of inherited retinal disorders characterized by alterations of photoreceptors and retinal pigment epithelium leading to a progressive concentric visual field restriction, which may bring about severe central vision impairment. Haemodynamic studies in patients with retinitis pigmentosa have demonstrated ocular blood flow abnormalities both in retina-choroidal and in retroocular vascular system. Moreover, several investigations have studied the augmentation of endothelin-1 plasma levels systemically in the body and locally in the eye. This might account for vasoconstriction and ischemia, typical in vascular dysregulation syndrome, which can be considered an important factor of reduction of the ocular blood flow in subjects affected by retinitis pigmentosa. PMID:26613048

  10. Pharmacological approaches to retinitis pigmentosa: A laboratory perspective.

    PubMed

    Guadagni, Viviana; Novelli, Elena; Piano, Ilaria; Gargini, Claudia; Strettoi, Enrica

    2015-09-01

    Retinal photoreceptors are highly specialized and performing neurons. Their cellular architecture is exquisitely designed to host a high concentration of molecules involved in light capture, phototransduction, electric and chemical signaling, membrane and molecular turnover, light and dark adaption, network activities etc. Such high efficiency and molecular complexity require a great metabolic demand, altogether conferring to photoreceptors particular susceptibility to external and internal insults, whose occurrence usually precipitate into degeneration of these cells and blindness. In Retinitis Pigmentosa, an impressive number of mutations in genes expressed in the retina and coding for a large varieties of proteins leads to the progressive death of photoreceptors and blindness. Recent advances in molecular tools have greatly facilitated the identification of the underlying genetics and molecular bases of RP leading to the successful implementation of gene therapy for some types of mutations, with visual restoration in human patients. Yet, genetic heterogeneity of RP makes mutation-independent approaches highly desirable, although many obstacles pave the way to general strategies for treating this complex disease, which remains orphan. The review will focus on treatments for RP based on pharmacological tools, choosing, among the many ongoing studies, approaches which rely on strong experimental evidence or rationale. For perspective treatments, new concepts are foreseen to emerge from basic studies elucidating the pathways connecting the primary mutations to photoreceptor death, possibly revealing common molecular targets for drug intervention. PMID:26113212

  11. Novel mutations in PDE6B causing human retinitis pigmentosa

    PubMed Central

    Cheng, Lu-Lu; Han, Ru-Yi; Yang, Fa-Yu; Yu, Xin-Ping; Xu, Jin-Ling; Min, Qing-Jie; Tian, Jie; Ge, Xiang-Lian; Zheng, Si-Si; Lin, Ye-Wen; Zheng, Yi-Han; Qu, Jia; Gu, Feng

    2016-01-01

    AIM To identify the genetic defects of a Chinese patient with sporadic retinitis pigmentosa (RP). METHODS Ophthalmologic examinations were performed on the sporadic RP patient, 144 genes associated with retinal diseases were scanned with capture next generation sequencing (CNGS) approach. Two heterozygous mutations in PDE6B were confirmed in the pedigree by Sanger sequencing subsequently. The carrier frequency of PDE6B mutations of reported PDE6B mutations based on the available two public exome databases (1000 Genomes Project and ESP6500 Genomes Project) and one in-house exome database was investigated. RESULTS We identified compound heterozygosity of two novel nonsense mutations c.1133G>A (p.W378X) and c.2395C>T (p.R799X) in PDE6B, one reported causative gene for RP. Neither of the two mutations in our study was presented in three exome databases. Two mutations (p.R74C and p.T604I) in PDE6B have relatively high frequencies in the ESP6500 and in-house databases, respectively, while no common dominant mutation in each of the database or across all databases. CONCLUSION We demonstrates that compound heterozygosity of two novel nonsense mutations in PDE6B could lead to RP. These results collectively point to enormous potential of next-generation sequencing in determining the genetic etiology of RP and how various mutations in PDE6B contribute to the genetic heterogeneity of RP. PMID:27588261

  12. Genomic DNA nanoparticles rescue rhodopsin-associated retinitis pigmentosa phenotype.

    PubMed

    Han, Zongchao; Banworth, Marcellus J; Makkia, Rasha; Conley, Shannon M; Al-Ubaidi, Muayyad R; Cooper, Mark J; Naash, Muna I

    2015-06-01

    Mutations in the rhodopsin gene cause retinal degeneration and clinical phenotypes including retinitis pigmentosa (RP) and congenital stationary night blindness. Effective gene therapies have been difficult to develop, however, because generating precise levels of rhodopsin expression is critical; overexpression causes toxicity, and underexpression would result in incomplete rescue. Current gene delivery strategies routinely use cDNA-based vectors for gene targeting; however, inclusion of noncoding components of genomic DNA (gDNA) such as introns may help promote more endogenous regulation of gene expression. Here we test the hypothesis that inclusion of genomic sequences from the rhodopsin gene can improve the efficacy of rhodopsin gene therapy in the rhodopsin knockout (RKO) mouse model of RP. We utilize our compacted DNA nanoparticles (NPs), which have the ability to transfer larger and more complex genetic constructs, to deliver murine rhodopsin cDNA or gDNA. We show functional and structural improvements in RKO eyes for up to 8 months after NP-mediated gDNA but not cDNA delivery. Importantly, in addition to improvements in rod function, we observe significant preservation of cone function at time points when cones in the RKO model are degenerated. These results suggest that inclusion of native expression elements, such as introns, can significantly enhance gene expression and therapeutic efficacy and may become an essential option in the array of available gene delivery tools. PMID:25713057

  13. Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa.

    PubMed

    Xu, Mingchu; Yamada, Takeyuki; Sun, Zixi; Eblimit, Aiden; Lopez, Irma; Wang, Feng; Manya, Hiroshi; Xu, Shan; Zhao, Li; Li, Yumei; Kimchi, Adva; Sharon, Dror; Sui, Ruifang; Endo, Tamao; Koenekoop, Robert K; Chen, Rui

    2016-04-15

    A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle-eye-brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have identified recessive mutations inPOMGNT1, which encodes an essential component in O-mannosylation pathway, in three unrelated families with autosomal recessive retinitis pigmentosa (RP), but without extraocular involvement. Enzymatic assay of these mutant alleles demonstrate that they greatly reduce the POMGNT1 enzymatic activity and are likely to be hypomorphic. Immunohistochemistry shows that POMGNT1 is specifically expressed in photoreceptor basal body. Taken together, our work identifies a novel disease-causing gene for RP and indicates that proper protein O-mannosylation is not only essential for early organ development, but also important for maintaining survival and function of the highly specialized retinal cells at later stages. PMID:26908613

  14. The Role of Fundus Autofluorescence in Late-Onset Retinitis Pigmentosa (LORP) Diagnosis

    PubMed Central

    Lee, Tamara J.; Hwang, John C.; Chen, Royce W. S.; Lima, Luiz H.; Wang, Nan-Kai; Tosi, Joaquin; Freund, K. Bailey; Yannuzzi, Lawrence A.; Tsang, Stephen H.

    2015-01-01

    Purpose To demonstrate the utility and characteristics of fundus autofluorescence in late-onset retinitis pigmentosa. Methods Observational case series. Patients diagnosed with late-onset retinitis pigmentosa were identified retrospectively in an institutional setting. Twelve eyes of six patients were identified and medical records were reviewed. Results All patients presented with slowly progressive peripheral field loss and initial clinical examination revealed only subtle retinal changes. There was a notable lack of intraretinal pigment migration in all patients. Five out of six patients underwent magnetic resonance imaging of the brain to rule out intracranial processes and all were referred from another ophthalmologist for further evaluation. Fundus autofluorescence was ultimately employed in all patients and revealed more extensive retinal pathology than initially appreciated on clinical examination. Fundus autofluorescence directed the workup toward a retinal etiology in all cases and led to the eventual diagnosis of late-onset retinitis pigmentosa through electroretinogram testing. Conclusion Fundus autofluorescence may be a more sensitive marker for retinal pathology than stereo fundus biomicroscopy alone in late-onset retinitis pigmentosa. Early use of fundus autofluorescence imaging in the evaluation of patients with subtle retinal lesions and complaints of peripheral field loss may be an effective strategy for timely and cost-efficient diagnosis. PMID:23899229

  15. Thermal Stability of Rhodopsin and Progression of Retinitis Pigmentosa

    PubMed Central

    Liu, Monica Yun; Liu, Jian; Mehrotra, Devi; Liu, Yuting; Guo, Ying; Baldera-Aguayo, Pedro A.; Mooney, Victoria L.; Nour, Adel M.; Yan, Elsa C. Y.

    2013-01-01

    Over 100 point mutations in the rhodopsin gene have been associated with retinitis pigmentosa (RP), a family of inherited visual disorders. Among these, we focused on characterizing the S186W mutation. We compared the thermal properties of the S186W mutant with another RP-causing mutant, D190N, and with WT rhodopsin. To assess thermal stability, we measured the rate of two thermal reactions contributing to the thermal decay of rhodopsin as follows: thermal isomerization of 11-cis-retinal and hydrolysis of the protonated Schiff base linkage between the 11-cis-retinal chromophore and opsin protein. We used UV-visible spectroscopy and HPLC to examine the kinetics of these reactions at 37 and 55 °C for WT and mutant rhodopsin purified from HEK293 cells. Compared with WT rhodopsin and the D190N mutant, the S186W mutation dramatically increases the rates of both thermal isomerization and dark state hydrolysis of the Schiff base by 1–2 orders of magnitude. The results suggest that the S186W mutant thermally destabilizes rhodopsin by disrupting a hydrogen bond network at the receptor's active site. The decrease in the thermal stability of dark state rhodopsin is likely to be associated with higher levels of dark noise that undermine the sensitivity of rhodopsin, potentially accounting for night blindness in the early stages of RP. Further studies of the thermal stability of additional pathogenic rhodopsin mutations in conjunction with clinical studies are expected to provide insight into the molecular mechanism of RP and test the correlation between rhodopsin's thermal stability and RP progression in patients. PMID:23625926

  16. Macular pigment optical density is related to serum lutein in retinitis pigmentosa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Purpose: To determine whether macular pigment optical density (MPOD) is related to the degree of cystoid macular edema (CME) in patients with retinitis pigmentosa. Methods: We measured MPOD with heterochromatic flicker photometry and central foveal retinal thickness with optical coherence tomography...

  17. Inherent Instability of the Retinitis Pigmentosa P23H Mutant Opsin*

    PubMed Central

    Chen, Yuanyuan; Jastrzebska, Beata; Cao, Pengxiu; Zhang, Jianye; Wang, Benlian; Sun, Wenyu; Yuan, Yiyuan; Feng, Zhaoyang; Palczewski, Krzysztof

    2014-01-01

    The P23H opsin mutation is the most common cause of autosomal dominant retinitis pigmentosa. Even though the pathobiology of the resulting retinal degeneration has been characterized in several animal models, its complex molecular mechanism is not well understood. Here, we expressed P23H bovine rod opsin in the nervous system of Caenorhabditis elegans. Expression was low due to enhanced protein degradation. The mutant opsin was glycosylated, but the polysaccharide size differed from that of the normal protein. Although P23H opsin aggregated in the nervous system of C. elegans, the pharmacological chaperone 9-cis-retinal stabilized it during biogenesis, producing a variant of rhodopsin called P23H isorhodopsin. In vitro, P23H isorhodopsin folded correctly, formed the appropriate disulfide bond, could be photoactivated but with reduced sensitivity, and underwent Meta II decay at a rate similar to wild type isorhodopsin. In worm neurons, P23H isorhodopsin initiated phototransduction by coupling with the endogenous Gi/o signaling cascade that induced loss of locomotion. Using pharmacological interventions affecting protein synthesis and degradation, we showed that the chromophore could be incorporated either during or after mutant protein translation. However, regeneration of P23H isorhodopsin with chromophore was significantly slower than that of wild type isorhodopsin. This effect, combined with the inherent instability of P23H rhodopsin, could lead to the structural cellular changes and photoreceptor death found in autosomal dominant retinitis pigmentosa. These results also suggest that slow regeneration of P23H rhodopsin could prevent endogenous chromophore-mediated stabilization of rhodopsin in the retina. PMID:24515108

  18. Heterogeneity analysis in 40 X-linked retinitis pigmentosa families

    SciTech Connect

    Teague, P.W.; Aldred, M.A.; Dempster, M.; Harrison, C.; Carothers, A.D.; Hardwick, L.J.; Evans, H.J.; Wright, A.F.; Strain, L.; Brock, D.J.H. )

    1994-07-01

    Analysis of genetic heterogeneity in 40 kindreds with X-linked retinitis pigmentosa (XLRP), with 20 polymorphic markers, showed that significant heterogeneity is present (P=.001) and that 56% of kindreds are of RP3 type and that 26% are of RP2 type. The location of the RP3 locus was found to be 0.4 cM distal to OTC in the Xp21.1 region, and that of the RP2 locus was 6.5 cM proximal to DXS7 in Xp11.2-p11.3. Bayesian probabilities of linkage to RP2, RP3, or to neither locus were calculated. This showed that 20 of 40 kindreds could be assigned to one or the other locus, with a probability >.70 (14 kindreds with RP3 and 6 kindreds with RP2 disease). A further three kindreds were found to be unlinked to either locus, with a probability >.8. The remaining 17 kindreds could not be classified unambiguously. This highlights the difficulty of classifying families in the presence of genetic heterogeneity, where two loci are separated by an estimated 16 cM. 34 refs., 1 fig., 4 tabs.

  19. Peripheral absolute threshold spectral sensitivity in retinitis pigmentosa.

    PubMed Central

    Massof, R W; Johnson, M A; Finkelstein, D

    1981-01-01

    Dark-adapted spectral sensitivities were measured in the peripheral retinas of 38 patients diagnosed as having typical retinitis pigmentosa (RP) and in 3 normal volunteers. The patients included those having autosomal dominant and autosomal recessive inheritance patterns. Results were analysed by comparisons with the CIE standard scotopic spectral visibility function and with Judd's modification of the photopic spectral visibility function, with consideration of contributions from changes in spectral transmission of preretinal media. The data show 3 general patterns. One group of patients had absolute threshold spectral sensitivities that were fit by Judd's photopic visibility curve. Absolute threshold spectral sensitivities for a second group of patients were fit by a normal scotopic spectral visibility curve. The third group of patients had absolute threshold spectral sensitivities that were fit by a combination of scotopic and photopic spectral visibility curves. The autosomal dominant and autosomal recessive modes of inheritance were represented in each group of patients. These data indicate that RP patients have normal rod and/or cone spectral sensitivities, and support the subclassification of patients described previously by Massof and Finkelstein. PMID:7459312

  20. Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa.

    PubMed

    Roche, Sarah L; Wyse-Jackson, Alice C; Byrne, Ashleigh M; Ruiz-Lopez, Ana M; Cotter, Thomas G

    2016-01-01

    Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period. We report novel findings that the mutation in the rd10 mouse results in retinal abnormalities earlier than was previously thought. Defects in rod and cone outer segments, bipolar cells, amacrine cells and photoreceptor synapses were apparent in the retina during early stages of postnatal retinal development and prior to the loss of photoreceptors. Additionally, we observed a dramatic response of glial cells during this period. Microglia responded as early as postnatal day (P) 5; ?13 days before any photoreceptor loss is detected with Müller glia and astrocytes exhibiting changes from P10 and P15 respectively. Overall, these findings present pathological aspects to the postnatal development of the rd10 retina, contributing significantly to our understanding of disease onset and progression in the rd10 mouse and provide a valuable resource for the study of retinal dystrophies. PMID:27160072

  1. Effect of Purified Murine NGF on Isolated Photoreceptors of a Rodent Developing Retinitis Pigmentosa

    PubMed Central

    Rocco, Maria Luisa; Balzamino, Bijorn Omar; Petrocchi Passeri, Pamela; Micera, Alessandra; Aloe, Luigi

    2015-01-01

    A number of different studies have shown that neurotrophins, including nerve growth factor (NGF) support the survival of retinal ganglion neurons during a variety if insults. Recently, we have reported that that eye NGF administration can protect also photoreceptor degeneration in a mice and rat with inherited retinitis pigmentosa. However, the evidence that NGF acts directly on photoreceptors and that other retinal cells mediate the NGF effect could not be excluded. In the present study we have isolated retinal cells from rats with inherited retinitis pigmentosa (RP) during the post-natal stage of photoreceptor degenerative. In presence of NGF, these cells are characterized by enhanced expression of NGF-receptors and rhodopsin, the specific marker of photoreceptor and better cell survival, as well as neuritis outgrowth. Together these observations support the hypothesis that NGF that NGF acts directly on photoreceptors survival and prevents photoreceptor degeneration as previously suggested by in vivo studies. PMID:25897972

  2. De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa

    PubMed Central

    Strom, Samuel P.; Clark, Michael J.; Martinez, Ariadna; Garcia, Sarah; Abelazeem, Amira A.; Matynia, Anna; Parikh, Sachin; Sullivan, Lori S.; Bowne, Sara J.; Daiger, Stephen P.; Gorin, Michael B.

    2016-01-01

    Background Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa. Methods Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing. Results and Conclusions A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon. PMID:26964041

  3. Molecular analysis and genetic mapping of the rhodopsin gene in families with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Bunge, S.; Wedemann, H.; Samanns, C.; Horn, M.; Schwinger, E.; Gal, A. ); David, D. ); Terwilliger, D.J.; Ott, J. ); Born, L.I. van den )

    1993-07-01

    Eighty-eight patients/families with autosomal dominant retinitis pigmentosa (RP) were screened for rhodopsin mutations. Direct sequencing revealed 13 different mutations in a total of 14 (i.e., 16%) unrelated patients. Five of these mutations (T4K, Q28H, R135G, F220C, and C222R) have not been reported so far. In addition, multipoint linkage analysis was performed on two large families with autosomal dominant RP due to rhodopsin mutations by using five DNA probes from 3q21-q24. No tight linkage was found between the rhodopsin locus (RHO) and D3S47 ([theta][sub max] = 0.08). By six-point analysis, RHO was localized in the region between D3S21 and D3S47, with a maximum lod score of 13.447 directly at D3S20. 13 refs., 1 fig., 2 tabs.

  4. Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa.

    PubMed

    Berger, Adeline; Lorain, Stéphanie; Joséphine, Charlène; Desrosiers, Melissa; Peccate, Cécile; Voit, Thomas; Garcia, Luis; Sahel, José-Alain; Bemelmans, Alexis-Pierre

    2015-05-01

    The promising clinical results obtained for ocular gene therapy in recent years have paved the way for gene supplementation to treat recessively inherited forms of retinal degeneration. The situation is more complex for dominant mutations, as the toxic mutant gene product must be removed. We used spliceosome-mediated RNA trans-splicing as a strategy for repairing the transcript of the rhodopsin gene, the gene most frequently mutated in autosomal dominant retinitis pigmentosa. We tested 17 different molecules targeting the pre-mRNA intron 1, by transient transfection of HEK-293T cells, with subsequent trans-splicing quantification at the transcript level. We found that the targeting of some parts of the intron promoted trans-splicing more efficiently than the targeting of other areas, and that trans-splicing rate could be increased by modifying the replacement sequence. We then developed cell lines stably expressing the rhodopsin gene, for the assessment of phenotypic criteria relevant to the pathogenesis of retinitis pigmentosa. Using this model, we showed that trans-splicing restored the correct localization of the protein to the plasma membrane. Finally, we tested our best candidate by AAV gene transfer in a mouse model of retinitis pigmentosa that expresses a mutant allele of the human rhodopsin gene, and demonstrated the feasibility of trans-splicing in vivo. This work paves the way for trans-splicing gene therapy to treat retinitis pigmentosa due to rhodopsin gene mutation and, more generally, for the treatment of genetic diseases with dominant transmission. PMID:25619725

  5. Repair of Rhodopsin mRNA by Spliceosome-Mediated RNA Trans-Splicing: A New Approach for Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Berger, Adeline; Lorain, Stéphanie; Joséphine, Charlène; Desrosiers, Melissa; Peccate, Cécile; Voit, Thomas; Garcia, Luis; Sahel, José-Alain; Bemelmans, Alexis-Pierre

    2015-01-01

    The promising clinical results obtained for ocular gene therapy in recent years have paved the way for gene supplementation to treat recessively inherited forms of retinal degeneration. The situation is more complex for dominant mutations, as the toxic mutant gene product must be removed. We used spliceosome-mediated RNA trans-splicing as a strategy for repairing the transcript of the rhodopsin gene, the gene most frequently mutated in autosomal dominant retinitis pigmentosa. We tested 17 different molecules targeting the pre-mRNA intron 1, by transient transfection of HEK-293T cells, with subsequent trans-splicing quantification at the transcript level. We found that the targeting of some parts of the intron promoted trans-splicing more efficiently than the targeting of other areas, and that trans-splicing rate could be increased by modifying the replacement sequence. We then developed cell lines stably expressing the rhodopsin gene, for the assessment of phenotypic criteria relevant to the pathogenesis of retinitis pigmentosa. Using this model, we showed that trans-splicing restored the correct localization of the protein to the plasma membrane. Finally, we tested our best candidate by AAV gene transfer in a mouse model of retinitis pigmentosa that expresses a mutant allele of the human rhodopsin gene, and demonstrated the feasibility of trans-splicing in vivo. This work paves the way for trans-splicing gene therapy to treat retinitis pigmentosa due to rhodopsin gene mutation and, more generally, for the treatment of genetic diseases with dominant transmission. PMID:25619725

  6. CNTF gene therapy confers lifelong neuroprotection in a mouse model of human retinitis pigmentosa

    PubMed Central

    Lipinski, Daniel M.; Barnard, Alun R.; Singh, Mandeep S.; Martin, Chris; Lee, Edward; Davies, Wayne I.L.; MacLaren, Robert E.

    2015-01-01

    The long-term outcome of neuroprotection as a therapeutic strategy for preventing cell death in neurodegenerative disorders remains unknown, primarily due to slow disease progression and the inherent difficulty of assessing neuronal survival in vivo. Employing a murine model of retinal disease, we demonstrate that ciliary neurotrophic factor (CNTF) confers life-long protection against photoreceptor degeneration. Repetitive retinal imaging allowed the survival of intrinsically fluorescent cone photoreceptors to be quantified in vivo. Imaging of the visual cortex and assessment of visually-evoked behavioural responses demonstrated that surviving cones retain function and signal correctly to the brain. The mechanisms underlying CNTF-mediated neuroprotection were explored through transcriptome analysis, revealing widespread up-regulation of proteolysis inhibitors, which may prevent cellular/extracellular matrix degradation and complement activation in neurodegenerative diseases. These findings provide insights into potential novel therapeutic avenues for diseases such as retinitis pigmentosa and amyotrophic lateral sclerosis, for which CNTF has been evaluated unsuccessfully in clinical trials. PMID:25896245

  7. The Self-Concept of Spanish Young Adults with Retinitis Pigmentosa

    ERIC Educational Resources Information Center

    Lopez-Justicia, Maria Dolores; Cordoba, Inmaculada Nieto

    2006-01-01

    Retinitis pigmentosa (RP) is a degenerative disease of the retina that causes the severe impairment of visual functioning similar to low vision, leading, in many cases, to blindness. Because the construct of self-concept plays a key role in personality, this study was designed to measure self-concept in a group of young adults with RP. The…

  8. Subjective Perception of Visual Distortions or Scotomas in Individuals with Retinitis Pigmentosa

    ERIC Educational Resources Information Center

    Wittich, Walter; Watanabe, Donald H.; Kapusta, Michael A.; Overbury, Olga

    2011-01-01

    It is often assumed that persons who develop ocular disease have some form of visual experience that makes them aware of their deficits. However, in the case of peripheral field loss or decreasing vision in dim lighting, as in retinitis pigmentosa, for example, symptoms are more obscure and may not be as easily identified by the persons who have…

  9. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We sought to determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A. DESIGN: Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received ...

  10. Connecting Research on Retinitis Pigmentosa to the Practice of Orientation and Mobility.

    ERIC Educational Resources Information Center

    Geruschat, Duane R.; Turano, Kathleen A.

    2002-01-01

    Retinitis pigmentosa (RP) causes restriction of the visual field, progressive vision loss, and night blindness. This article presents an overview of the most common problems in orientation and mobility (O&M) for individuals with RP, appropriate interventions, vision science discoveries related to RP, and the impact of RP on functional visual…

  11. Further screening of the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Vaithinathan, R.; Berson, E.L.; Dryja, T.P. )

    1994-05-15

    Here the authors report 8 novel mutations and 8 previously reported mutations found from further analysis of the rhodopsin gene in a large set of additional patients with autosomal dominant retinitis pigmentosa. Leukocyte DNA was purified from 122 unrelated patients with autosomal dominant retinitis pigmentosa who were not included in previous analyses. The coding region and splice donor and acceptor sites of the rhodopsin gene were screened for mutations using single-strand conformation polymorphism analysis and direct genomic sequencing. They found 29 patients with varient bands that were due to mutations. Sequence analysis showed that 20 cases each had 1 of 9 previously published mutations: Pro23His, Thr58Arg, Gly89Asp, Pro171Leu, Glu181Lys, Pro347Leu, Phe45Leu, Arg135Trp, and Lys296Glu. In 9 other cases, they found 8 novel mutations. One was a 3-bp deletion (Cys264-del), and the rest were point mutations resulting in an altered amino acid: Gly51Arg (GGC [yields] CGC), Cys110Tyr (TCG [yields] TAC), Gly114Asp (GGC [yields] GAC), Ala164Glu (GCG [yields] GAG), Pro171Ser (CCA [yields] TCA), Val345Leu (GTG [yields] CTG), and Pro347Gln (CCG [yields] CAG). Each of these novel mutations was found in only one family except for Gly51Arg, which was found in two. In every family tested, the mutation cosegregated with the disease. However, in pedigree D865 only one affected member was available for analysis. About two-thirds of the mutations affect amino acids in transmembrane domains, yet only one-half of opsin's residues are in these regions. One-third of the mutations alter residues in the extracellular/intradiscal space, which includes only 25% of the protein.

  12. AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa

    PubMed Central

    Dalkara, Deniz; Kolstad, Kathleen D; Guerin, Karen I; Hoffmann, Natalie V; Visel, Meike; Klimczak, Ryan R; Schaffer, David V; Flannery, John G

    2011-01-01

    Mutations in over 80 identified genes can induce apoptosis in photoreceptors, resulting in blindness with a prevalence of 1 in 3,000 individuals. This broad genetic heterogeneity of disease impacting a wide range of photoreceptor functions renders the design of gene-specific therapies for photoreceptor degeneration impractical and necessitates the development of mutation-independent treatments to slow photoreceptor cell death. One promising strategy for photoreceptor neuroprotection is neurotrophin secretion from Müller cells, the primary retinal glia. Müller glia are excellent targets for secreting neurotrophins as they span the entire tissue, ensheath all neuronal populations, are numerous, and persist through retinal degeneration. We previously engineered an adeno-associated virus (AAV) variant (ShH10) capable of efficient and selective glial cell transduction through intravitreal injection. ShH10-mediated glial-derived neurotrophic factor (GDNF) secretion from glia, generates high GDNF levels in treated retinas, leading to sustained functional rescue for over 5 months. This GDNF secretion from glia following intravitreal vector administration is a safe and effective means to slow the progression of retinal degeneration in a rat model of retinitis pigmentosa (RP) and shows significant promise as a gene therapy to treat human retinal degenerations. These findings also demonstrate for the first time that glia-mediated secretion of neurotrophins is a promising treatment that may be applicable to other neurodegenerative conditions. PMID:21522134

  13. LOCAL SIGNALING FROM A RETINAL PROSTHETIC IN A RODENT RETINITIS PIGMENTOSA MODEL IN VIVO

    PubMed Central

    Fransen, James W.; Pangeni, Gobinda; Pardue, Machelle T.; McCall, Maureen A.

    2014-01-01

    Objective In clinical trials, retinitis pigmentosa (RP) patients implanted with a retinal prosthetic device show enhanced spatial vision, including the ability to read large text and navigate. New prosthetics aim to increase spatial resolution by decreasing pixel/electrode size and limiting current spread. To examine spatial resolution of a new prosthetic design, we characterized and compared two photovoltaic array (PVA) designs and their interaction with the retina after subretinal implantation in transgenic S334ter line 3 rats (Tg S334ter-3). Approach PVAs were implanted subretinally at two stages of degeneration and assessed in vivo using extracellular recordings in the superior colliculus (SC). Several aspects of this interaction were evaluated by varying duration, irradiance and position of a near infrared (NIR) laser focused on the PVA. These characteristics included: activation threshold, response linearity, SC signal topography and spatial localization. The major design difference between the two PVA designs is the inclusion of local current returns in the newer design. Main Results When tested in vivo, PVA-evoked response thresholds were independent of pixel/electrode size, but differ between the new and old PVA designs. Response thresholds were independent of implantation age and duration (≤ 7.5 months). For both prosthesis designs, threshold intensities were within established safety limits. PVA-evoked responses require inner retina synaptic transmission and do not directly activate retinal ganglion cells (RGCs). The new PVA design evokes local retinal activation, which is not found with the older PVA design that lacks local current returns. Significance Our study provides in vivo evidence that prosthetics make functional contacts with the inner nuclear layer at several stages of degeneration. The new PVA design enhances local activation within the retina and SC. Together these results predict that the new design can potentially harness the inherent

  14. Local signaling from a retinal prosthetic in a rodent retinitis pigmentosa model in vivo

    NASA Astrophysics Data System (ADS)

    Fransen, James W.; Pangeni, Gobinda; Pardue, Machelle T.; McCall, Maureen A.

    2014-08-01

    Objective. In clinical trials, retinitis pigmentosa patients implanted with a retinal prosthetic device show enhanced spatial vision, including the ability to read large text and navigate. New prosthetics aim to increase spatial resolution by decreasing pixel/electrode size and limiting current spread. To examine spatial resolution of a new prosthetic design, we characterized and compared two photovoltaic array (PVA) designs and their interaction with the retina after subretinal implantation in transgenic S334ter line 3 rats (Tg S334ter-3). Approach. PVAs were implanted subretinally at two stages of degeneration and assessed in vivo using extracellular recordings in the superior colliculus (SC). Several aspects of this interaction were evaluated by varying duration, irradiance and position of a near infrared laser focused on the PVA. These characteristics included: activation threshold, response linearity, SC signal topography and spatial localization. The major design difference between the two PVA designs is the inclusion of local current returns in the newer design. Main results. When tested in vivo, PVA-evoked response thresholds were independent of pixel/electrode size, but differ between the new and old PVA designs. Response thresholds were independent of implantation age and duration (⩽7.5 months). For both prosthesis designs, threshold intensities were within established safety limits. PVA-evoked responses require inner retina synaptic transmission and do not directly activate retinal ganglion cells. The new PVA design evokes local retinal activation, which is not found with the older PVA design that lacks local current returns. Significance. Our study provides in vivo evidence that prosthetics make functional contacts with the inner nuclear layer at several stages of degeneration. The new PVA design enhances local activation within the retina and SC. Together these results predict that the new design can potentially harness the inherent processing within

  15. Radial fundus autofluorescence in the periphery in patients with X-linked retinitis pigmentosa

    PubMed Central

    Ogino, Ken; Oishi, Maho; Oishi, Akio; Morooka, Satoshi; Sugahara, Masako; Gotoh, Norimoto; Kurimoto, Masafumi; Yoshimura, Nagahisa

    2015-01-01

    Purpose To describe the peripheral autofluorescence images and clinical features of patients with retinal dystrophy who showed radial fundus autofluorescence (FAF) at the posterior pole. Methods The authors retrospectively reviewed pooled wide-field FAF images of 711 patients with retinal dystrophy and 56 family members. Results Eleven eyes of seven women exhibited radial FAF at the posterior pole. Wide-field FAF showed extension of the radial pattern to the periphery in all eyes except one. One woman showed radial hyper-FAF only in the periphery, not at the posterior pole. These eight individuals were X-linked retinitis pigmentosa patients or carriers. The tapetal-like reflex was not observed in their color fundus photographs. The peripheral visual field showed wedge-shaped restriction in some individuals. Conclusion Wide-field FAF imaging can depict radial FAF not only at the posterior pole but also in the periphery in X-linked retinitis pigmentosa carriers. The authors therefore agree with previous reports that radial FAF may be a hallmark of X-linked retinitis pigmentosa. PMID:26316687

  16. Post-Cataract Surgery Visual Disturbance in a Retinitis Pigmentosa Patient with Asteroid Hyalosis

    PubMed Central

    Jingami, Yoko; Otani, Atsushi; Kojima, Hiroshi; Makiyama, Yukiko; Yoshimura, Nagahisa

    2011-01-01

    A patient with retinitis pigmentosa showed visual disturbances following successful cataract surgery. He had a dense asteroid hyalosis in the eye before cataract surgery. After the surgery he noticed that his vision became worse. The visual disturbance was explained as being caused by the progression of retinal degeneration. Although the electroretinogram was non-recordable, the degeneration of macular area appeared relatively small. We considered that dense asteroid hyalosis was responsible for his visual disturbances, and pars plana vitrectomy (PPV) was performed to remove the asteroid hyalosis. After the PPV, rapid improvement of his visual acuity was observed. Cataract surgery may affect the status of asteroid hyalosis and cause rapid visual loss. PPV should be considered for retinitis pigmentosa patients with dense asteroid hyalosis, especially when a large decrease in visual acuity is noted shortly after cataract surgery. PMID:21941506

  17. Automated segmentation of outer retinal layers in macular OCT images of patients with retinitis pigmentosa

    PubMed Central

    Yang, Qi; Reisman, Charles A.; Chan, Kinpui; Ramachandran, Rithambara; Raza, Ali; Hood, Donald C.

    2011-01-01

    To provide a tool for quantifying the effects of retinitis pigmentosa (RP) seen on spectral domain optical coherence tomography images, an automated layer segmentation algorithm was developed. This algorithm, based on dual-gradient information and a shortest path search strategy, delineates the inner limiting membrane and three outer retinal boundaries in optical coherence tomography images from RP patients. In addition, an automated inner segment (IS)/outer segment (OS) contour detection method based on the segmentation results is proposed to quantify the locus of points at which the OS thickness goes to zero in a 3D volume scan. The segmentation algorithm and the IS/OS contour were validated with manual segmentation data. The segmentation and IS/OS contour results on repeated measures showed good within-day repeatability, while the results on data acquired on average 22.5 months afterward demonstrated a possible means to follow disease progression. In particular, the automatically generated IS/OS contour provided a possible objective structural marker for RP progression. PMID:21991543

  18. Retinitis Pigmentosa with EYS Mutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations

    PubMed Central

    Arai, Yuuki; Maeda, Akiko; Hirami, Yasuhiko; Ishigami, Chie; Kosugi, Shinji; Mandai, Michiko; Kurimoto, Yasuo; Takahashi, Masayo

    2015-01-01

    The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is, ABCA4 for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic. EYS mutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two major EYS mutations identified in this cohort. EYS mutations are the most prevalent among Japanese patients with IRD. PMID:26161267

  19. Mutation Screening of Multiple Genes in Spanish Patients with Autosomal Recessive Retinitis Pigmentosa by Targeted Resequencing

    PubMed Central

    González-del Pozo, María; Borrego, Salud; Barragán, Isabel; Pieras, Juan I.; Santoyo, Javier; Matamala, Nerea; Naranjo, Belén; Dopazo, Joaquín; Antiñolo, Guillermo

    2011-01-01

    Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing. PMID:22164218

  20. Early structural anomalies observed by high-resolution imaging in two related cases of autosomal-dominant retinitis pigmentosa.

    PubMed

    Park, Sung Pyo; Lee, Winston; Bae, Eun Jin; Greenstein, Vivianne; Sin, Bum Ho; Chang, Stanley; Tsang, Stephen H

    2014-01-01

    The authors report the use of adaptive-optics scanning laser ophthalmoscopy (AO-SLO) to investigate RHO, D190N autosomal-dominant retinitis pigmentosa in two siblings (11 and 16 years old, respectively). Each patient exhibited distinct hyperautofluorescence patterns in which the outer borders corresponded to inner segment ellipsoid band disruption. Areas within the hyperautofluorescence patterns exhibited normal photoreceptor outer segments and retinal pigment epithelium. However, AO-SLO imaging revealed noticeable spacing irregularities in the cone mosaic. AO-SLO allows researchers to characterize retinal structural abnormalities with precision so that early structural changes in retinitis pigmentosa can be identified and reconciled with genetic findings. PMID:25215869

  1. Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa.

    PubMed

    Millington-Ward, Sophia; Chadderton, Naomi; O'Reilly, Mary; Palfi, Arpad; Goldmann, Tobias; Kilty, Claire; Humphries, Marian; Wolfrum, Uwe; Bennett, Jean; Humphries, Peter; Kenna, Paul F; Farrar, G Jane

    2011-04-01

    For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in the rhodopsin gene. Validation of a mutation-independent suppression and replacement gene therapy for this disorder has been undertaken. The therapy provides a means of correcting the genetic defect in a mutation-independent manner thereby circumventing the mutational diversity. Separate adeno-associated virus (AAV) vectors were used to deliver an RNA interference (RNAi)-based rhodopsin suppressor and a codon-modified rhodopsin replacement gene resistant to suppression due to nucleotide alterations at degenerate positions over the RNAi target site. Viruses were subretinally coinjected into P347S mice, a model of dominant rhodopsin-linked retinitis pigmentosa. Benefit in retinal function and structure detected by electroretinography (ERG) and histology, respectively, was observed for at least 5 months. Notably, the photoreceptor cell layer, absent in 5-month-old untreated retinas, contained 3-4 layers of nuclei, whereas photoreceptor ultrastructure, assessed by transmission electron microscopy (TEM) improved significantly. The study provides compelling evidence that codelivered suppression and replacement is beneficial, representing a significant step toward the clinic. Additionally, dual-vector delivery of combined therapeutics represents an exciting approach, which is potentially applicable to other inherited disorders. PMID:21224835

  2. [The nurse's work in the application of ozone therapy in retinitis pigmentosa. January-May 1996].

    PubMed

    Guerra Veranes, X; Limonta Nápoles, Y; Contrera Hechavarría, I; Freyre Luque, R; Martínez Blanco, C

    1998-01-01

    A descriptive and prospective study of 73 patients suffering from retinitis pigmentosa, who were attended at the Provincial Center of Retinitis Pigmentosa, in Santiago de Cuba, from January to May, 1996, was conducted aimed at emphasizing the nurse's role in the application of ozonotherapy. There are different ways to administer this gast: autohemotherapy, intramuscular, artrectal insufflation. The information obtained was manually processed and percentage was used as a summary measure. The predominance of young and male patients is among the main results. Most of the patients were in stage II and III of the disease, and the rectal administration of ozone was the most used. This last aspect shows the significance of the nurse-patient relationship, which contributed decisively to the acceptance of rectal administration that was rejected by a great number of patients. PMID:9934231

  3. Astrocytes and Müller Cell Alterations During Retinal Degeneration in a Transgenic Rat Model of Retinitis Pigmentosa

    PubMed Central

    Fernández-Sánchez, Laura; Lax, Pedro; Campello, Laura; Pinilla, Isabel; Cuenca, Nicolás

    2015-01-01

    Purpose: Retinitis pigmentosa includes a group of progressive retinal degenerative diseases that affect the structure and function of photoreceptors. Secondarily to the loss of photoreceptors, there is a reduction in retinal vascularization, which seems to influence the cellular degenerative process. Retinal macroglial cells, astrocytes, and Müller cells provide support for retinal neurons and are fundamental for maintaining normal retinal function. The aim of this study was to investigate the evolution of macroglial changes during retinal degeneration in P23H rats. Methods: Homozygous P23H line-3 rats aged from P18 to 18 months were used to study the evolution of the disease, and SD rats were used as controls. Immunolabeling with antibodies against GFAP, vimentin, and transducin were used to visualize macroglial cells and cone photoreceptors. Results: In P23H rats, increased GFAP labeling in Müller cells was observed as an early indicator of retinal gliosis. At 4 and 12 months of age, the apical processes of Müller cells in P23H rats clustered in firework-like structures, which were associated with ring-like shaped areas of cone degeneration in the outer nuclear layer. These structures were not observed at 16 months of age. The number of astrocytes was higher in P23H rats than in the SD matched controls at 4 and 12 months of age, supporting the idea of astrocyte proliferation. As the disease progressed, astrocytes exhibited a deteriorated morphology and marked hypertrophy. The increase in the complexity of the astrocytic processes correlated with greater connexin 43 expression and higher density of connexin 43 immunoreactive puncta within the ganglion cell layer (GCL) of P23H vs. SD rat retinas. Conclusions: In the P23H rat model of retinitis pigmentosa, the loss of photoreceptors triggers major changes in the number and morphology of glial cells affecting the inner retina. PMID:26733810

  4. Rapid anterior capsular contraction after phacoemulsification surgery in a patient with retinitis pigmentosa.

    PubMed

    Jin-Poi, Tan; Shatriah, Ismail; Khairy-Shamel, Sonny Teo; Zunaina, Embong

    2013-01-01

    A decrease in the anterior capsule opening after cataract surgery has been observed in eyes with weakened lens zonules. It commonly occurs in diabetes mellitus, uveitis, pseudoexfoliation syndrome, high myopia, and elderly patients. Herein, we report the case of a middle-aged man with advanced retinitis pigmentosa who developed a rapid contraction of the anterior capsule after an uneventful phacoemulsification surgery that resulted in severe visual loss during the early postoperative period. PMID:23674886

  5. Rapid anterior capsular contraction after phacoemulsification surgery in a patient with retinitis pigmentosa

    PubMed Central

    Jin-Poi, Tan; Shatriah, Ismail; Khairy-Shamel, Sonny Teo; Zunaina, Embong

    2013-01-01

    A decrease in the anterior capsule opening after cataract surgery has been observed in eyes with weakened lens zonules. It commonly occurs in diabetes mellitus, uveitis, pseudoexfoliation syndrome, high myopia, and elderly patients. Herein, we report the case of a middle-aged man with advanced retinitis pigmentosa who developed a rapid contraction of the anterior capsule after an uneventful phacoemulsification surgery that resulted in severe visual loss during the early postoperative period. PMID:23674886

  6. Emotional Health of People with Visual Impairment Caused by Retinitis Pigmentosa

    PubMed Central

    Latham, Keziah; Baranian, Mohammad; Timmis, Matthew; Pardhan, Shahina

    2015-01-01

    Purpose To understand the emotional difficulties associated with living with the ocular condition Retinitis Pigmentosa, and to examine the functioning of a self-report instrument used to assess this construct. Methods The difficulty of goals and tasks in the emotional health domain of the Dutch ICF Activity Inventory were rated by 166 people with Retinitis Pigmentosa in a cross-sectional study. Demographic factors were also assessed. Results Responses to the 23 emotional health tasks were Rasch analysed and could be used to form either one 20 item overview scale with some multidimensionality, or three unidimensional subscales addressing feelings (4 items), communicating visual loss (5 items) and fatigue (7 items). The most difficult individual tasks related to communicating visual loss to other people, and dealing with feelings such as frustration, anxiety and stress. The use of mobility aids and female gender were associated with increased difficulty with emotional health, explaining 19% of the variance in the overview scale. Conclusions The emotional health domain of the Dutch ICF Activity Inventory is a valid tool to assess emotional difficulties arising from visual loss. Interventions to aid people with Retinitis Pigmentosa deal with emotional difficulties should particularly address communicating vision loss effectively to others and coping with negative feelings. PMID:26713624

  7. Choroidal thickness profile in Retinitis Pigmentosa – Correlation with outer retinal structures

    PubMed Central

    Chhablani, Jay; Jonnadula, Ganesh Babu; Srinivasa Rao, P.; Venkata, Amarnath; Jalali, Subhadra

    2015-01-01

    Purpose To compare the choroidal thickness (CT) of subjects with Retinitis Pigmentosa (RP) with age-matched healthy subjects and to correlate the visual acuity with retinal parameters including central macular thickness (CMT), inner segment/outer segment junction (IS/OS junction) integrity, external limiting membrane (ELM) integrity and choroidal thickness in subjects with RP. Methods Eighty-eight eyes (69 patients) with typical RP and 188 eyes of 104 healthy subjects were enrolled between September 2012 and January 2013. All subjects underwent a comprehensive ocular examination including choroidal imaging using enhanced depth imaging with spectral domain optical coherence tomography. Outcome measures were CT difference between RP and age-matched healthy subjects; and correlation of various factors such CMT, IS/OS junction integrity, ELM integrity, and CT with visual acuity. Results Among RP subjects, mean age was 31.39 ± 13.4 years with a mean BCVA of 0.99 ± 0.94 logMAR. Mean spherical equivalent was −0.6 ± 1.6D. Mean CMT was 148.48 ± 119 μm. Mean subfoveal CT was 296.9 ± 72 μm. Mean IS/OS and ELM integrity was 42.2 ± 46.6% and 43.75 ± 45.7%, respectively. The mean age was 40.0 ± 13.5 years with a mean spherical equivalent of 0.18 ± 0.6D for the normal age-matched healthy group. Mean subfoveal CT was 283.1 ± 47.8 μm. CT at various locations in patients of various ages in the RP group did not show any statistical significant difference (P = ≫0.05) in comparison with age-matched healthy subjects. On multivariate regression, ELM percentage integrity had the strongest association with best corrected visual acuity, followed by IS/OS junction percentage integrity. Subfoveal choroidal thickness had very weak correlation with visual acuity as well other retinal parameters. There was a significant difference in the outer retinal structure integrity (p = 0.002) and CMT (p = 0.02) between the eyes with good (⩾20/200) and

  8. The Stiles-Crawford Effect: spot-size ratio departure in retinitis pigmentosa

    NASA Astrophysics Data System (ADS)

    Sharma, Nachieketa K.; Lakshminarayanan, Vasudevan

    2016-04-01

    The Stiles-Crawford effect of the first kind is the retina's compensative response to loss of luminance efficiency for oblique stimulation manifested as the spot-size ratio departure from the perfect power coupling for a normal human eye. In a retinitis pigmentosa eye (RP), the normal cone photoreceptor morphology is affected due to foveal cone loss and disrupted cone mosaic spatial arrangement with reduction in directional sensitivity. We show that the flattened Stiles-Crawford function (SCF) in a RP eye is due to a different spot-size ratio departure profile, that is, for the same loss of luminance efficiency, a RP eye has a smaller departure from perfect power coupling compared to a normal eye. Again, the difference in spot-size ratio departure increases from the centre towards the periphery, having zero value for axial entry and maximum value for maximum peripheral entry indicating dispersal of photoreceptor alignment which prevents the retina to go for a bigger compensative response as it lacks both in number and appropriate cone morphology to tackle the loss of luminance efficiency for oblique stimulation. The slope of departure profile also testifies to the flattened SCF for a RP eye. Moreover, the discrepancy in spot-size ratio departure between a normal and a RP eye is shown to have a direct bearing on the Stiles-Crawford diminution of visibility.

  9. Wide-Field Fundus Autofluorescence for Retinitis Pigmentosa and Cone/Cone-Rod Dystrophy.

    PubMed

    Oishi, Akio; Oishi, Maho; Ogino, Ken; Morooka, Satoshi; Yoshimura, Nagahisa

    2016-01-01

    Retinitis pigmentosa and cone/cone-rod dystrophy are inherited retinal diseases characterized by the progressive loss of rod and/or cone photoreceptors. To evaluate the status of rod/cone photoreceptors and visual function, visual acuity and visual field tests, electroretinogram, and optical coherence tomography are typically used. In addition to these examinations, fundus autofluorescence (FAF) has recently garnered attention. FAF visualizes the intrinsic fluorescent material in the retina, which is mainly lipofuscin contained within the retinal pigment epithelium. While conventional devices offer limited viewing angles in FAF, the recently developed Optos machine enables recording of wide-field FAF. With wide-field analysis, an association between abnormal FAF areas and visual function was demonstrated in retinitis pigmentosa and cone-rod dystrophy. In addition, the presence of "patchy" hypoautofluorescent areas was found to be correlated with symptom duration. Although physicians should be cautious when interpreting wide-field FAF results because the peripheral parts of the image are magnified significantly, this examination method provides previously unavailable information. PMID:26427426

  10. Screening for mutations in rhodopsin and peripherin/RDS in patients with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Rodriguez, J.A.; Gannon, A.M.; Daiger, S.P.

    1994-09-01

    Mutations in rhodopsin account for approximately 30% of all cases of autosomal dominant retinits pigmentosa (adRP) and mutations in peripherin/RDS account for an additional 5% of cases. Also, mutations in rhodopsin can cause autosomal recessive retinitis pigmentosa and mutations in peripherin/RDS can cause dominant macular degeneration. Most disease-causing mutations in rhodopsin and peripherin/RDS are unique to one family or, at most, to a few families within a limited geographic region, though a few mutations are found in multiple, unrelated families. To further determine the spectrum of genetic variation in these genes, we screened DNA samples from 134 unrelated patients with retinitis pigmentosa for mutations in both rhodopsin and peripherin/RDS using SSCP followed by genomic sequencing. Of the 134 patients, 86 were from families with apparent adRP and 48 were either isolated cases or were from families with an equivocal mode of inheritance. Among these patients we found 14 distinct rhodopsin mutations which are likely to cause retinal disease. Eleven of these mutations were found in one individual or one family only, whereas the Pro23His mutation was found in 14 {open_quotes}unrelated{close_quotes}individuals. The splice-site mutation produces dominant disease though with highly variable expression. Among the remaining patients were found 6 distinct peripherin/RDS mutations which are likely to cause retinal disease. These mutations were also found in one patient or family only, except the Gly266Asp mutation which was found in two unrelated patients. These results confirm the expected frequency and broad spectrum of mutations causing adRP.

  11. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands

    PubMed Central

    Zhang, Qi; Xu, Mingchu; Verriotto, Jennifer D.; Li, Yumei; Wang, Hui; Gan, Lin; Lam, Byron L.; Chen, Rui

    2016-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases. The prevalence of RP and the mutation spectrum vary across populations. Hispanic people account for approximately 17% of the United States population, and the genetic etiologies of RP of this ethnic group still remain not well defined. Utilizing next-generation sequencing (NGS), we screened mutations in known retinal disease-causing genes in an RP cohort of 35 unrelated Hispanic probands from the Miami area. We achieved a solving rate of 66% and identified 15 novel putative pathogenic mutations, including a frequent founder mutation disrupting PRPF31 splicing. Our data show that the mutation spectrum of Hispanic RP receives a significant impact from disease-causing alleles of Spanish origin and may also contain population-specific alleles. PMID:27596865

  12. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands.

    PubMed

    Zhang, Qi; Xu, Mingchu; Verriotto, Jennifer D; Li, Yumei; Wang, Hui; Gan, Lin; Lam, Byron L; Chen, Rui

    2016-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases. The prevalence of RP and the mutation spectrum vary across populations. Hispanic people account for approximately 17% of the United States population, and the genetic etiologies of RP of this ethnic group still remain not well defined. Utilizing next-generation sequencing (NGS), we screened mutations in known retinal disease-causing genes in an RP cohort of 35 unrelated Hispanic probands from the Miami area. We achieved a solving rate of 66% and identified 15 novel putative pathogenic mutations, including a frequent founder mutation disrupting PRPF31 splicing. Our data show that the mutation spectrum of Hispanic RP receives a significant impact from disease-causing alleles of Spanish origin and may also contain population-specific alleles. PMID:27596865

  13. Transplantation of Reprogrammed Embryonic Stem Cells Improves Visual Function in a Mouse Model for Retinitis Pigmentosa

    PubMed Central

    Wang, Nan-Kai; Tosi, Joaquin; Kasanuki, Jennifer Mie; Chou, Chai Lin; Kong, Jian; Parmalee, Nancy; Wert, Katherine J.; Allikmets, Rando; Lai, Chi-Chun; Chien, Chung-Liang; Nagasaki, Takayuki; Lin, Chyuan-Sheng; Tsang, Stephen H.

    2010-01-01

    Background To study whether C57BL/6J-Tyrc−2j/J (C2J) mouse embryonic stem (ES) cells can differentiate into retinal pigment epithelial (RPE) cells in vitro and then restore retinal function in a model for retinitis pigmentosa: Rpe65rd12/Rpe65rd12 C57BL6 mice. Methods Yellow fluorescent protein (YFP)-labeled C2J ES cells were induced to differentiate into RPE-like structures on PA6 feeders. RPE-specific markers are expressed from differentiated cells in vitro. After differentiation, ES cell-derived RPE-like cells were transplanted into the subretinal space of postnatal day 5 Rpe65rd12/Rpe65rd12 mice. Live imaging of YFP-labeled C2J ES cells demonstrated survival of the graft. Electroretinograms (ERGs) were performed on transplanted mice to evaluate the functional outcome of transplantation. Results RPE-like cells derived from ES cells sequentially express multiple RPE-specific markers. After transplantation, YFP-labeled cells can be tracked with live imaging for as long as 7 months. Although more than half of the mice were complicated with retinal detachments or tumor development, one fourth of the mice showed increased electroretinogram responses in the transplanted eyes. Rpe65rd12/Rpe65rd12 mice transplanted with RPE-like cells showed significant visual recovery during a 7-month period, whereas those injected with saline, PA6 feeders, or undifferentiated ES cells showed no rescue. Conclusions ES cells can differentiate, morphologically, and functionally, into RPE-like cells. Based on these findings, differentiated ES cells have the potential for the development of new therapeutic approaches for RPE-specific diseases such as certain forms of retinitis pigmentosa and macular degeneration. Nevertheless, stringent control of retinal detachment and teratoma development will be necessary before initiation of treatment trials. PMID:20164818

  14. Heading perception in patients with advanced retinitis pigmentosa

    NASA Technical Reports Server (NTRS)

    Li, Li; Peli, Eli; Warren, William H.

    2002-01-01

    PURPOSE: We investigated whether retinis pigmentosa (RP) patients with residual visual field of < 100 degrees could perceive heading from optic flow. METHODS: Four RP patients and four age-matched normally sighted control subjects viewed displays simulating an observer walking over a ground. In experiment 1, subjects viewed either the entire display with free fixation (full-field condition) or through an aperture with a fixation point at the center (aperture condition). In experiment 2, patients viewed displays of different durations. RESULTS: RP patients' performance was comparable to that of the age-matched control subjects: heading judgment was better in the full-field condition than in the aperture condition. Increasing display duration from 0.5 s to 1 s improved patients' heading performance, but giving them more time (3 s) to gather more visual information did not consistently further improve their performance. CONCLUSIONS: RP patients use active scanning eye movements to compensate for their visual field loss in heading perception; they might be able to gather sufficient optic flow information for heading perception in about 1 s.

  15. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa

    PubMed Central

    Wert, Katherine J.; Davis, Richard J.; Sancho-Pelluz, Javier; Nishina, Patsy M.; Tsang, Stephen H.

    2013-01-01

    Approximately 36 000 cases of simplex and familial retinitis pigmentosa (RP) worldwide are caused by a loss in phosphodiesterase (PDE6) function. In the preclinical Pde6αnmf363 mouse model of this disease, defects in the α-subunit of PDE6 result in a progressive loss of photoreceptors and neuronal function. We hypothesized that increasing PDE6α levels using an AAV2/8 gene therapy vector could improve photoreceptor survival and retinal function. We utilized a vector with the cell-type-specific rhodopsin (RHO) promoter: AAV2/8(Y733F)-Rho-Pde6α, to transduce Pde6αnmf363 retinas and monitored its effects over a 6-month period (a quarter of the mouse lifespan). We found that a single injection enhanced survival of photoreceptors and improved retinal function. At 6 months of age, the treated eyes retained photoreceptor cell bodies, while there were no detectable photoreceptors remaining in the untreated eyes. More importantly, the treated eyes demonstrated functional visual responses even after the untreated eyes had lost all vision. Despite focal rescue of the retinal structure adjacent to the injection site, global functional rescue of the entire retina was observed. These results suggest that RP due to PDE6α deficiency in humans, in addition to PDE6β deficiency, is also likely to be treatable by gene therapy. PMID:23108158

  16. Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa.

    PubMed

    Wert, Katherine J; Davis, Richard J; Sancho-Pelluz, Javier; Nishina, Patsy M; Tsang, Stephen H

    2013-02-01

    Approximately 36 000 cases of simplex and familial retinitis pigmentosa (RP) worldwide are caused by a loss in phosphodiesterase (PDE6) function. In the preclinical Pde6α(nmf363) mouse model of this disease, defects in the α-subunit of PDE6 result in a progressive loss of photoreceptors and neuronal function. We hypothesized that increasing PDE6α levels using an AAV2/8 gene therapy vector could improve photoreceptor survival and retinal function. We utilized a vector with the cell-type-specific rhodopsin (RHO) promoter: AAV2/8(Y733F)-Rho-Pde6α, to transduce Pde6α(nmf363) retinas and monitored its effects over a 6-month period (a quarter of the mouse lifespan). We found that a single injection enhanced survival of photoreceptors and improved retinal function. At 6 months of age, the treated eyes retained photoreceptor cell bodies, while there were no detectable photoreceptors remaining in the untreated eyes. More importantly, the treated eyes demonstrated functional visual responses even after the untreated eyes had lost all vision. Despite focal rescue of the retinal structure adjacent to the injection site, global functional rescue of the entire retina was observed. These results suggest that RP due to PDE6α deficiency in humans, in addition to PDE6β deficiency, is also likely to be treatable by gene therapy. PMID:23108158

  17. Low-dose-rate, low-dose irradiation delays neurodegeneration in a model of retinitis pigmentosa.

    PubMed

    Otani, Atsushi; Kojima, Hiroshi; Guo, Congrong; Oishi, Akio; Yoshimura, Nagahisa

    2012-01-01

    The existence of radiation hormesis is controversial. Several stimulatory effects of low-dose (LD) radiation have been reported to date; however, the effects on neural tissue or neurodegeneration remain unknown. Here, we show that LD radiation has a neuroprotective effect in mouse models of retinitis pigmentosa, a hereditary, progressive neurodegenerative disease that leads to blindness. Various LD radiation doses were administered to the eyes in a retinal degeneration mouse model, and their pathological and physiological effects were analyzed. LD gamma radiation in a low-dose-rate (LDR) condition rescues photoreceptor cell apoptosis both morphologically and functionally. The greatest effect was observed in a condition using 650 mGy irradiation and a 26 mGy/minute dose rate. Multiple rounds of irradiation strengthened this neuroprotective effect. A characteristic up-regulation (563%) of antioxidative gene peroxiredoxin-2 (Prdx2) in the LDR-LD-irradiated retina was observed compared to the sham-treated control retina. Silencing the Prdx2 using small-interfering RNA administration reduced the LDR-LD rescue effect on the photoreceptors. Our results demonstrate for the first time that LDR-LD irradiation has a biological effect in neural cells of living animals. The results support that radiation exhibits hormesis, and this effect may be applied as a novel therapeutic concept for retinitis pigmentosa and for other progressive neurodegenerative diseases regardless of the mechanism of degeneration involved. PMID:22074737

  18. Optical imaging of oxidative stress in retinitis pigmentosa (RP) in rodent model

    NASA Astrophysics Data System (ADS)

    Ghanian, Zahra; Maleki, Sepideh; Gopalakrishnan, Sandeep; Sepehr, Reyhaneh; Eells, Janis T.; Ranji, Mahsa

    2013-02-01

    Oxidative stress (OS), which increases during retinal degenerative disorders, contributes to photoreceptor cell loss. The objective of this study was to investigate the changes in the metabolic state of the eye tissue in rodent models of retinitis pigmentosa by using the cryofluorescence imaging technique. The mitochondrial metabolic coenzymes NADH and FADH2 are autofluorescent and can be monitored without exogenous labels using optical techniques. The NADH redox ratio (RR), which is the ratio of the fluorescence intensity of these fluorophores (NADH/FAD), was used as a quantitative diagnostic marker. The NADH RR was examined in an established rodent model of retinitis pigmentosa (RP), the P23H rat, and compared to that of control Sprague-Dawley (SD) rats and P23H NIR treated rats. Our results demonstrated 24% decrease in the mean NADH RR of the eyes from P23H transgenic rats compared to normal rats and 20% increase in the mean NADH RR of the eyes from the P23H NIR treated rats compared to P23H non-treated rats.

  19. Carnosic acid slows photoreceptor degeneration in the Pde6brd10 mouse model of retinitis pigmentosa

    PubMed Central

    Kang, Kai; Tarchick, Matthew J.; Yu, Xiaoshan; Beight, Craig; Bu, Ping; Yu, Minzhong

    2016-01-01

    The photoreceptor cell death associated with the various genetic forms of retinitis pigmentosa (RP) is currently untreatable and leads to partial or complete vision loss. Carnosic acid (CA) upregulates endogenous antioxidant enzymes and has proven neuroprotective in studies of neurodegenerative models affecting the brain. In this study, we examined the potential effect of CA on photoreceptor death in the Pde6brd10 mouse model of RP. Our data shows that CA provided morphological and functional preservation of photoreceptors. CA appears to exert its neuroprotective effects through inhibition of oxidative stress and endoplasmic reticulum stress. PMID:26961159

  20. Fine genetic mapping of a gene for autosomal recessive retinitis pigmentosa on chromosome 6p21

    SciTech Connect

    Shugart, Yin Y.; Banerjee, P.; Knowles, J.A.

    1995-08-01

    The inherited retinal degenerations known as retinitis pigmentosa (RP) can be caused by mutations at many different loci and can be inherited as an autosomal recessive, autosomal dominant, or X-linked recessive trait. Two forms of autosomal recessive (arRP) have been reported to cosegregate with mutations in the rhodopsin gene and the beta-subunit of rod phosphodiesterase on chromosome 4p. Genetic linkage has been reported on chromosomes 6p and 1q. In a large Dominican family, we reported an arRp gene near the region of the peripherin/RDS gene. Four recombinations were detected between the disease locus and an intragenic marker derived from peripherin/RDS. 26 refs., 2 figs., 1 tab.

  1. Variant haploinsufficiency and phenotypic non-penetrance in PRPF31-associated retinitis pigmentosa.

    PubMed

    Rose, A M; Bhattacharya, S S

    2016-08-01

    Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited disorders, characterized by death of the retinal photoreceptor cells, leading to progressive visual impairment. One form of RP is caused by mutations in the ubiquitously expressed splicing factor, PRPF31, this form being known as RP11. An intriguing feature of RP11 is the presence of non-penetrance, which has been observed in the majority of PRPF31 mutation-carrying families. In contrast to variable expressivity, which is highly pervasive, true non-penetrance is a very rare phenomenon in Mendelian disorders. In this article, the molecular mechanisms underlying phenotypic non-penetrance in RP11 are explored. It is an elegant example of how our understanding of monogenic disorders has evolved from studying only the disease gene, to considering a mutation on the genetic background of the individual - the logical evolution in this genomic era. PMID:26853529

  2. Autosomal dominant retinitis pigmentosa mapping to chromosome 7p exhibits variable expression.

    PubMed Central

    Kim, R Y; Fitzke, F W; Moore, A T; Jay, M; Inglehearn, C; Arden, G B; Bhattacharya, S S; Bird, A C

    1995-01-01

    The genetic locus causing autosomal dominant retinitis pigmentosa (adRP) has recently been mapped in a large English family to chromosome 7p. Eight affected members of this family were studied electrophysiologically and psychophysically with dark adapted static threshold perimetry and dark adaptometry. The phenotypes observed fell into three categories: minimally affected with no symptoms, and normal (or near normal) electrophysiology and psychophysics; moderately affected with mild symptoms, abnormal electroretinograms, and equal loss of rod and cone function in affected areas of the retina; and severely affected with extinguished electroretinograms and barely detectable dark adapted static threshold sensitivities. The mutation in the gene on 7p causing adRP in this family causes regional retinal dysfunction with greatly variable expressivity ranging from normal to profoundly abnormal in a manner not explained by age. PMID:7880785

  3. Autosomal dominant retinitis pigmentosa with apparent incomplete penetrance: a clinical, electrophysiological, psychophysical, and molecular genetic study.

    PubMed Central

    Moore, A T; Fitzke, F; Jay, M; Arden, G B; Inglehearn, C F; Keen, T J; Bhattacharya, S S; Bird, A C

    1993-01-01

    Twenty five symptomatic individuals and six asymptomatic obligate gene carriers from four families with autosomal dominant retinitis pigmentosa (adRP) showing apparent incomplete penetrance have been studied. Symptomatic individuals from three families showed early onset of night blindness, non-recordable rod electroretinograms, and marked elevation of both rod and cone thresholds in all subjects tested. In the fourth family, there was more variation in the age of onset of night blindness and some symptomatic individuals showed well preserved rod and cone function in some retinal areas. All asymptomatic individuals tested had evidence of mild abnormalities of rod and cone function, indicating that these families show marked variation in expressivity rather than true non-penetrance of the adRP gene. No mutations of the rhodopsin or RDS genes were found in these families and the precise genetic mutation(s) remain to be identified. PMID:8025041

  4. A novel start codon mutation of the MERTK gene in a patient with retinitis pigmentosa

    PubMed Central

    Jinda, Worapoj; Poungvarin, Naravat; Taylor, Todd D.; Suzuki, Yutaka; Thongnoppakhun, Wanna; Limwongse, Chanin; Lertrit, Patcharee; Suriyaphol, Prapat

    2016-01-01

    Purpose Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations characterized by progressive loss of photoreceptor cells and RPE functions. More than 70 causative genes are known to be responsible for RP. This study aimed to identify the causative gene in a patient from a consanguineous family with childhood-onset severe retinal dystrophy. Methods To identify the defective gene, whole exome sequencing was performed. Candidate causative variants were selected and validated using Sanger sequencing. Segregation analysis of the causative gene was performed in additional family members. To verify that the mutation has an effect on protein synthesis, an expression vector containing the first ten amino acids of the mutant protein fused with the DsRed2 fluorescent protein was constructed and transfected into HEK293T cells. Expression of the fusion protein in the transfected cells was measured using fluorescence microscopy. Results By filtering against public variant databases, a novel homozygous missense mutation (c.3G>A) localized in the start codon of the MERTK gene was detected as a potentially pathogenic mutation for autosomal recessive RP. The c.3G>A mutation cosegregated with the disease phenotype in the family. No expression of the first ten amino acids of the MerTK mutant fused with the DsRed2 fluorescent protein was detected in HEK293T cells, indicating that the mutation affects the translation initiation site of the gene that may lead to loss of function of the MerTK signaling pathway. Conclusions We report a novel missense mutation (c.3G>A, p.0?) in the MERTK gene that causes severe vision impairment in a patient. Taken together with previous reports, our results expand the spectrum of MERTK mutations and extend our understanding of the role of the MerTK protein in the pathogenesis of retinitis pigmentosa. PMID:27122965

  5. Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa

    SciTech Connect

    Aldred, M.A.; Dry, K.L.; Hardwick, L.J.; Teague, P.W.; Lester, D.H.; Brown, J.; Spowart, G.; Carothers, A.D.; Wright, A.F.; Knight-Jones, E.B.

    1994-11-01

    A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5{prime}-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. 33 refs., 2 figs., 2 tabs.

  6. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Dryja, T.P.; Han, L.B.; Cowley, G.S.; McGee, T.L.; Berson, E.L. )

    1991-10-15

    The authors searched for point mutations in every exon of the rhodopsin gene in 150 patients from separate families with autosomal dominant retinitis pigmentosa. Including the 4 mutations the authors reported previously, they found a total of 17 different mutations that correlate with the disease. Each of these mutations is a single-base substitution corresponding to a single amino acid substitution. Based on current models for the structure of rhodopsin, 3 of the 17 mutant amino acids are normally located on the cytoplasmic side of the protein, 6 in transmembrane domains, and 8 on the intradiscal side. Forty-three of the 150 patients (29%) carry 1 of these mutations, and no patient has more than 1 mutation. In every family with a mutation so far analyzed, the mutation cosegregates with the disease. They found one instance of a mutation in an affected patient that was absent in both unaffected parents (i.e., a new germ-line mutation), indicating that some isolate cases of retinitis pigmentosa carry a mutation of the rhodopsin gene.

  7. Novel deletions involving the USH2A gene in patients with Usher syndrome and retinitis pigmentosa

    PubMed Central

    García-García, Gema; Jaijo, Teresa; Aparisi, Maria J.; Larrieu, Lise; Faugère, Valérie; Blanco-Kelly, Fiona; Ayuso, Carmen; Roux, Anne-Francoise; Millán, José M.

    2014-01-01

    Purpose The aim of the present work was to identify and characterize large rearrangements involving the USH2A gene in patients with Usher syndrome and nonsyndromic retinitis pigmentosa. Methods The multiplex ligation-dependent probe amplification (MLPA) technique combined with a customized array-based comparative genomic hybridization (aCGH) analysis was applied to 40 unrelated patients previously screened for point mutations in the USH2A gene in which none or only one pathologic mutation was identified. Results We detected six large deletions involving USH2A in six out of the 40 cases studied. Three of the patients were homozygous for the deletion, and the remaining three were compound heterozygous with a previously identified USH2A point mutation. In five of these cases, the patients displayed Usher type 2, and the remaining case displayed nonsyndromic retinitis pigmentosa. The exact breakpoint junctions of the deletions found in USH2A in four of these cases were characterized. Conclusions Our study highlights the need to develop improved efficient strategies of mutation screening based upon next generation sequencing (NGS) that reduce cost, time, and complexity and allow simultaneous identification of all types of disease-causing mutations in diagnostic procedures. PMID:25352746

  8. Genetic Analysis of a Kindred With X-linked Mental Handicap and Retinitis Pigmentosa

    PubMed Central

    Aldred, M. A.; Dry, K. L.; Knight-Jones, E. B.; Hardwick, L. J.; Teague, P. W.; Lester, D. H.; Brown, J.; Spowart, G.; Carothers, A. D.; Raeburn, J. A.; Bird, A. C.; Fielder, A. R.; Wright, A. F.

    1994-01-01

    A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. PMID:7977353

  9. A Dominant Mutation in Hexokinase 1 (HK1) Causes Retinitis Pigmentosa

    PubMed Central

    Sullivan, Lori S.; Koboldt, Daniel C.; Bowne, Sara J.; Lang, Steven; Blanton, Susan H.; Cadena, Elizabeth; Avery, Cheryl E.; Lewis, Richard A.; Webb-Jones, Kaylie; Wheaton, Dianna H.; Birch, David G.; Coussa, Razck; Ren, Huanan; Lopez, Irma; Chakarova, Christina; Koenekoop, Robert K.; Garcia, Charles A.; Fulton, Robert S.; Wilson, Richard K.; Weinstock, George M.; Daiger, Stephen P.

    2014-01-01

    Purpose. To identify the cause of retinitis pigmentosa (RP) in UTAD003, a large, six-generation Louisiana family with autosomal dominant retinitis pigmentosa (adRP). Methods. A series of strategies, including candidate gene screening, linkage exclusion, genome-wide linkage mapping, and whole-exome next-generation sequencing, was used to identify a mutation in a novel disease gene on chromosome 10q22.1. Probands from an additional 404 retinal degeneration families were subsequently screened for mutations in this gene. Results. Exome sequencing in UTAD003 led to identification of a single, novel coding variant (c.2539G>A, p.Glu847Lys) in hexokinase 1 (HK1) present in all affected individuals and absent from normal controls. One affected family member carries two copies of the mutation and has an unusually severe form of disease, consistent with homozygosity for this mutation. Screening of additional adRP probands identified four other families (American, Canadian, and Sicilian) with the same mutation and a similar range of phenotypes. The families share a rare 450-kilobase haplotype containing the mutation, suggesting a founder mutation among otherwise unrelated families. Conclusions. We identified an HK1 mutation in five adRP families. Hexokinase 1 catalyzes phosphorylation of glucose to glucose-6-phosphate. HK1 is expressed in retina, with two abundant isoforms expressed at similar levels. The Glu847Lys mutation is located at a highly conserved position in the protein, outside the catalytic domains. We hypothesize that the effect of this mutation is limited to the retina, as no systemic abnormalities in glycolysis were detected. Prevalence of the HK1 mutation in our cohort of RP families is 1%. PMID:25190649

  10. Identification of a nuclear localization signal in the retinitis pigmentosa-mutated RP26 protein, ceramide kinase-like protein

    SciTech Connect

    Inagaki, Yuichi; Mitsutake, Susumu; Igarashi, Yasuyuki . E-mail: yigarash@pharm.hokudai.ac.jp

    2006-05-12

    Retinitis pigmentosa (RP) is a genetically heterogeneous disease characterized by degeneration of the retina. A mutation in a new ceramide kinase (CERK) homologous gene, named CERK-like protein (CERKL), was found to cause autosomal recessive retinitis pigmentosa (RP26). Here, we show a point mutation of one of two putative nuclear localization signal (NLS) sequences inhibited the nuclear localization of the protein. Furthermore, the tetra-GFP-tagged NLS, which cannot passively enter the nucleus, was observed not only in the nucleus but also in the nucleolus. Our results provide First evidence of the active nuclear import of CERKL and suggest that the identified NLS might be responsible for nucleolar retention of the protein. As recent studies have shown other RP-related proteins are localized in the nucleus or the nucleolus, our identification of NLS in CERKL suggests that CERKL likely plays important roles for retinal functions in the nucleus and the nucleolus.

  11. A Case Report of Vogt's Limbal Girdle and Retinitis Pigmentosa in a Thirteen-Year-Old Boy: A Rare and Unusual Association

    PubMed Central

    Vignesh, A.P.; Srinivasan, Renuka; Karanth, Swathi; Vijitha, Sai

    2015-01-01

    Aim To describe a rare case of Vogt's limbal girdle in a boy with retinitis pigmentosa. Methods A 13-year-old boy from India presented to us with progressive diminution of vision and nyctalopia for 5 years. On examination, he had the characteristic features of retinitis pigmentosa with the fundus showing disc pallor, bony spicules and arteriolar attenuation. His anterior segment examination showed Vogt's limbal girdle in both eyes. Results Vogt's limbal girdle is a corneal degeneration usually seen in elderly individuals. This is the first time it is seen in association with retinitis pigmentosa. It has also never been reported at such a young age. Conclusion We report a rare case where Vogt's limbal girdle was observed in a 13-year-old boy with retinitis pigmentosa. This gives further insight into the pathogenesis of the disease. PMID:26483674

  12. Identification of a rhodopsin gene mutation in a large family with autosomal dominant retinitis pigmentosa.

    PubMed

    Yu, Xinping; Shi, Wei; Cheng, Lulu; Wang, Yanfang; Chen, Ding; Hu, Xuting; Xu, Jinling; Xu, Limin; Wu, Yaming; Qu, Jia; Gu, Feng

    2016-01-01

    Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses. PMID:26794436

  13. Localization of a new autosomal dominant retinitis pigmentosa gene on chromosome 17p screeningof candidate genes

    SciTech Connect

    Greenberg, J.; Goliath, R.; Shugart, Y.Y.

    1994-09-01

    A new gene locus for autosomal dominant retinitis pigmentosa (ADRP) on 17p has been identified in a large South African (SA) family consisting of 28 living affected individuals in 4 successive generations. This is the first ADRP gene to be reported from SA. The human recoverin (RCVN) gene, which codes for a retinal-specific protein important in recovery to the dark state after visual excitation, has been mapped to 17p13.1 and was considered as a prime candidate gene for the disorder in this family. Mutation screening (using 8 different electrophoretic conditions to resolve heteroduplexes and SSCPs) did not produce any evidence of RCVN being involved in the pathogenesis of ADRP in this SA family. In addition, a mobility shift detected within exon 1 of the RCVN gene did not track with the ADRP phenotype. RP patients from 77 SA families and 30 normal individuals are being examined to establish the frequency of this polymorphism in the SA population. Highly polymorphic markers from 17p13 are now being sought in order to establish the minimum region containing this novel ADRP-SA gene. Two additional recently described retinal-expressed cDNAs, guanylyl cyclase and pigment epithelium-derived factor, which map to 17p13.1, will be tested for tight linkage to ADRP-SA.

  14. Human iPSC derived disease model of MERTK-associated retinitis pigmentosa

    PubMed Central

    Lukovic, Dunja; Artero Castro, Ana; Delgado, Ana Belen Garcia; Bernal, María de los Angeles Martín; Luna Pelaez, Noelia; Díez Lloret, Andrea; Perez Espejo, Rocío; Kamenarova, Kunka; Fernández Sánchez, Laura; Cuenca, Nicolás; Cortón, Marta; Avila Fernandez, Almudena; Sorkio, Anni; Skottman, Heli; Ayuso, Carmen; Erceg, Slaven; Bhattacharya, Shomi S.

    2015-01-01

    Retinitis pigmentosa (RP) represents a genetically heterogeneous group of retinal dystrophies affecting mainly the rod photoreceptors and in some instances also the retinal pigment epithelium (RPE) cells of the retina. Clinical symptoms and disease progression leading to moderate to severe loss of vision are well established and despite significant progress in the identification of causative genes, the disease pathology remains unclear. Lack of this understanding has so far hindered development of effective therapies. Here we report successful generation of human induced pluripotent stem cells (iPSC) from skin fibroblasts of a patient harboring a novel Ser331Cysfs*5 mutation in the MERTK gene. The patient was diagnosed with an early onset and severe form of autosomal recessive RP (arRP). Upon differentiation of these iPSC towards RPE, patient-specific RPE cells exhibited defective phagocytosis, a characteristic phenotype of MERTK deficiency observed in human patients and animal models. Thus we have created a faithful cellular model of arRP incorporating the human genetic background which will allow us to investigate in detail the disease mechanism, explore screening of a variety of therapeutic compounds/reagents and design either combined cell and gene- based therapies or independent approaches. PMID:26263531

  15. Optical imaging of mitochondrial redox state in rodent model of retinitis pigmentosa

    PubMed Central

    Ghanian, Zahra; Sepehr, Reyhaneh; Schmitt, Heather; Eells, Janis; Ranji, Mahsa

    2013-01-01

    Abstract. Oxidative stress (OS) and mitochondrial dysfunction contribute to photoreceptor cell loss in retinal degenerative disorders. The metabolic state of the retina in a rodent model of retinitis pigmentosa (RP) was investigated using a cryo-fluorescence imaging technique. The mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent and can be monitored without exogenous labels using optical techniques. The cryo-fluorescence redox imaging technique provides a quantitative assessment of the metabolism. More specifically, the ratio of the fluorescence intensity of these fluorophores (NADH/FAD), the NADH redox ratio (RR), is a marker of the metabolic state of the tissue. The NADH RR and retinal function were examined in an established rodent model of RP, the P23H rat compared to that of nondystrophic Sprague-Dawley (SD) rats. The NADH RR mean values were 1.11±0.03 in the SD normal and 0.841±0.01 in the P23H retina, indicating increased OS in the P23H retina. Electroretinographic data revealed a significant reduction in photoreceptor function in P23H animals compared to SD nozrmal rats. Thus, cryo-fluorescence redox imaging was used as a quantitative marker of OS in eyes from transgenic rats and demonstrated that alterations in the oxidative state of eyes occur during the early stages of RP. PMID:23291617

  16. Precision Medicine: Genetic Repair of Retinitis Pigmentosa in Patient-Derived Stem Cells

    PubMed Central

    Bassuk, Alexander G.; Zheng, Andrew; Li, Yao; Tsang, Stephen H.; Mahajan, Vinit B.

    2016-01-01

    Induced pluripotent stem cells (iPSCs) generated from patient fibroblasts could potentially be used as a source of autologous cells for transplantation in retinal disease. Patient-derived iPSCs, however, would still harbor disease-causing mutations. To generate healthy patient-derived cells, mutations might be repaired with new gene-editing technology based on the bacterial system of clustered regularly interspersed short palindromic repeats (CRISPR)/Cas9, thereby yielding grafts that require no patient immunosuppression. We tested whether CRISPR/Cas9 could be used in patient-specific iPSCs to precisely repair an RPGR point mutation that causes X-linked retinitis pigmentosa (XLRP). Fibroblasts cultured from a skin-punch biopsy of an XLRP patient were transduced to produce iPSCs carrying the patient’s c.3070G > T mutation. The iPSCs were transduced with CRISPR guide RNAs, Cas9 endonuclease, and a donor homology template. Despite the gene’s repetitive and GC-rich sequences, 13% of RPGR gene copies showed mutation correction and conversion to the wild-type allele. This is the first report using CRISPR to correct a pathogenic mutation in iPSCs derived from a patient with photoreceptor degeneration. This important proof-of-concept finding supports the development of personalized iPSC-based transplantation therapies for retinal disease. PMID:26814166

  17. Identification of a rhodopsin gene mutation in a large family with autosomal dominant retinitis pigmentosa

    PubMed Central

    Yu, Xinping; Shi, Wei; Cheng, Lulu; Wang, Yanfang; Chen, Ding; Hu, Xuting; Xu, Jinling; Xu, Limin; Wu, Yaming; Qu, Jia; Gu, Feng

    2016-01-01

    Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses. PMID:26794436

  18. A profile of transcriptomic changes in the rd10 mouse model of retinitis pigmentosa

    PubMed Central

    Uren, Philip J.; Lee, Justine T.; Doroudchi, M. Mehdi; Smith, Andrew D.

    2014-01-01

    Purpose Retinitis pigmentosa (RP) is a photoreceptor disease that affects approximately 100,000 people in the United States. Treatment options are limited, and the prognosis for most patients is progressive vision loss. Unfortunately, understanding of the molecular underpinnings of RP initiation and progression is still limited. However, the development of animal models of RP, coupled with high-throughput sequencing, has provided an opportunity to study the underlying cellular and molecular changes in this disease. Methods Using RNA-Seq, we present the first retinal transcriptome analysis of the rd10 murine model of retinal degeneration. Results Our data confirm the loss of rod-specific transcripts and the increased relative expression of Müller-specific transcripts, emphasizing the important role of reactive gliosis and innate immune activation in RP. Moreover, we report substantial changes in relative isoform usage among neuronal differentiation and morphogenesis genes, including a marked shift to shorter transcripts. Conclusions Our analyses implicate remodeling of the inner retina and possible Müller cell dedifferentiation. PMID:25489233

  19. Optical imaging of mitochondrial redox state in rodent model of retinitis pigmentosa

    NASA Astrophysics Data System (ADS)

    Maleki, Sepideh; Gopalakrishnan, Sandeep; Ghanian, Zahra; Sepehr, Reyhaneh; Schmitt, Heather; Eells, Janis; Ranji, Mahsa

    2013-01-01

    Oxidative stress (OS) and mitochondrial dysfunction contribute to photoreceptor cell loss in retinal degenerative disorders. The metabolic state of the retina in a rodent model of retinitis pigmentosa (RP) was investigated using a cryo-fluorescence imaging technique. The mitochondrial metabolic coenzymes nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent and can be monitored without exogenous labels using optical techniques. The cryo-fluorescence redox imaging technique provides a quantitative assessment of the metabolism. More specifically, the ratio of the fluorescence intensity of these fluorophores (NADH/FAD), the NADH redox ratio (RR), is a marker of the metabolic state of the tissue. The NADH RR and retinal function were examined in an established rodent model of RP, the P23H rat compared to that of nondystrophic Sprague-Dawley (SD) rats. The NADH RR mean values were 1.11±0.03 in the SD normal and 0.841±0.01 in the P23H retina, indicating increased OS in the P23H retina. Electroretinographic data revealed a significant reduction in photoreceptor function in P23H animals compared to SD nozrmal rats. Thus, cryo-fluorescence redox imaging was used as a quantitative marker of OS in eyes from transgenic rats and demonstrated that alterations in the oxidative state of eyes occur during the early stages of RP.

  20. A Missense Mutation in HK1 Leads to Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Wang, Feng; Wang, Yandong; Zhang, Bin; Zhao, Li; Lyubasyuk, Vera; Wang, Keqing; Xu, Mingchu; Li, Yumei; Wu, Frances; Wen, Cindy; Bernstein, Paul S.; Lin, Danni; Zhu, Susanna; Wang, Hui; Zhang, Kang; Chen, Rui

    2014-01-01

    Purpose. Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 60 causative genes known to date. Nevertheless, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing genes are yet to be identified. In this study, we aimed to identify the causative mutation for a large autosomal dominant RP (adRP) family with negative results from known retinal disease gene screening. Methods. Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation. Results. Linkage analysis identified a minimal disease region of 8 Mb on chromosome 10 with a peak parametric logarithm (base 10) of odds (LOD) score of 3.500. Further whole-exome sequencing identified a heterozygous missense mutation (NM_000188.2:c.2539G>A, p.E847K) in hexokinase 1 (HK1) that segregated with the disease phenotype in the family. Biochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1. Conclusions. Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism. PMID:25316723

  1. Retinitis pigmentosa, ataxia, and mental retardation associated with mitochondrial DNA mutation in an Italian family.

    PubMed Central

    Puddu, P; Barboni, P; Mantovani, V; Montagna, P; Cerullo, A; Bragliani, M; Molinotti, C; Caramazza, R

    1993-01-01

    An Italian pedigree including two sisters and their mother affected by a neuro-ophthalmic disease characterised by retinitis pigmentosa, ataxia, and psychomotor retardation is reported. Molecular analysis of mitochondrial DNA showed the presence of heteroplasmic 8993 point mutation in the subunit 6 of the ATPase gene. The clinical features and genetic findings in this family were comparable with those recently described in an English family. The mitochondrial DNA analysis of the family showed a correlation between the amount of mutated DNA and the disease severity in the probands, and indicated the presence of a threshold amount of mutated genome inducing ophthalmic defects. Moreover, the comparative analysis of blood, hairs, muscle, and urinary tract epithelia of two probands revealed an essentially similar distribution of mutated and wild type mitochondrial genomes. Our results suggest that the 8993 mitochondrial DNA mutation characterises a disease with similar clinical features in different populations. Images PMID:8435424

  2. A YAC contig spanning the dominant retinitis pigmentosa locus (RP9) on chromosome 7p

    SciTech Connect

    Keen, T.J.; Inglehearn, C.F.; Patel, R.J.; Peacock, R.E.

    1995-08-10

    The dominant retinitis pigmentosa locus RP9 has previously been localized to 7p13-p15, in the interval D7S526-D7S484. We now report refinement of the locus to the interval D7S795-D7S484 and YAC contig of approximately 4.8 Mb spanning this region and extending both distally and proximally from it. The contig was constructed by STS content mapping and physically orders 29 STSs in 28 YAC clones. The order of polymorphic markers in the contig is consistent with a genetic map that has been assembled using haplotype data from the CEPH pedigrees. This contig will provide a primary resource for the construction of a transcriptional map of this region and for the identification of the defective gene causing this form of adRP. 27 refs., 3 figs., 1 tab.

  3. Spectrum of rhodopsin gene mutations in Chinese patients with retinitis pigmentosa

    PubMed Central

    Yang, Guoxing; Xie, Shipeng; Feng, Na; Yuan, Zhifeng; Zhang, Minglian

    2014-01-01

    Purpose This study was to analyze the spectrum and frequency of rhodopsin gene (RHO) mutations in Chinese patients with retinitis pigmentosa (RP). Methods Patients were given physical examinations, and blood samples were collected for DNA extraction. The RHO mutations were screened with direct sequencing. Results Eight heterozygous nucleotide changes were detected in eight of 300 probands with RP, including six novel mutations and two known mutations. p.R21C, p.C110S, p.G182V, p.C187G, c.409–426delGTGGTGGTGTGTAAGCCC, and p.P347L were found in six autosomal dominant families. p.T92I and p.Y178C were found in two isolated cases. Conclusions The results reveal the spectrum and frequency of RHO mutations in Chinese patients with different forms of RP and demonstrate that RHO mutations account for a high proportion of autosomal dominant RP (adRP) cases. PMID:25221422

  4. Acute unilateral vision loss with optic disc oedema in retinitis pigmentosa.

    PubMed

    Patil-Chhablani, Preeti; Tyagi, Mudit; Kekunnaya, Ramesh; Narayanan, Raja

    2015-01-01

    A 36-year-old woman presented with acute vision loss and was found to have disc oedema and retinitis pigmentosa (RP). She presented with a history of acute, painless vision loss in her left eye over a period of 10 days. Her best-corrected visual acuity was 20/50, N6 in the right eye (OD) and 20/160, N6 in the left eye (OS). She was found to have a swollen optic disc and the examination of her fundus showed changes suggestive of RP. The diagnosis of RP was confirmed by electroretinogram, and after ruling out demyelinating changes in the central nervous system and other possible infectious causes of papillitis, she was treated with intravenous steroids followed by a course of oral steroid therapy. Following treatment, her visual acuity improved to 20/60. Acute vision loss may occur in patients with RP and prompt steroid therapy may result in partial visual recovery. PMID:26240107

  5. Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases

    PubMed Central

    Ullah, Inayat; Kabir, Firoz; Iqbal, Muhammad; Gottsch, Clare Brooks S.; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

    2016-01-01

    Purpose To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families. PMID:27440997

  6. Missense mutation (E150K) of rhodopsin in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Orth, U.; Oehlmann, R.; Gal, A.

    1994-09-01

    Missense or nonsense mutations of the rhodopsin gene have been implied in the pathogenesis of at least 3 different traits; autosomal dominant retinitis pigmentosa (adRP), congenital stationary night blindness (CSNB), and autosomal recessive retinitis pigmentosa (arRP). For the latter, a single patient has been reported with a nonsense mutation at codon 249 on both alleles. Heterozygous carriers of missense mutations of rhodopsin develop either adRP or CSNB depending on the particular amino acid substitution. Four of the 9 siblings from a consanguineous marriage in southern India were reported the have arRP. Mutational screening and sequencing of the rhodopsin gene revealed a G-to-A transition of the first nucleotide at codon 150 in exon II, which alters glutamate to lysine. The E150K mutation was present in the 4 patients in homozygous form, whereas the parents and 2 of the siblings were heterozygotes. Two-point analysis produced a Zmax=3.46 at theta=0.00. Two unaffected siblings who are heterozygotes for the E150K mutation underwent a thorough ophthalmological and psychophysical examination. No clinical abnormalities were found although these individuals were over forty, whereas the onset of RP in their affected siblings was in the second decade. Collectively, both the genetic and clinical findings strongly suggest that the E150K mutation of rhodopsin is recessive in this family. Glu150 forms part of the CD cytoplasmic loop of rhodopsin, which has been implicated in the binding and activation of transducin. We speculate that E150K leads to RP because the mutant protein may be incapable of activating transducin. It is tempting to speculate that, in addition to mutations in the genes for rhodopsin and the {beta}-subunit of PDE, mutations in the genes for transducin may also result in arRP.

  7. Retinitis pigmentosa

    MedlinePlus

    ... including the use of DHA, which is an omega-3 fatty acid. Other treatments, such as microchip implants ... counseling and testing may help determine whether your children are at risk for this disease.

  8. Retinitis pigmentosa

    MedlinePlus

    RP; Vision loss - RP; Night vision loss - RP; Rod Cone dystrophy; Peripheral vision loss - RP ... by several genetic defects. The cells controlling night vision (rods) are most likely to be affected. However, ...

  9. Necrotic enlargement of cone photoreceptor cells and the release of high-mobility group box-1 in retinitis pigmentosa

    PubMed Central

    Murakami, Y; Ikeda, Y; Nakatake, S; Tachibana, T; Fujiwara, K; Yoshida, N; Notomi, S; Nakao, S; Hisatomi, T; Miller, J W; Vavvas, DG; Sonoda, KH; Ishibashi, T

    2015-01-01

    Retinitis pigmentosa (RP) refers to a group of inherited retinal degenerations resulting form rod and cone photoreceptor cell death. The rod cell death due to deleterious genetic mutations has been shown to occur mainly through apoptosis, whereas the mechanisms and features of the secondary cone cell death have not been fully elucidated. Our previous study showed that the cone cell death in rd10 mice, an animal model of RP, involves necrotic features and is partly mediated by the receptor interacting protein kinase. However, the relevancy of necrotic cone cell death in human RP patients remains unknown. In the present study, we showed that dying cone cells in rd10 mice exhibited cellular enlargement, along with necrotic changes such as cellular swelling and mitochondrial rupture. In human eyes, live imaging of cone cells by adaptive optics scanning laser ophthalmoscopy revealed significantly increased percentages of enlarged cone cells in the RP patients compared with the control subjects. The vitreous of the RP patients contained significantly higher levels of high-mobility group box-1, which is released extracellularly associated with necrotic cell death. These findings suggest that necrotic enlargement of cone cells is involved in the process of cone degeneration, and that necrosis may be a novel target to prevent or delay the loss of cone-mediated central vision in RP. PMID:27551484

  10. The Relationship of Central Foveal Thickness to Urinary Iodine Concentration in Retinitis Pigmentosa Patients with or without Cystoid Macular Edema

    PubMed Central

    Sandberg, Michael A.; Pearce, Elizabeth N.; Harper, Shyana; Weigel-DiFranco, Carol; Hart, Lois; Rosner, Bernard; Berson, Eliot L.

    2014-01-01

    Importance Current treatments for cystoid macular edema in retinitis pigmentosa are not always effective, may lead to adverse side effects, and may not restore loss of visual acuity. The present research lays the rationale for evaluating whether an iodine supplement could reduce cystoid macular edema in retinitis pigmentosa. Objective To determine whether central foveal thickness in the presence of cystoid macular edema is related to dietary iodine intake inferred from urinary iodine concentration in non-smoking adults with retinitis pigmentosa. Design Cross-sectional study. Setting Institutional referral center. Participants Non-smoking adult patients with retinitis pigmentosa (n = 212, ages 18 to 69 years) with a visual acuity ≥ 20/200 in at least one eye. Main outcome measure The relationship of log central foveal thickness measured by optical coherence tomography to urinary iodine concentration measured from multiple spot samples and represented as a 3-level classification variable (< 100 μg/L, 100 μg/L - 199 μg/L, and ≥ 200 μg/L), assigning greater weight to patients with more reliable urinary iodine concentration estimates. Results Analyses were limited to 199 patients after excluding 11 patients who failed to return urine samples for measuring urinary iodine concentration and 2 outliers for urinary iodine concentration. Thirty-six percent of these patients had cystoid macular edema in one or both eyes. Although log central foveal thickness was inversely related to urinary iodine concentration based on all patients (p = 0.02), regression of log central foveal thickness on urinary iodine concentration separately for patients with and without cystoid macular edema showed a strong inverse significant relationship for the former group (p < 0.001) and no significant relationship for the latter group as tested (p = 0.66). In contrast, we found no significant association between cystoid macular edema prevalence and urinary iodine concentration based on the

  11. Unfolded protein response-induced dysregulation of calcium homeostasis promotes retinal degeneration in rat models of autosomal dominant retinitis pigmentosa

    PubMed Central

    Shinde, V; Kotla, P; Strang, C; Gorbatyuk, M

    2015-01-01

    The molecular mechanism of autosomal dominant retinitis pigmentosa (ADRP) in rats is closely associated with a persistently activated unfolded protein response (UPR). If unchecked, the UPR might trigger apoptosis, leading to photoreceptor death. One of the UPR-activated cellular signaling culminating in apoptotic photoreceptor cell death is linked to an increase in intracellular Ca2+. Therefore, we validated whether ADRP retinas experience a cytosolic Ca2+ overload, and whether sustained UPR in the wild-type retina could promote retinal degeneration through Ca2+-mediated calpain activation. We performed an ex vivo experiment to measure intracellular Ca2+ in ADRP retinas as well as to detect the expression levels of proteins that act as Ca2+ sensors. In separate experiments with the subretinal injection of tunicamycin (UPR inducer) and a mixture of calcium ionophore (A231278) and thapsigargin (SERCA2b inhibitor) we assessed the consequences of a sustained UPR activation and increased intracellular Ca2+ in the wild-type retina, respectively, by performing scotopic ERG, histological, and western blot analyses. Results of the study revealed that induced UPR in the retina activates calpain-mediated signaling, and increased intracellular Ca2+ is capable of promoting retinal degeneration. A significant decline in ERG amplitudes at 6 weeks post treatment was associated with photoreceptor cell loss that occurred through calpain-activated CDK5-pJNK-Csp3/7 pathway. Similar calpain activation was found in ADRP rat retinas. A twofold increase in intracellular Ca2+ and up- and downregulations of ER membrane-associated Ca2+-regulated IP3R channels and SERCA2b transporters were detected. Therefore, sustained UPR activation in the ADRP rat retinas could promote retinal degeneration through increased intracellular Ca2+ and calpain-mediated apoptosis.

  12. Unfolded protein response-induced dysregulation of calcium homeostasis promotes retinal degeneration in rat models of autosomal dominant retinitis pigmentosa

    PubMed Central

    Shinde, V; Kotla, P; Strang, C; Gorbatyuk, M

    2016-01-01

    The molecular mechanism of autosomal dominant retinitis pigmentosa (ADRP) in rats is closely associated with a persistently activated unfolded protein response (UPR). If unchecked, the UPR might trigger apoptosis, leading to photoreceptor death. One of the UPR-activated cellular signaling culminating in apoptotic photoreceptor cell death is linked to an increase in intracellular Ca2+. Therefore, we validated whether ADRP retinas experience a cytosolic Ca2+ overload, and whether sustained UPR in the wild-type retina could promote retinal degeneration through Ca2+-mediated calpain activation. We performed an ex vivo experiment to measure intracellular Ca2+ in ADRP retinas as well as to detect the expression levels of proteins that act as Ca2+ sensors. In separate experiments with the subretinal injection of tunicamycin (UPR inducer) and a mixture of calcium ionophore (A231278) and thapsigargin (SERCA2b inhibitor) we assessed the consequences of a sustained UPR activation and increased intracellular Ca2+ in the wild-type retina, respectively, by performing scotopic ERG, histological, and western blot analyses. Results of the study revealed that induced UPR in the retina activates calpain-mediated signaling, and increased intracellular Ca2+ is capable of promoting retinal degeneration. A significant decline in ERG amplitudes at 6 weeks post treatment was associated with photoreceptor cell loss that occurred through calpain-activated CDK5-pJNK-Csp3/7 pathway. Similar calpain activation was found in ADRP rat retinas. A twofold increase in intracellular Ca2+ and up- and downregulations of ER membrane-associated Ca2+-regulated IP3R channels and SERCA2b transporters were detected. Therefore, sustained UPR activation in the ADRP rat retinas could promote retinal degeneration through increased intracellular Ca2+ and calpain-mediated apoptosis. PMID:26844699

  13. Screening for mutations in RPGR and RP2 genes in Jordanian families with X-linked retinitis pigmentosa.

    PubMed

    Haddad, M F; Khabour, O F; Abuzaideh, K A Y; Shihadeh, W

    2016-01-01

    Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disease causing progressive degeneration of retinal photoreceptor cells. X-linked RP (XLRP), in which photoreceptor degeneration begins in early childhood and complete blindness often occurs by the fourth decade of life, constitutes the most severe form of this disease. Two genes commonly associated with XLRP have previously been cloned: retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 (RP2). We sought to identify mutations in these genes in Jordanian families suffering from this disease. Five unrelated Jordanian families with confirmed XLRP were screened for such mutations using direct sequencing. Three mutations were identified in the ORF15 exon of RPGR. The silent g.ORF15+470G>A substitution and the g.ORF15+1822insA insertion in the 3ꞌ-untranslated region were found in both normal and affected male family members at comparable frequencies, and thus were considered normal variants. The third mutation, g.ORF15+588G>A, in which alanine is substituted by threonine, was found in all affected men and one unaffected man in the two families harboring this variant. Thus, this mutation may be pathogenic, but with incomplete penetrance. No RP2 mutations were found among the examined families. Mutation screening of RP patients is essential to understand the mechanism behind this disease and develop treatments. A complete family history is required to identify its inheritance pattern and provide genetic counseling for patients and their families. PMID:27323122

  14. A Large Animal Model for CNGB1 Autosomal Recessive Retinitis Pigmentosa

    PubMed Central

    Winkler, Paige A.; Ekenstedt, Kari J.; Occelli, Laurence M.; Frattaroli, Anton V.; Bartoe, Joshua T.; Venta, Patrick J.; Petersen-Jones, Simon M.

    2013-01-01

    Retinal dystrophies in dogs are invaluable models of human disease. Progressive retinal atrophy (PRA) is the canine equivalent of retinitis pigmentosa (RP). Similar to RP, PRA is a genetically heterogenous condition. We investigated PRA in the Papillon breed of dog using homozygosity mapping and haplotype construction of single nucleotide polymorphisms within a small family group to identify potential positional candidate genes. Based on the phenotypic similarities between the PRA-affected Papillons, mouse models and human patients, CNGB1 was selected as the most promising positional candidate gene. CNGB1 was sequenced and a complex mutation consisting of the combination of a one basepair deletion and a 6 basepair insertion was identified in exon 26 (c.2387delA;2389_2390insAGCTAC) leading to a frameshift and premature stop codon. Immunohistochemistry (IHC) of pre-degenerate retinal sections from a young affected dog showed absence of labeling using a C-terminal CNGB1 antibody. Whereas an antibody directed against the N-terminus of the protein, which also recognizes the glutamic acid rich proteins arising from alternative splicing of the CNGB1 transcript (upstream of the premature stop codon), labeled rod outer segments. CNGB1 combines with CNGA1 to form the rod cyclic nucleotide gated channel and previous studies have shown the requirement of CNGB1 for normal targeting of CNGA1 to the rod outer segment. In keeping with these previous observations, IHC showed a lack of detectable CNGA1 protein in the rod outer segments of the affected dog. A population study did not identify the CNGB1 mutation in PRA-affected dogs in other breeds and documented that the CNGB1 mutation accounts for ∼70% of cases of Papillon PRA in our PRA-affected canine DNA bank. CNGB1 mutations are one cause of autosomal recessive RP making the CNGB1 mutant dog a valuable large animal model of the condition. PMID:23977260

  15. Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families

    PubMed Central

    Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N.; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

    2015-01-01

    Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 – 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier. PMID:26147992

  16. A population survey of retinitis pigmentosa and allied disorders in Denmark. Completeness of registration and quality of data.

    PubMed

    Haim, M; Holm, N V; Rosenberg, T

    1992-04-01

    The aim of this study was a complete survey of all patients in Denmark with a diagnosis of retinitis pigmentosa. The study was performed during the period 1986-1989 and included all persons living in Denmark from 1850 to 1989. We describe the methods of registration from medical and non-medical sources, based on defined criteria. The inclusion criteria were fulfilled by 1890 persons, 1056 males and 834 females. Evaluation of this 'Danish Retinitis Pigmentosa Register' demonstrates an overall completeness of about 80%, increasing from 40% for birth cohorts before 1911 to 90% for patients born since 1981. Concerning diagnostic confidence, 73% of the probands were characterized as certain, 16% as probable, and 11% as possible. Non-systemic cases comprised 61% of all probands and 31% had systemic disease, the rest being unclassified with respect to systemic involvement. The material is considered very suitable for epidemiological treatment and continuous clinical and genetic investigations. PMID:1609564

  17. X-linked retinitis pigmentosa: Report of a large kindred with loss of central vision and preserved peripheral function

    SciTech Connect

    Shastry, B.S.; Trese, M.T.

    1995-11-20

    X-linked retinitis pigmentosa (XLRP) is the most severe form of the inherited forms of retinitis pigmentosa and is clinically variable and genetically heterogeneous. It affects one in 20,000 live births. The affected individuals manifest degeneration of the peripheral retina during the first two decades of life on the basis of night blindness. Central vision usually is preserved until age 50, when the disease advances, affecting central vision and ultimately leading to complete loss of sight. Linkage analysis has shown two loci with a possibility of a third locus on the human X chromosome. The genetic abnormality that causes XLRP is not known at present. Here we describe a large kindred which manifests central loss of field with the preservation of peripheral vision. 5 refs., 1 fig.

  18. Anthocyanin can arrest the cone photoreceptor degeneration and act as a novel treatment for retinitis pigmentosa

    PubMed Central

    Tao, Ye; Chen, Tao; Yang, Guo-Qing; Peng, Guang-Hua; Yan, Zhong-Jun; Huang, Yi-Fei

    2016-01-01

    Retinitis pigmentosa (RP) is a group of heterogeneous inherited retinal diseases that is characterized by primary death rod photoreceptors and the secondary loss of cones. The degeneration of cones causes gradual constriction of visual fields, leaving the central islands that are eventually snuffed out. Studies indicate that the hyperoxia causes oxidative damage in the retina and contributes to the cone death of RP. Moreover, abundant reactive oxidative species (ROS) which are generated in cones may result in mitochondria membrane depolarization, which has been ascribed a central role in the apoptotic process and has been proposed to act as a forward feeding loop for the activation of downstream cascades. Anthocyanin is a potent antioxidant which has been evidenced to be able to counteract oxidative damages, scavenge surplus ROS, and rectify abnormities in the apoptotic cascade. Taken together with its ability to attenuate inflammation which also contributes to the etiology of RP, it is reasonable to hypothesize that the anthocyanin could act as a novel therapeutic strategy to retard or prevent cone degeneration in RP retinas, particularly if the treatment is timed appropriately and delivered efficiently. Future pharmacological investigations will identify the anthocyanin as an effective candidate for PR therapy and refinements of that knowledge would ignite the hope of restoring the visual function in RP patients. PMID:26949626

  19. Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.

    PubMed

    Barragán, Isabel; Borrego, Salud; Pieras, Juan Ignacio; González-del Pozo, María; Santoyo, Javier; Ayuso, Carmen; Baiget, Montserrat; Millan, José M; Mena, Marcela; Abd El-Aziz, Mai M; Audo, Isabelle; Zeitz, Christina; Littink, Karin W; Dopazo, Joaquín; Bhattacharya, Shomi S; Antiñolo, Guillermo

    2010-11-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study. PMID:21069908

  20. NGS-based Molecular diagnosis of 105 eyeGENE® probands with Retinitis Pigmentosa

    PubMed Central

    Ge, Zhongqi; Bowles, Kristen; Goetz, Kerry; Scholl, Hendrik P. N.; Wang, Feng; Wang, Xinjing; Xu, Shan; Wang, Keqing; Wang, Hui; Chen, Rui

    2015-01-01

    The National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE®) was established in an effort to facilitate basic and clinical research of human inherited eye disease. In order to provide high quality genetic testing to eyeGENE®’s enrolled patients which potentially aids clinical diagnosis and disease treatment, we carried out a pilot study and performed Next-generation sequencing (NGS) based molecular diagnosis for 105 Retinitis Pigmentosa (RP) patients randomly selected from the network. A custom capture panel was designed, which incorporated 195 known retinal disease genes, including 61 known RP genes. As a result, disease-causing mutations were identified in 52 out of 105 probands (solving rate of 49.5%). A total of 82 mutations were identified, and 48 of them were novel. Interestingly, for three probands the molecular diagnosis was inconsistent with the initial clinical diagnosis, while for five probands the molecular information suggested a different inheritance model other than that assigned by the physician. In conclusion, our study demonstrated that NGS target sequencing is efficient and sufficiently precise for molecular diagnosis of a highly heterogeneous patient cohort from eyeGENE®. PMID:26667666

  1. Use of Hydrogen as a Novel Therapeutic Strategy Against Photoreceptor Degeneration in Retinitis Pigmentosa Patients

    PubMed Central

    Tao, Ye; Geng, Lei; Wang, Liqiang; Xu, Weiwei; Qin, Limin; Peng, Guanghua; Huang, Yi Fei; Yang, Ji xue

    2016-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor apoptosis. Reactive oxygen species (ROS) have been recognized as critical initiators of the photoreceptor apoptosis in RP. Photoreceptor survival in RP mutants will not only require the inhibition of effectors of apoptotic machinery, but also the elimination of the initiating upstream signals, such as ROS. These cytotoxic ROS should be neutralized by the antioxidant defense system, otherwise they would interact with the macromolecules essential for photoreceptor survival. Hydrogen is a promising gaseous agent that has come to the forefront of therapeutic research over the last few years. It has been verified that hydrogen is capable of neutralizing the cytotoxic ROS selectively, rectifying abnormities in the apoptotic cascades, and attenuating the related inflammatory response. Hydrogen is so mild that it does not disturb the metabolic oxidation-reduction reactions or disrupt the physiologic ROS involved in cell signaling. Based on these findings, we hypothesize that hydrogen might be an effective therapeutic agent to slow or prevent photoreceptor degeneration in RP retinas. It is a logical step to test hydrogen for therapeutic use in multiple RP animal models, and ultimately in human RP patients. PMID:26952558

  2. Mutation Spectrum of EYS in Spanish Patients with Autosomal Recessive Retinitis Pigmentosa

    PubMed Central

    Barragán, Isabel; Borrego, Salud; Pieras, Juan Ignacio; Pozo, María González-del; Santoyo, Javier; Ayuso, Carmen; Baiget, Montserrat; Millan, José M; Mena, Marcela; El-Aziz, Mai M Abd; Audo, Isabelle; Zeitz, Christina; Littink, Karin W; Dopazo, Joaquín; Bhattacharya, Shomi S; Antiñolo, Guillermo

    2010-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene (EYS) encoding an ortholog of Drosophila spacemaker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28) are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain. Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study. © 2010 Wiley-Liss, Inc. PMID:21069908

  3. Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa.

    PubMed

    Peng, Bo; Xiao, Jia; Wang, Ke; So, Kwok-Fai; Tipoe, George L; Lin, Bin

    2014-06-11

    Retinitis pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations and is characterized by death of rod photoreceptor cell followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to rod and cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, it remains to be determined how microglia contribute to photoreceptor disruption in RP. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP. First, we demonstrated that microglia activation was an early alteration in RP retinas. Inhibition of microglia activation by minocycline reduced photoreceptor apoptosis and significantly improved retinal structure and function and visual behavior in rd10 mice. Second, we identified that minocycline exerted its neuroprotective effects through both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency dysregulated microglia activation and subsequently resulted in increased photoreceptor vulnerability in rd10 mice, suggesting that the Cx3cl1/Cx3cr1 signaling pathway might protect against microglia neurotoxicity. We concluded that suppression of neuroinflammatory responses could be a potential treatment strategy aimed at improving photoreceptor survival in human RP. PMID:24920619

  4. A new autosomal recessive retinitis pigmentosa locus maps on chromosome 2q31-q33.

    PubMed Central

    Bayés, M; Goldaracena, B; Martínez-Mir, A; Iragui-Madoz, M I; Solans, T; Chivelet, P; Bussaglia, E; Ramos-Arroyo, M A; Baiget, M; Vilageliu, L; Balcells, S; Gonzàlez-Duarte, R; Grinberg, D

    1998-01-01

    Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disease. To date, mutations in four members of the phototransduction cascade have been implicated in ARRP. Additionally, linkage of the disease to three loci on 1p, 1q, and 6p has been described. However, the majority of cases are still uncharacterised. We have performed linkage analysis in a large nuclear ARRP family with five affected sibs. After exclusion of several regions of the genome known to contain loci for retinal dystrophies, a genomic search for linkage to ARRP was undertaken. Positive lod scores were obtained with markers on 2q31-q33 (Zmax at theta = 0.00 of 4.03, 4.12, and 4.12 at D2S364, D2S118, and D2S389, respectively) defining an interval of about 7 cM for this new ARRP locus, between D2S148 and D2S161. Forty-four out of 47 additional ARRP families, tested with markers on 2q32, failed to show linkage, providing evidence of further genetic heterogeneity. Images PMID:9507394

  5. Interpretation of Flood-Illuminated Adaptive Optics Images in Subjects with Retinitis Pigmentosa.

    PubMed

    Gale, Michael J; Feng, Shu; Titus, Hope E; Smith, Travis B; Pennesi, Mark E

    2016-01-01

    The purpose of this study was to correlate features on flood-illuminated adaptive optics (AO) images with color fundus, fundus autofluorescence (FAF) and spectral domain optical coherence tomography (SD-OCT) images in patients with retinitis pigmentosa (RP). We imaged 39 subjects diagnosed with RP using the rtx1™ flood-illuminated AO camera from Imagine Eyes (Orsay, France). We observed a correlation between hyper-autofluoresence changes on FAF, disruption of the interdigitation zone (IZ) on SD-OCT and loss of reflective cone profiles on AO. Four main patterns of cone-reflectivity were seen on AO: presumed healthy cone mosaics, hypo-reflective blurred cone-like structures, higher frequency disorganized hyper-reflective spots, and lower frequency hypo-reflective spots. These regions were correlated to progressive phases of cone photoreceptor degeneration observed using SD-OCT and FAF. These results help provide interpretation of en face images obtained by flood-illuminated AO in subjects with RP. However, significant ambiguity remains as to what truly constitutes a cone, especially in areas of degeneration. With further refinements in technology, flood illuminated AO imaging has the potential to provide rapid, standardized, longitudinal and lower cost imaging in patients with retinal degeneration. PMID:26427424

  6. Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

    PubMed Central

    Perez-Carro, Raquel; Corton, Marta; Sánchez-Navarro, Iker; Zurita, Olga; Sanchez-Bolivar, Noelia; Sánchez-Alcudia, Rocío; Lelieveld, Stefan H.; Aller, Elena; Lopez-Martinez, Miguel Angel; López-Molina, Mª Isabel; Fernandez-San Jose, Patricia; Blanco-Kelly, Fiona; Riveiro-Alvarez, Rosa; Gilissen, Christian; Millan, Jose M; Avila-Fernandez, Almudena; Ayuso, Carmen

    2016-01-01

    Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis. PMID:26806561

  7. Microincision Vitrectomy Surgery in Vitreomacular Traction Syndrome of Retinitis Pigmentosa Patients

    PubMed Central

    Vingolo, Enzo Maria; Gerace, Emanuele; Valente, Stefano; Spadea, Leopoldo; Nebbioso, Marcella

    2014-01-01

    Purpose. To investigate long-term retinal changes after microincision pars plana vitrectomy surgery (MIVS) and internal limiting membrane (ILM) peeling outcome in retinitis pigmentosa (RP) patients affected by vitreomacular traction syndrome (VMT) with higher vitreous surface adhesion or coexisting epiretinal membrane (ERM). Methods. Eight RP patients suffering from VMT were evaluated by means of best corrected visual acuity (BCVA), anterior and posterior binocular examination, spectral-domain optical coherence tomography (SD-OCT), MP-1 microperimetry (MP-1), and full-field electroretinogram (ERG), before MIVS and ILM peeling and during the 36-month follow-up. Patients were hospitalized for two days after the surgery. Surgical procedure was performed following this schedule: surgical removal of crystalline lens (MICS), MIVS with 23-gauge sutureless system trocars, core vitreous body removal, and balanced-sterile-salin-solution- (BSS-) air-gas (SF6) exchange. Results. All patients presented visual acuity (VA) increase after MIVS. None of the patients developed ocular hypertension or vitreomacular adhesions during the 3-year follow-up. MP-1 bivariate contour ellipse area (BCEA) was reduced in its dimensions and improved in all patients demonstrating a better fixation. Conclusions. MIVS could be the gold standard therapy in RP patients with VMT and higher vitreous surface adhesion or coexisting ERM if medical therapy is not applicable or not effective. PMID:25009817

  8. Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Kasmala, Lorraine; Bond, Wesley S.; de Lucas Cerrillo, Ana M.; Wynn, Kristi; Lewin, Alfred S.

    2016-01-01

    Purpose To test the efficacy of systemic gene delivery of a mutant form of erythropoietin (EPO-R76E) that has attenuated erythropoietic activity, in a mouse model of autosomal dominant retinitis pigmentosa. Methods Ten-day old mice carrying one copy of human rhodopsin with the P23H mutation and both copies of wild-type mouse rhodopsin (hP23H RHO+/-,mRHO+/+) were injected into the quadriceps with recombinant adeno-associated virus (rAAV) carrying either enhanced green fluorescent protein (eGFP) or EpoR76E. Visual function (electroretinogram) and retina structure (optical coherence tomography, histology, and immunohistochemistry) were assessed at 7 and 12 months of age. Results The outer nuclear layer thickness decreased over time at a slower rate in rAAV.EpoR76E treated as compared to the rAAV.eGFP injected mice. There was a statistically significant preservation of the electroretinogram at 7, but not 12 months of age. Conclusions Systemic EPO-R76E slows death of the photoreceptors and vision loss in hP23H RHO+/-,mRHO+/+ mice. Treatment with EPO-R76E may widen the therapeutic window for retinal degeneration patients by increasing the number of viable cells. Future studies might investigate if co-treatment with EPO-R76E and gene replacement therapy is more effective than gene replacement therapy alone. PMID:27299810

  9. A partial structural and functional rescue of a retinitis pigmentosa model with compacted DNA nanoparticles.

    PubMed

    Cai, Xue; Nash, Zack; Conley, Shannon M; Fliesler, Steven J; Cooper, Mark J; Naash, Muna I

    2009-01-01

    Previously we have shown that compacted DNA nanoparticles can drive high levels of transgene expression after subretinal injection in the mouse eye. Here we delivered compacted DNA nanoparticles containing a therapeutic gene to the retinas of a mouse model of retinitis pigmentosa. Nanoparticles containing the wild-type retinal degeneration slow (Rds) gene were injected into the subretinal space of rds(+/-) mice on postnatal day 5. Gene expression was sustained for up to four months at levels up to four times higher than in controls injected with saline or naked DNA. The nanoparticles were taken up into virtually all photoreceptors and mediated significant structural and biochemical rescue of the disease without histological or functional evidence of toxicity. Electroretinogram recordings showed that nanoparticle-mediated gene transfer restored cone function to a near-normal level in contrast to transfer of naked plasmid DNA. Rod function was also improved. These findings demonstrate that compacted DNA nanoparticles represent a viable option for development of gene-based interventions for ocular diseases and obviate major barriers commonly encountered with non-viral based therapies. PMID:19390689

  10. [Possible role of altered levels of plasma docosahexaenoic acid in the pathogenesis of retinitis pigmentosa. Preliminary results].

    PubMed

    Simonelli, F; Milone, A; Iura, A; Picardi, C; La Banca, A M; Cotticelli, L; Rinaldi, E

    1990-09-01

    Plasma samples obtained from Retinitis Pigmentosa (R.P.) patients and controls were assayed for docosahexaenoic acid (DXA), the major fatty acid in photoreceptor cells, in order to evaluate the possibility that abnormalities in PUFA metabolism could be involved in R.P. pathogenesis. Our preliminary results show levels of plasma DXA in dominantly inherited R.P. lower than in the recessive forms and controls. PMID:2149985

  11. Linkage and clinical characterization of families with the RP10 (chromosome 7q) form of autosomal dominant retinitis pigmentosa

    SciTech Connect

    Jordan, S.A.; Humphries, P.; McGuire, R.E.

    1994-09-01

    Retinitis pigmentosa is a set of degenerative retinal diseases characterized by night blindness and loss of peripheral vision, often followed by loss of central vision. Genetically heterogeneous, retinitis pigmentosa has been found in autosomal dominant, autosomal recessive and X-linked forms. For autosomal dominant retinitis pigmentosa (adRP), 6 loci have been mapped: rhodopsin on chromosome 3q, peripherin/RDS on 6p, RP9 on 7p, RP10 on 7q, RP1 on 8q, and RP11 on 19q. Jordan et al. first reported linkage to 7q in a Spanish family with early onset disease. Recently, McGuire et al. reported the existence of a second, unrelated family of American descent with adRP that maps to the same region of 7q. The second family also has classical, diffuse retinitis pigmentosa though with later onset. The finding of two unrelated families that map to this region suggests that RP10 may account for a significant fraction of retinitis pigmentosa cases. Combining data from both families localizes the disease gene to 7q31.1-q35. In the Spanish family a Z{sub max} of 7.2 at 0% recombination was found with the marker D7S480 and affected individuals recombinant for D7S486 and D7S650 flank the disease. The American family showed a Z{sub max} of 5.3 at 0% recombination wtih the marker D7S514 and there are affected individuals recombinant for the markers D7S522, D7S677 and D7S486, and one affected individual recombinant for D7S530. Together, these data place the disease locus between D7S522 and D7S650. In addition, blue cone pigment, which maps to 7q31.3-q32, was excluded as a candidate gene in both families by linkage testing using intragenic polymorphisms and mutation screening.

  12. Alterations in glutamate cysteine ligase content in the retina of two retinitis pigmentosa animal models.

    PubMed

    Sánchez-Vallejo, Violeta; Benlloch-Navarro, Soledad; Trachsel-Moncho, Laura; López-Pedrajas, Rosa; Almansa, Inmaculada; Romero, Francisco Javier; Miranda, María

    2016-07-01

    Retinitis Pigmentosa (RP) comprises a group of rare genetic retinal disorders in which one of several different mutations induces photoreceptor death. Oxidative stress and glutathione (GSH) alterations may be related to the pathogenesis of RP. GSH has been shown to be present in high concentrations in the retina. In addition, the retina has the capability to synthesize GSH. In this study, we tested whether the two subunits of glutamate cysteine ligase, the rate-limiting enzyme in GSH synthesis, and the concentrations of retinal GSH, oxidized glutathione (GSSG), cysteine (Cys) and glutamate are altered in the retina of two different RP mice models. Retinas from C3H and rd1 mice at different postnatal days (P7, P11, P15, P19, P21 and P28) and from C57BL/6 and rd10 mice at P21 were obtained. Western blot analysis was performed to determine the protein content of catalytic and modulatory subunits from glutamate cysteine ligase (GCLC and GCLM, respectively). In another set of experiments, control and rd1 mice were administered buthinine sulfoximine, a glutathione synthase inhibitor, or paraquat. GSH, GSSG, glutamate and Cys concentrations were determined, by HPLC. A decrease in retinal GCLC content was observed in C3H and rd1 mice with age, nevertheless, there was an increase in retinal GCLC in rd1 mice compared to control retinas at P19. No modifications in GCLM content with age and no difference between GCLM content in rd1 and control retinas were observed. The GSH concentration decreased in the rd1 retinas compared with control ones at P15, it increased at P19, and was again similar at P21 and P28. No changes in GSSG concentration in control retinas with age were observed; the GSSG levels in rd1 retinas were similar from P7 to P19 and then increased significantly at P21 and P28. Glutamate concentration was increased in the rd1 retinas compared to control mice from P7 to P15 and were comparable at P21 and P28. The Cys concentrations was measured in control and rd1

  13. Clinical presentation and visual status of retinitis pigmentosa patients: a multicenter study in southwestern Nigeria

    PubMed Central

    Onakpoya, Oluwatoyin Helen; Adeoti, Caroline Olufunlayo; Oluleye, Tunji Sunday; Ajayi, Iyiade Adeseye; Majengbasan, Timothy; Olorundare, Olayemi Kolawole

    2016-01-01

    Background To review the visual status and clinical presentation of patients with retinitis pigmentosa (RP). Methodology Multicenter, retrospective, and analytical review was conducted of the visual status and clinical characteristics of patients with RP at first presentation from January 2007 to December 2011. Main outcome measure was the World Health Organization’s visual status classification in relation to sex and age at presentation. Data analysis by SPSS (version 15) and statistical significance was assumed at P<0.05. Results One hundred and ninety-two eyes of 96 patients with mean age of 39.08±18.5 years and mode of 25 years constituted the study population; 55 (57.3%) were males and 41 (42.7%) females. Loss of vision 67 (69.8%) and night blindness 56 (58.3%) were the leading symptoms. Twenty-one (21.9%) patients had a positive family history, with RP present in their siblings 15 (71.4%), grandparents 11 (52.3%), and parents 4 (19.4%). Forty (41.7%) were blind at presentation and 23 (24%) were visually impaired. Blindness in six (15%) patients was secondary to glaucoma. Retinal vascular narrowing and retinal pigmentary changes of varying severity were present in all patients. Thirty-five (36.5%) had maculopathy, 36 (37.5%) refractive error, 19 (20%) lenticular opacities, and eleven (11.5%) had glaucoma. RP was typical in 85 patients (88.5%). Older patients had higher rates of blindness at presentation (P=0.005); blindness and visual impairment rate at presentation were higher in males than females (P=0.029). Conclusion Clinical presentation with advanced diseases, higher blindness rate in older patients, sex-related difference in blindness/visual impairment rates, as well as high glaucoma blindness in RP patients requires urgent attention in southwestern Nigeria. PMID:27601870

  14. Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype.

    PubMed

    Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Jiao, Kangwei; Buena-Atienza, Elena; Sahaboglu, Ayse; Trifunović, Dragana; Balendran, Sukirthini; Koepfli, Tanja; Mühlfriedel, Regine; Schön, Christian; Biel, Martin; Heckmann, Angelique; Beck, Susanne C; Michalakis, Stylianos; Wissinger, Bernd; Seeliger, Mathias W; Paquet-Durand, François

    2015-10-01

    Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the Pde6a R562W mutation in combination with an existing line carrying the V685M mutation to generate compound heterozygous Pde6a V685M/R562W animals, exactly homologous to a case of human RP. We compared the progression of photoreceptor degeneration in these compound heterozygous mice with the homozygous V685M and R562W mutants, and additionally with the D670G line that is known for a relatively mild phenotype. We investigated PDE6A expression, cyclic guanosine mono-phosphate accumulation, calpain and caspase activity, in vivo retinal function and morphology, as well as photoreceptor cell death and survival. This analysis confirms the severity of different Pde6a mutations and indicates that compound heterozygous mutants behave like intermediates of the respective homozygous situations. Specifically, the severity of the four different Pde6a situations may be categorized by the pace of photoreceptor degeneration: V685M (fastest) > V685M/R562W > R562W > D670G (slowest). While calpain activity was strongly increased in all four mutants, caspase activity was not. This points to the execution of non-apoptotic cell death and may lead to the identification of new targets for therapeutic interventions. For individual RP patients, our study may help to predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window-of-opportunity for clinical interventions. PMID:26188004

  15. Contrast visual acuity in patients with retinitis pigmentosa assessed by a contrast sensitivity tester

    PubMed Central

    Oishi, Maho; Nakamura, Hajime; Hangai, Masanori; Oishi, Akio; Otani, Atsushi; Yoshimura, Nagahisa

    2012-01-01

    Purpose: To assess contrast visual acuity (CVA) in patients with retinitis pigmentosa (RP) and compare the result with standard visual acuity (VA), retinal thickness, status of inner segment/outer segment junction, and central visual field. Materials and Methods: Thirty-nine eyes of 39 patients with RP and 39 eyes of 39 healthy individuals were studied. To see the difference in CVA between RP patients and normal controls, only subjects with standard VA of 1.0 (20/20) or better were included. This was a cross-sectional study. CVA in various light conditions was measured with CAT-2000 and was compared between patients and controls. CVA of patients was further analyzed for association with other parameters including foveal retinal thickness, outer nuclear layer thickness, the status of inner segment/outer segment junction measured with optical coherence tomography (OCT), and visual field mean deviation (MD) measured with Humphrey field analyzer 10-2 program. Results: CVA impairment was evident in RP patients compared to controls (P < 0.01, in all measurement conditions). Multivariate analysis showed association of logarithm of the minimum angle of resolution (logMAR) with CVAs in several conditions. None of the OCT measurements was associated with CVA. When patients were divided into three groups based on MD, the most advanced group (MD worse than or equal to –20 dB) showed impairment of mesopic CVA (P < 0.05, under mesopic condition of 100% without glare, with glare, and 25% without glare). Conclusion: CVA impairment was confirmed in RP patients, especially in advanced cases. CVA measured with CAT-2000 may be a useful tool for assessing foveal function in RP patients. PMID:23202395

  16. Distilling a Visual Network of Retinitis Pigmentosa Gene-Protein Interactions to Uncover New Disease Candidates

    PubMed Central

    Boloc, Daniel; Castillo-Lara, Sergio; Marfany, Gemma; Gonzàlez-Duarte, Roser; Abril, Josep F.

    2015-01-01

    Background Retinitis pigmentosa (RP) is a highly heterogeneous genetic visual disorder with more than 70 known causative genes, some of them shared with other non-syndromic retinal dystrophies (e.g. Leber congenital amaurosis, LCA). The identification of RP genes has increased steadily during the last decade, and the 30% of the cases that still remain unassigned will soon decrease after the advent of exome/genome sequencing. A considerable amount of genetic and functional data on single RD genes and mutations has been gathered, but a comprehensive view of the RP genes and their interacting partners is still very fragmentary. This is the main gap that needs to be filled in order to understand how mutations relate to progressive blinding disorders and devise effective therapies. Methodology We have built an RP-specific network (RPGeNet) by merging data from different sources: high-throughput data from BioGRID and STRING databases, manually curated data for interactions retrieved from iHOP, as well as interactions filtered out by syntactical parsing from up-to-date abstracts and full-text papers related to the RP research field. The paths emerging when known RP genes were used as baits over the whole interactome have been analysed, and the minimal number of connections among the RP genes and their close neighbors were distilled in order to simplify the search space. Conclusions In contrast to the analysis of single isolated genes, finding the networks linking disease genes renders powerful etiopathological insights. We here provide an interactive interface, RPGeNet, for the molecular biologist to explore the network centered on the non-syndromic and syndromic RP and LCA causative genes. By integrating tissue-specific expression levels and phenotypic data on top of that network, a more comprehensive biological view will highlight key molecular players of retinal degeneration and unveil new RP disease candidates. PMID:26267445

  17. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.

    PubMed

    Bakondi, Benjamin; Lv, Wenjian; Lu, Bin; Jones, Melissa K; Tsai, Yuchun; Kim, Kevin J; Levy, Rachelle; Akhtar, Aslam Abbasi; Breunig, Joshua J; Svendsen, Clive N; Wang, Shaomei

    2016-03-01

    Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of Rho(S334), which prevented retinal degeneration and improved visual function. PMID:26666451

  18. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Bakondi, Benjamin; Lv, Wenjian; Lu, Bin; Jones, Melissa K; Tsai, Yuchun; Kim, Kevin J; Levy, Rachelle; Akhtar, Aslam Abbasi; Breunig, Joshua J; Svendsen, Clive N; Wang, Shaomei

    2016-01-01

    Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (RhoS334) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of RhoS334, which prevented retinal degeneration and improved visual function. PMID:26666451

  19. Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases

    PubMed Central

    Kabir, Firoz; Ullah, Inayat; Ali, Shahbaz; Gottsch, Alexander D.H.; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

    2016-01-01

    Purpose This study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families. Methods Large consanguineous families were ascertained from the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon–intron boundaries of RP1 were sequenced to identify the causal mutation. Results The ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples. Conclusions These results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families. PMID:27307693

  20. Mutations in FLVCR1 Cause Posterior Column Ataxia and Retinitis Pigmentosa

    PubMed Central

    Rajadhyaksha, Anjali M.; Elemento, Olivier; Puffenberger, Erik G.; Schierberl, Kathryn C.; Xiang, Jenny Z.; Putorti, Maria L.; Berciano, José; Poulin, Chantal; Brais, Bernard; Michaelides, Michel; Weleber, Richard G.; Higgins, Joseph J.

    2010-01-01

    The study of inherited retinal diseases has advanced our knowledge of the cellular and molecular mechanisms involved in sensory neural signaling. Dysfunction of two specific sensory modalities, vision and proprioception, characterizes the phenotype of the rare, autosomal-recessive disorder posterior column ataxia and retinitis pigmentosa (PCARP). Using targeted DNA capture and high-throughput sequencing, we analyzed the entire 4.2 Mb candidate sequence on chromosome 1q32 to find the gene mutated in PCARP in a single family. Employing comprehensive bioinformatic analysis and filtering, we identified a single-nucleotide coding variant in the feline leukemia virus subgroup C cellular receptor 1 (FLVCR1), a gene encoding a heme-transporter protein. Sanger sequencing confirmed the FLVCR1 mutation in this family and identified different homozygous missense mutations located within the protein's transmembrane channel segment in two other unrelated families with PCARP. To determine whether the selective pathologic features of PCARP correlated with FLVCR1 expression, we examined wild-type mouse Flvcr1 mRNA levels in the posterior column of the spinal cord and the retina via quantitative real-time reverse-transcriptase PCR. The Flvcr1 mRNA levels were most abundant in the retina, followed by the posterior column of the spinal cord and other brain regions. These results suggest that aberrant FLVCR1 causes a selective degeneration of a subpopulation of neurons in the retina and the posterior columns of the spinal cord via dysregulation of heme or iron homeostasis. This finding broadens the molecular basis of sensory neural signaling to include common mechanisms that involve proprioception and vision. PMID:21070897

  1. Hypomorphic mutations in TRNT1 cause retinitis pigmentosa with erythrocytic microcytosis.

    PubMed

    DeLuca, Adam P; Whitmore, S Scott; Barnes, Jenna; Sharma, Tasneem P; Westfall, Trudi A; Scott, C Anthony; Weed, Matthew C; Wiley, Jill S; Wiley, Luke A; Johnston, Rebecca M; Schnieders, Michael J; Lentz, Steven R; Tucker, Budd A; Mullins, Robert F; Scheetz, Todd E; Stone, Edwin M; Slusarski, Diane C

    2016-01-01

    Retinitis pigmentosa (RP) is a highly heterogeneous group of disorders characterized by degeneration of the retinal photoreceptor cells and progressive loss of vision. While hundreds of mutations in more than 100 genes have been reported to cause RP, discovering the causative mutations in many patients remains a significant challenge. Exome sequencing in an individual affected with non-syndromic RP revealed two plausibly disease-causing variants in TRNT1, a gene encoding a nucleotidyltransferase critical for tRNA processing. A total of 727 additional unrelated individuals with molecularly uncharacterized RP were completely screened for TRNT1 coding sequence variants, and a second family was identified with two members who exhibited a phenotype that was remarkably similar to the index patient. Inactivating mutations in TRNT1 have been previously shown to cause a severe congenital syndrome of sideroblastic anemia, B-cell immunodeficiency, recurrent fevers and developmental delay (SIFD). Complete blood counts of all three of our patients revealed red blood cell microcytosis and anisocytosis with only mild anemia. Characterization of TRNT1 in patient-derived cell lines revealed reduced but detectable TRNT1 protein, consistent with partial function. Suppression of trnt1 expression in zebrafish recapitulated several features of the human SIFD syndrome, including anemia and sensory organ defects. When levels of trnt1 were titrated, visual dysfunction was found in the absence of other phenotypes. The visual defects in the trnt1-knockdown zebrafish were ameliorated by the addition of exogenous human TRNT1 RNA. Our findings indicate that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina. PMID:26494905

  2. A YAC contig encompassing the chromosome 7p locus for autosomal dominant retinitis pigmentosa

    SciTech Connect

    Inglehearn, C.F.; Keen, T.J.; Ratel, R.

    1994-09-01

    Retinitis pigmentosa is an inherited retinal degeneration characterized by night blindness and loss of peripheral vision, often leading to complete blindness. The autosomal dominant form (adRP) maps to at least six different loci, including the rhodopsin and peripherin/Rds genes and four loci identified only by linkage analysis on chromosomes 7p, 7q, 8cen and 19q. The 7p locus was reported by this laboratory in a large English family, with a lod score of 16.5. Several new genetic markers have been tested in the family and this locus has now been refined to an interval of approximately 1 cM between markers D7S795 and D7S484 in the 7p13-15 region. In order to clone the gene for adRP, we have used microsatellites and STSs from the region to identify over 80 YACs, from four different libraries, which map to this interval. End clones from key YACs were isolated for the generation of additional STSs. Eleven microsatellite markers between D7S435 (distal) and D7S484 (proximal) have been ordered by a combination of both physical and genetic mapping. In this way we have now obtained a YAC contig spanning approximately 3 megabases of chromosome 7p within which the adRP gene must lie. One gene (aquaporin) and one chromosome 7 brain EST have been placed on the contig but both map distal to the region of interest. Sixteen other ESTs and three further known 7p genes mapping in the region have been excluded. We are now attempting to build a cosmid contig in the defined interval and identify further expressed sequences from both YACs and cosmids to test as candidates for the adRP gene.

  3. A new locus for autosomal dominant retinitis pigmentosa on the short arm of chromosome 17.

    PubMed

    Greenberg, J; Goliath, R; Beighton, P; Ramesar, R

    1994-06-01

    Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous retinopathies, some of which have been shown to result from mutations in two different known retinal genes, rhodopsin (3q) and peripherin-rds (6p). Three additional anonymous loci at 7p, 7q and pericentric 8 have been implicated by linkage studies. There are still, however, a few families in which all known loci have been excluded. In this report we present data indicating a location, on the short arm of chromosome 17, for the autosomal dominant RP (ADRP) locus in a large South African (SA) family of British ancestry. Positive two-point lod scores have been obtained for nine markers (D17S938, Z = 5.43; D17S796, Z = 4.82; D17S849, Z = 3.6; D17S786, Z = 3.55; TP53, Z = 3.55; D17S578, Z = 3.29; D17S960, Z = 3.16; D17S926, Z = 1.51; D17S804, Z = 0.47 all at theta = 0.10 except D17S804 and D17S926, theta = 0.20). These data provide definitive evidence for the localization of an ADRP gene on chromosome 17p. The human recoverin gene has been localized to 17p13.1 and was consequently a prime candidate for ADRP in the family studied. However, mutation screening of the three exons of this gene failed to produce any evidence of recoverin being the gene involved in the pathogenesis of ADRP in this SA family. PMID:7951236

  4. The Artificial Silicon Retina in Retinitis Pigmentosa Patients (An American Ophthalmological Association Thesis)

    PubMed Central

    Chow, Alan Y.; Bittner, Ava K.; Pardue, Machelle T.

    2010-01-01

    Purpose: In a published pilot study, a light-activated microphotodiode-array chip, the artificial silicon retina (ASR), was implanted subretinally in 6 retinitis pigmentosa (RP) patients for up to 18 months. The ASR electrically induced retinal neurotrophic rescue of visual acuity, contrast, and color perception and raised several questions: (1) Would neurotrophic effects develop and persist in additionally implanted RP patients? (2) Could vision in these patients be reliably assessed? (3) Would the ASR be tolerated and function for extended periods? Methods: Four additional RP patients were implanted and observed along with the 6 pilot patients. Of the 10 patients, 6 had vision levels that allowed for more standardized testing and were followed up for 7+ years utilizing ETDRS charts and a 4-alternative forced choice (AFC) Chow grating acuity test (CGAT). A 10-AFC Chow color test (CCT) extended the range of color vision testing. Histologic examination of the eyes of one patient, who died of an unrelated event, was performed. Results: The ASR was well tolerated, and improvement and/or slowing of vision loss occurred in all 6 patients. CGAT extended low vision acuity testing by logMAR 0.6. CCT expanded the range of color vision testing and correlated well with PV-16 (r = 0.77). An ASR recovered from a patient 5 years after implantation showed minor disruption and excellent electrical function. Conclusion: ASR-implanted RP patients experienced prolonged neurotrophic rescue of vision. CGAT and CCT extended the range of acuity and color vision testing in low vision patients. ASR implantation may improve and prolong vision in RP patients. PMID:21212852

  5. Retinitis Pigmentosa Treatment with Western Medicine and Traditional Chinese Medicine Therapies

    PubMed Central

    Xu, Jian; Peng, Qinghua

    2015-01-01

    Current management of retinitis pigmentosa (RP) includes an attempt at slowing down the degenerative process through therapies that use either Western or traditional Chinese medicine (TCM). Novel therapies in Western medicine (WM) include use of tailor-made gene therapy, transplantation of stem cells, or neuroprotection treatment. TCM treatment includes two major approaches. These are orally applied herbal decoctions and acupuncture. In fact, all TCM treatments are based on the differentiation of a symptom-complex, which is the characteristic essence of TCM. Thus, diagnosed RP may be treated via the liver, the kidney, and the spleen. The principle behind these treatments is to invigorate the blood and brighten the eyes by toning up the liver and the kidney. Also treatments to cope with deficiencies in the two concepts that are unique and fundamental to TCM are considered: Qi or “vital energy” and Yin and Yang or the harmony of all the opposite elements and forces that make up existence. In particular, the Qi deficiency that results from blood stasis is addressed in these treatments. This paper also puts forward the existing problems and the prospect of the future development on integrating TCM with WM. PMID:26124961

  6. Further refinement of the location for autosomal dominant retinitis pigmentosa on chromosome 7p (RP9)

    SciTech Connect

    Inglehearn, C.F.; Keen, T.J.; Al-Maghtheh, M.; Gregory, C.Y.; Bhattacharya, S.S.; Jay, M.R.; Moore, A.T.; Bird, A.C. )

    1994-04-01

    A form of autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 7p was recently reported by this laboratory, in a single large family from southeastern England. Further sampling of the family and the use a number of genetic markers from 7p have facilitated the construction of a series of multipoint linkage maps of the region with the most likely disease gene location. From this and haplotype data, the locus can now be placed between the markers D7S484 and D7S526, in an interval estimated to be 1.6-4 cM. Genetic distances between the markers previously reported to be linked to this region and those described in the recent whole-genome poly-CA map were estimated from data in this and other families. These data should assist in the construction of a physical map of the region and will help to identify candidate genes for the 7p adRP locus. 21 refs., 3 figs., 1 tab.

  7. Localizing multiple X chromosome-linked retinitis pigmentosa loci using multilocus homogeneity tests

    SciTech Connect

    Ott, J.; Terwilliger, J.D. ); Bhattacharya, S. ); Chen, J.D.; Denton, J.; Donald, J. ); Dubay, C.; Litt, M.; Weleber, R.G. ); Farrar, G.J.; Humphries, P. ); Fishman, G.A.; Wong, F. ); Frey, D.; Maechler, M. )

    1990-01-01

    Multilocus linkage analysis of 62 family pedigrees with X chromosome-linked retinitis pigmentosa (XLRP) was undertaken to determine the presence of possible multiple disease loci and to reliability estimate their map location. Multilocus homogeneity tests furnish convincing evidence for the presence of two XLRP loci, the likelihood ratio being 6.4 {times} 10{sup 9}:1 in a favor of two versus a single XLRP locus and gave accurate estimates for their map location. In 60-75% of the families, location of an XLRP gene was estimated at 1 centimorgan distal to OTC, and in 25-40% of the families, an XLRP locus was located halfway between DXS14 (p58-1) and DXZ1 (Xcen), with an estimated recombination fraction of 25% between the two XLRP loci. There is also good evidence for third XLRP locus, midway between DXS28 (C7) and DXS164 (pERT87), supported by a likelihood ratio of 293:1 for three versus two XLRP loci.

  8. Evaluation of the arrestin gene in patients with retinitis pigmentosa or an allied disease

    SciTech Connect

    DeStefano, D.J.; Berson, E.L.; Dryja, T.P.

    1994-09-01

    Arrestin, also called 48K protein or S-antigen, plays a role in deactivating rhodopsin, the photosensitive, seven-helix, G-protein receptor found in rod photoreceptors. In Drosophila, null mutations in arrestin genes cause a light-dependent photoreceptor degeneration. It is possible that a comparable photoreceptor degeneration in humans is caused by defects in the rod arrestin gene. In order to evaluate this possibility, we are characterizing the human arrestin locus on chromosome 2q. We screened a genomic library (5 million plaques) using an arrestin cDNA clone. Sixty-eight hybridizing clones were identified; portions of 7 clones were sequenced to determine the intron sequence flanking the exons. We are using SSCP analysis and direct genomic sequencing to screen the entire coding region, splice donor and acceptor sites, and the promoter region of the arrestin gene in 188 patients with autosomal dominant and 104 patients with autosomal recessive retinitis pigmentosa. We have already obtained flanking intron sequences necessary for SSCP analysis for 13 of 16 exons. So far, we have identified 4 silent base changes at codons 67 (TGC-to-TGT), 107 (CTG-to-CTC), 163 (GCC-to-GCT), and 288 (CTG-to-TGT), all with allele frequencies at 1% or less. Several other variant bands detected by SSCP analysis are currently being sequenced.

  9. Towards isolation of the gene for X-linked retinitis pigmentosa (RP3)

    SciTech Connect

    Dry, K.L.; Aldred, M.A.; Hardwick, L.J.

    1994-09-01

    Until recently the region of interest containing the gene for X-linked retinitis pigmentosa (RP3) was thought to lie between CYBB (Xp21.1) and the proximal end of the deletion in patient BB (JBBprox). This region was thought to span 100-150 kb. Here we present new mapping data to show that the distance between the 5{prime} (most proximal) end of CYBB and JBBprox is only 50 kb. Recently Roux et al. (1994) have described the isolation of a gene within this region but this showed no disease-associated changes. Further evidence from mapping the deletion in patient NF (who suffered from McLead`s syndrome and CGD but not RP) and from linkage analysis of our RP3 families with a new dinucleotide repeat suggests that the gene must extend proximally from JBBprox. In order to extend the region of search we have constructed a YAC contig spanning 800 kb to OTC. We are continuing our search for the RP3 gene using a variety of strategies including exon trapping and cDNA enrichment as well as direct screening of cDNA libraries with subclones from this region.

  10. Functional Cone Rescue by RdCVF Protein in a Dominant Model of Retinitis Pigmentosa

    PubMed Central

    Yang, Ying; Mohand-Said, Saddek; Danan, Aude; Simonutti, Manuel; Fontaine, Valérie; Clerin, Emmanuelle; Picaud, Serge; Léveillard, Thierry; Sahel, José-Alain

    2009-01-01

    In retinitis pigmentosa (RP), a majority of causative mutations affect genes solely expressed in rods; however, cone degeneration inevitably follows rod cell loss. Following transplantation and in vitro studies, we demonstrated the role of photoreceptor cell paracrine interactions and identified a Rod-derived Cone Viability Factor (RdCVF), which increases cone survival. In order to establish the clinical relevance of such mechanism, we assessed the functional benefit afforded by the injection of this factor in a frequent type of rhodopsin mutation, the P23H rat. In this model of autosomal dominant RP, RdCVF expression decreases in parallel with primary rod degeneration, which is followed by cone loss. RdCVF protein injections induced an increase in cone cell number and, more important, a further increase in the corresponding electroretinogram (ERG). These results indicate that RdCVF can not only rescue cones but also preserve significantly their function. Interestingly, the higher amplitude of the functional versus the survival effect of RdCVF on cones indicates that RdCVF is acting more directly on cone function. The demonstration at the functional level of the therapeutic potential of RdCVF in the most frequent of dominant RP mutations paves the way toward the use of RdCVF for preserving central vision in many RP patients. PMID:19277021

  11. Continued use of dorzolamide for the treatment of cystoid macular oedema in patients with retinitis pigmentosa

    PubMed Central

    Fishman, Gerald A; Apushkin, Marsha A

    2007-01-01

    Aim To determine the value of a topical carbonic anhydrase inhibitor for extended treatment of cystoid macular oedema (CME) in patients with retinitis pigmentosa (RP). Method Eight patients with RP and foveal cystic‐appearing lesions observed on fundus examination and by optical coherence tomography (OCT) testing were treated with a topical form of carbonic anhydrase inhibitor. Results Foveal cystic‐like spaces were documented by OCT testing in all eight patients before treatment. All patients had a significant reduction in their foveal thickness (FT) and foveal zone thickness (FZT) in at least one eye after using 2% dorzolamide three times a day for 1 or 2 months. Six patients had an improvement in both eyes. After an additional 6–13 months of the same treatment regimen, out of six patients who had a sustained reduction in FT and FZT in at least one eye, four had this reduction in both eyes. While they were still taking Trusopt, a recurrence (rebound) of CME in both eyes was observed in two patients, whereas one patient had a sustained improvement in one eye and rebound of CME in the other eye. Out of 8 patients, 3 showed an improvement in their visual acuity by ⩾7 letters, in at least one eye, on Snellen acuity charts, which was determined as clinically significant. Conclusion Results from this study suggest that patients with RP could potentially sustain a beneficial effect from continued treatment with a topical form of carbonic anhydrase inhibitor. PMID:17215269

  12. Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Danciger, M.; Blaney, J.; Gao, Y.Q.; Zhao, D.Y.

    1995-11-01

    We have studied 24 small families with presumed autosomal recessive inheritance of retinitis pigmentosa by a combination of haplotype analysis and exon screening. Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B). This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5{prime} untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease. Two probands were found with compound heterozygous mutations: Gly576Asp and His620(1-bp del) mutations were present in one proband, and a Lys706X null mutation and an AG to AT splice acceptor site mutation in intron 2 were present in the other. Only the affecteds of each of the two families carried both corresponding mutations. 29 refs., 3 figs., 1 tab.

  13. Clinical and Rehabilitative Management of Retinitis Pigmentosa: Up-to-Date

    PubMed Central

    Parmeggiani, Francesco; Sato, Giovanni; De Nadai, Katia; Romano, Mario R; Binotto, Andrea; Costagliola, Ciro

    2011-01-01

    The term retinitis pigmentosa (RP) indicates a heterogeneous group of genetic rare ocular diseases in which either rods or cones are prevalently damaged. RP represents the most common hereditary cause of blindness in people from 20 to 60 years old. In general, the different RP forms consist of progressive photo-receptorial neuro-degenerations, which are characterized by variable visual disabilities and considerable socio-sanitary burden. Sometimes, RP patients do not become visually impaired or legally blind until their 40-50 years of age and/or maintain a quite acceptable sight for all their life. Other individuals with RP become completely blind very early or in middle childhood. Although there is no treatment that can effectively cure RP, in some case-series the disease’s progression seems to be reducible by specific preventive approaches. In the most part of RP patients, the quality of vision can be considerably increased by means of nanometer-controlled filters. In the present review, the main aspects of the routine clinical and rehabilitative managements for RP patients are described, particularly focusing on the importance of specific referral Centers to practice a real multidisciplinary governance of these dramatic diseases. PMID:22131870

  14. Molecular genetic study of autosomal dominant retinitis pigmentosa in Lithuanian patients.

    PubMed

    Kucinskas, V; Payne, A M; Ambrasiene, D; Jurgelevicius, V; Steponaviciūte, D; Arciuliene, J V; Daktaraviciene, E; Bhattacharya, S

    1999-03-01

    Lithuanian patients with visual problems were clinically examined for retinitis pigmentosa (RP). A total of 33 unrelated families with autosomal dominant RP (adRP) were identified. Screening for mutations in the rhodopsin (RHO) and peripherin/RDS (RDS) genes was performed using DNA heteroduplex analysis. Direct DNA sequencing in the cases of heteroduplex formation showed the presence of the following mutations and polymorphisms in 14 adRP patients: RHO gene - Lys248Arg (1 case), and Pro347Leu (2 cases); RDS gene - Glu304Gln (12 cases), Lys310Arg (5 cases), and Gly338Asp (12 cases). The presence of these mutations (except Lys248Arg in the RHO gene) was confirmed by relevant restriction enzyme digestion. The frequency of the RDS gene mutations Glu304Gln and Gly338Asp was estimated to be 36.4%, while mutation Lys310Arg was less frequent (15.2%). These 3 RDS gene mutations appear to be polypeptide polymorphisms not related to adRP. PMID:10077725

  15. Further refinement of the location for autosomal dominant retinitis pigmentosa on chromosome 7p (RP9).

    PubMed Central

    Inglehearn, C. F.; Keen, T. J.; al-Maghtheh, M.; Gregory, C. Y.; Jay, M. R.; Moore, A. T.; Bird, A. C.; Bhattacharya, S. S.

    1994-01-01

    A form of autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 7p was recently reported by this laboratory, in a single large family from southeastern England. Further sampling of the family and the use a number of genetic markers from 7p have facilitated the construction of a series of multipoint linkage maps of the region with the most likely disease gene location. From this and haplotype data, the locus can now be placed between the markers D7S484 and D7S526, in an interval estimated to be 1.6-4 cM. Genetic distances between the markers previously reported to be linked to this region and those described in the recent whole-genome poly-CA map were estimated from data in this and other families. These data should assist in the construction of a physical map of the region and will help to identify candidate genes for the 7p adRP locus. PMID:8128965

  16. Bimodal expressivity in dominant retinitis pigmentosa genetically linked to chromosome 19q.

    PubMed Central

    Evans, K; al-Maghtheh, M; Fitzke, F W; Moore, A T; Jay, M; Inglehearn, C F; Arden, G B; Bird, A C

    1995-01-01

    A clinical, psychophysical, and electrophysiologic study was undertaken of two autosomal dominant retinitis pigmentosa pedigrees with a genetic mutation assigned to chromosome 19q by linkage analysis. Members with the abnormal haplotype were either symptomatic with adolescent onset nyctalopia, restricted visual fields, and non-detectable electroretinographic responses by 30 years of age, or asymptomatic with normal fundus appearance and minimal or no psychophysical or electroretinographic abnormalities. There was no correlation in the severity in parents and their offspring. Pedigree analysis suggested that although the offspring of parents with the genetic mutation were at 50% risk of having the genetic defect, the risk of being symptomatic during a working lifetime was only 31%. Such bimodal phenotypic expressivity in these particular pedigrees may be explained by a second, allelic genetic influence and may be a phenomenon unique to this genetic locus. Genetic counselling in families expressing this phenotype can only be based on haplotype analysis since clinical investigations, even in the most elderly, would not preclude the presence of the mutant gene. PMID:7488604

  17. Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa

    PubMed Central

    Züchner, Stephan; Dallman, Julia; Wen, Rong; Beecham, Gary; Naj, Adam; Farooq, Amjad; Kohli, Martin A.; Whitehead, Patrice L.; Hulme, William; Konidari, Ioanna; Edwards, Yvonne J.K.; Cai, Guiqing; Peter, Inga; Seo, David; Buxbaum, Joseph D.; Haines, Jonathan L.; Blanton, Susan; Young, Juan; Alfonso, Eduardo; Vance, Jeffery M.; Lam, Byron L.; Peričak-Vance, Margaret A.

    2011-01-01

    Increasingly, mutations in genes causing Mendelian disease will be supported by individual and small families only; however, exome sequencing studies have thus far focused on syndromic phenotypes characterized by low locus heterogeneity. In contrast, retinitis pigmentosa (RP) is caused by >50 known genes, which still explain only half of the clinical cases. In a single, one-generation, nonsyndromic RP family, we have identified a gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the power of combining whole-exome sequencing with rapid in vivo studies. DHDDS is a highly conserved essential enzyme for dolichol synthesis, permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin. The identified Lys42Glu variant likely arose from an ancestral founder, because eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. These findings demonstrate the power of exome sequencing linked to functional studies when faced with challenging study designs and, importantly, link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions. PMID:21295283

  18. Coping strategies to manage stress related to vision loss and fluctuations in retinitis pigmentosa

    PubMed Central

    Bittner, Ava K.; Edwards, Lori; George, Maureen

    2010-01-01

    Background Vision loss in retinitis pigmentosa (RP) is a slowly progressive and inexorable threat to patients’ independence. It is not surprising that RP patients, many of whom are young when diagnosed, are at high risk for stress related to their vision loss. To address these issues, eye care providers need to be aware of what coping strategies RP patients use to successfully manage their vision loss. Methods We held focus groups with eight legally blind RP patients to help us better understand how they cope with the stress that is generated from their progressive vision loss and fluctuations in vision. Focus group sessions were audiotaped and resulting notes were coded using conventional qualitative analytic techniques. Results Two themes were identified: 1) “kicking and screaming” captured the ways in which RP patients fight to maintain their independence in the face of worsening vision; and 2) “there are so many worse things” describes how RP patients keep their vision loss in perspective. These RP patients demonstrated high levels of resiliency. In particular, they often used humor as a coping mechanism. Conclusions Understanding the ways in which RP patients manage their gradual, impending vision loss may lead to improved quality of care for this patient population. PMID:20591747

  19. Fine localization of the locus for autosomal dominant retinitis pigmentosa on chromosome 17p

    SciTech Connect

    Goliath, R.; Janssens, P.; Beighton, P.

    1995-10-01

    The term {open_quotes}retintis pigmentosa{close_quotes} (RP) refers to a group of inherited retinal degenerative disorders. Clinical manifestations include night-blindness, with variable age of onset, followed by constriction of the visual field that may progress to total loss of sight in later life. Previous studies have shown that RP is caused by mutations within different genes and may be inherited as an X-linked recessive (XLRRP), autosomal recessive (ARRP), or autosomal dominant (ADRP) trait. The AD form of this group of conditions has been found to be caused by mutations within the rhodopsin gene in some families and the peripherin/RDS gene in others. In addition, some ADRP families have been found to be linked to anonymous markers on 8cen, 7p, 7q,19q, and, more recently, 17p. The ADRP gene locus on the short arm of chromosome 17 was identified in a large South African family (ADRP-SA) of British origin. The phenotypic expression of the disorder, which has been described elsewhere is consistent in the pedigree with an early onset of disease symptoms. In all affected subjects in the family, onset of symptoms commenced before the age of 10 years. 16 refs., 3 figs., 1 tab.

  20. Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice

    PubMed Central

    Venkatesh, Aditya; Ma, Shan; Le, Yun Z.; Hall, Michael N.; Rüegg, Markus A.; Punzo, Claudio

    2015-01-01

    Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP. PMID:25798619

  1. A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution

    PubMed Central

    Otto, Edgar; Hoefele, Julia; Ruf, Rainer; Mueller, Adelheid M.; Hiller, Karl S.; Wolf, Matthias T. F.; Schuermann, Maria J.; Becker, Achim; Birkenhäger, Ralf; Sudbrak, Ralf; Hennies, Hans C.; Nürnberg, Peter; Hildebrandt, Friedhelm

    2002-01-01

    Nephronophthisis (NPHP) comprises a group of autosomal recessive cystic kidney diseases, which constitute the most frequent genetic cause for end-stage renal failure in children and young adults. The most prominent histologic feature of NPHP consists of development of renal fibrosis, which, in chronic renal failure of any origin, represents the pathogenic event correlated most strongly to loss of renal function. Four gene loci for NPHP have been mapped to chromosomes 2q13 (NPHP1), 9q22 (NPHP2), 3q22 (NPHP3), and 1p36 (NPHP4). At all four loci, linkage has also been demonstrated in families with the association of NPHP and retinitis pigmentosa, known as “Senior-Løken syndrome” (SLS). Identification of the gene for NPHP type 1 had revealed nephrocystin as a novel docking protein, providing new insights into mechanisms of cell-cell and cell-matrix signaling. We here report identification of the gene (NPHP4) causing NPHP type 4, by use of high-resolution haplotype analysis and by demonstration of nine likely loss-of-function mutations in six affected families. NPHP4 encodes a novel protein, nephroretinin, that is conserved in evolution—for example, in the nematode Caenorhabditis elegans. In addition, we demonstrate two loss-of-function mutations of NPHP4 in patients from two families with SLS. Thus, we have identified a novel gene with critical roles in renal tissue architecture and ophthalmic function. PMID:12205563

  2. Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa?

    PubMed

    Campochiaro, Peter A; Strauss, Rupert W; Lu, Lili; Hafiz, Gulnar; Wolfson, Yulia; Shah, Syed M; Sophie, Raafay; Mir, Tahreem A; Scholl, Hendrik P

    2015-09-01

    Retinitis pigmentosa (RP) is a group of diseases in which a mutation in one of the large variety of genes causes death of rod photoreceptors. After rods die, cone photoreceptors gradually die resulting in constriction of visual fields and eventual blindness in many patients. Studies in animal models of RP have demonstrated that oxidative damage is a major contributor to cone cell death. In this study, we extended those findings to patients with RP, because compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione (GSH/GSSG) ratio in aqueous humor and a significant increase in aqueous protein carbonyl content. In contrast, there was no significant decrease in the serum GSH/GSSG ratio or increase in carbonyl content of serum proteins. These data indicate that patients with RP have ocular oxidative stress and damage in the absence of manifestations of systemic oxidative stress and/or damage indicating that demonstrations of oxidative damage-induced cone cell death in animal models of RP may translate to human RP. These observations lead to the hypothesis that potent antioxidants will promote cone survival and function in patients with RP and that the aqueous GSH/GSSG ratio and carbonyl content on proteins may provide useful biomarkers. Antioxid. Redox Signal. 23, 643-648. PMID:25820114

  3. Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa?

    PubMed Central

    Strauss, Rupert W.; Lu, Lili; Hafiz, Gulnar; Wolfson, Yulia; Shah, Syed M.; Sophie, Raafay; Mir, Tahreem A.; Scholl, Hendrik P.

    2015-01-01

    Abstract Retinitis pigmentosa (RP) is a group of diseases in which a mutation in one of the large variety of genes causes death of rod photoreceptors. After rods die, cone photoreceptors gradually die resulting in constriction of visual fields and eventual blindness in many patients. Studies in animal models of RP have demonstrated that oxidative damage is a major contributor to cone cell death. In this study, we extended those findings to patients with RP, because compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione (GSH/GSSG) ratio in aqueous humor and a significant increase in aqueous protein carbonyl content. In contrast, there was no significant decrease in the serum GSH/GSSG ratio or increase in carbonyl content of serum proteins. These data indicate that patients with RP have ocular oxidative stress and damage in the absence of manifestations of systemic oxidative stress and/or damage indicating that demonstrations of oxidative damage-induced cone cell death in animal models of RP may translate to human RP. These observations lead to the hypothesis that potent antioxidants will promote cone survival and function in patients with RP and that the aqueous GSH/GSSG ratio and carbonyl content on proteins may provide useful biomarkers. Antioxid. Redox Signal. 23, 643–648. PMID:25820114

  4. [Role of Heat Shock Protein 70 in Retinitis Pigmentosa and a Novel Strategy for Treatment].

    PubMed

    Koriyama, Yoshiki; Furukawa, Ayako

    2015-12-01

    Retinitis pigmentosa (RP) is a group of inherited disorders involving the photoreceptors of the retina and can lead to visual loss. There has been tremendous progress in the delineation of the biochemical and molecular basis of RP. Reactive oxygen species, calcium-calpain activation, and lipid peroxidation are known to be involved in the initiation of photoreceptor cell death, but the precise mechanisms of this process remain unknown. Heat shock protein 70 (HSP70) has been shown to function as a chaperone molecule that protects cells against environmental and physiological stresses. However, there are a few reports showing the role of HSP70 in photoreceptor cell death. Recently, we found that the production of 4-hydroxy-2-noneral caused the calpain-dependent cleavage of carbonylated HSP70 prior to photoreceptor cell death in RP model mice. Furthermore, HSP70 inducers, such as valproic acid and geranylgeranylacetone attenuated photoreceptor cell death. HSP70 inducers may be considered as candidate therapeutic agents for RP. PMID:26618767

  5. Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa*

    PubMed Central

    Imanishi, Yoshikazu; Zhu, Li; Filipek, Sławomir; Palczewski, Krzysztof; Kaushal, Shalesh

    2006-01-01

    Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration. PMID:12566452

  6. Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations

    PubMed Central

    Banin, Eyal

    2015-01-01

    Purpose Nonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal degeneration, and prevalence of the disease has been reported in populations of American and European origin with a relatively low consanguinity rate. Our aim was to determine the prevalence of nonsyndromic RP in the Jerusalem region, which has a population of about 1 million individuals with a high rate of consanguinity. Methods The patients’ clinical data included eye exam findings (visual acuity, anterior segment, and funduscopy) as well as electroretinographic (ERG) testing results under scotopic and photopic conditions. Mutation analysis on a subgroup of patients was performed mainly with candidate gene analysis and homozygosity mapping. Results We evaluated the medical records of patients with degenerative retinal diseases residing in the Jerusalem region who were examined over the past 20 years in a large tertiary medical center. A total of 453 individuals affected with nonsyndromic RP were diagnosed at our center, according to funduscopic findings and ERG testing. Based on the estimated population size of 945,000 individuals who reside in the vicinity of Jerusalem, the prevalence of nonsyndromic RP in this region is 1:2,086. The prevalence of RP was higher among Arab Muslims (1:1,798) compared to Jews (1:2,230), mainly due to consanguineous marriages that are more common in the Arab Muslim population. To identify the genetic causes of RP in our cohort, we recruited 383 patients from 183 different families for genetic analysis: 70 with autosomal recessive (AR) inheritance, 15 with autosomal dominant, 86 isolate cases, and 12 with an X-linked inheritance pattern. In 64 (35%) of the families, we identified the genetic cause of the disease, and we revised the inheritance pattern of 20 isolate cases to the AR pattern; 49% of the families in our cohort had AR inheritance. Interestingly, in 42 (66%) of the genetically identified families, the cause of disease was a founder

  7. Whole-exome Sequencing Analysis Identifies Mutations in the EYS Gene in Retinitis Pigmentosa in the Indian Population.

    PubMed

    Di, Yanan; Huang, Lulin; Sundaresan, Periasamy; Li, Shujin; Kim, Ramasamy; Ballav Saikia, Bibhuti; Qu, Chao; Zhu, Xiong; Zhou, Yu; Jiang, Zhilin; Zhang, Lin; Lin, Ying; Zhang, Dingding; Li, Yuanfen; Zhang, Houbin; Yin, Yibing; Lu, Fang; Zhu, Xianjun; Yang, Zhenglin

    2016-01-01

    Retinitis pigmentosa (RP) is a rare heterogeneous genetic retinal dystrophy disease, and despite years of research, known genetic mutations can explain only approximately 60% of RP cases. We sought to identify the underlying genetic mutations in a cohort of fourteen Indian autosomal recessive retinitis pigmentosa (arRP) families and 100 Indian sporadic RP cases. Whole-exome sequencing (WES) was performed on the probands of the arRP families and sporadic RP patients, and direct Sanger sequencing was used to confirm the causal mutations identified by WES. We found that the mutations of EYS are likely pathogenic mutations in two arRP families and eight sporadic patients. Specifically, we found a novel pair of compound heterozygous mutations and a novel homozygous mutation in two separate arRP families, and found two novel heterozygous mutations in two sporadic RP patients, whereas we found six novel homozygous mutations in six sporadic RP patients. Of these, one was a frameshift mutation, two were stop-gain mutations, one was a splicing mutation, and the others were missense mutations. In conclusion, our findings expand the spectrum of EYS mutations in RP in the Indian population and provide further support for the role of EYS in the pathogenesis and clinical diagnosis of RP. PMID:26787102

  8. Whole-exome Sequencing Analysis Identifies Mutations in the EYS Gene in Retinitis Pigmentosa in the Indian Population

    PubMed Central

    Di, Yanan; Huang, Lulin; Sundaresan, Periasamy; Li, Shujin; Kim, Ramasamy; Ballav Saikia, Bibhuti; Qu, Chao; Zhu, Xiong; Zhou, Yu; Jiang, Zhilin; Zhang, Lin; Lin, Ying; Zhang, Dingding; Li, Yuanfen; Zhang, Houbin; Yin, Yibing; Lu, Fang; Zhu, Xianjun; Yang, Zhenglin

    2016-01-01

    Retinitis pigmentosa (RP) is a rare heterogeneous genetic retinal dystrophy disease, and despite years of research, known genetic mutations can explain only approximately 60% of RP cases. We sought to identify the underlying genetic mutations in a cohort of fourteen Indian autosomal recessive retinitis pigmentosa (arRP) families and 100 Indian sporadic RP cases. Whole-exome sequencing (WES) was performed on the probands of the arRP families and sporadic RP patients, and direct Sanger sequencing was used to confirm the causal mutations identified by WES. We found that the mutations of EYS are likely pathogenic mutations in two arRP families and eight sporadic patients. Specifically, we found a novel pair of compound heterozygous mutations and a novel homozygous mutation in two separate arRP families, and found two novel heterozygous mutations in two sporadic RP patients, whereas we found six novel homozygous mutations in six sporadic RP patients. Of these, one was a frameshift mutation, two were stop-gain mutations, one was a splicing mutation, and the others were missense mutations. In conclusion, our findings expand the spectrum of EYS mutations in RP in the Indian population and provide further support for the role of EYS in the pathogenesis and clinical diagnosis of RP. PMID:26787102

  9. Identification of recurrent and novel mutations in TULP1 in Pakistani families with early-onset retinitis pigmentosa

    PubMed Central

    Ajmal, Muhammad; Khan, Muhammad Imran; Micheal, Shazia; Ahmed, Waqas; Shah, Ashfa; Venselaar, Hanka; Bokhari, Habib; Azam, Aisha; Waheed, Nadia Khalida; Collin, Rob W.J.; den Hollander, Anneke I.; Qamar, Raheel

    2012-01-01

    Purpose To identify the genetic defects underlying retinitis pigmentosa (RP) in Pakistani families. Methods Genome-wide high-density single-nucleotide-polymorphism microarray analysis was performed using the DNA of nine affected individuals from two large families with multiple consanguineous marriages. Data were analyzed to identify homozygous regions that are shared by affected sibs in each family. Sanger sequencing was performed for genes previously implicated in autosomal recessive RP and allied retinal dystrophies that resided in the identified homozygous regions. Probands from both families underwent fundus examination and electroretinogram measurements. Results The tubby-like protein 1 gene (TULP1) was present in the largest homozygous region in both families. Sequence analysis identified a previously reported mutation (c.1138A>G; p.Thr380Ala) in one family and a novel pathogenic variant (c.1445G>A; p.Arg482Gln) in the other family. Both variants were found to be present in a homozygous state in all affected individuals, were heterozygous present in the unaffected parents, and heterozygous present or absent in normal individuals. Affected individuals of both families showed an early-onset form of RP. Conclusions Homozygosity mapping, combined with candidate-gene analysis, successfully identified genetic defects in TULP1 in two large Pakistani families with early-onset retinitis pigmentosa. PMID:22665969

  10. Autosomal dominant retinitis pigmentosa: No evidence for nonallelic genetic heterogeneity on 3q

    SciTech Connect

    Kumar-Singh, R.; He Wang; Humphries, P.; Farrar, G.J. )

    1993-02-01

    Since the initial report of linkage of autosomal dominant retinitis pigmentosa (adRP) to the long arm of chromosome 3, several mutations in the gene encoding rhodopsin, which also maps to 3q, have been reported in adRP pedigrees. However, there has been some discussion as to the possibility of a second adRP locus on 3q. This suggestion has important diagnostic and research implications and must raise doubts about the usefulness of linked markers for reliable diagnosis of RP patients. In order to address this issue the authors have performed an admixture test (A-test) on 10 D3S47-linked adRP pedigrees and have found a likelihood ratio of heterogeneity versus homogeneity of 4.90. They performed a second A-test, combining the data from all families with known rhodopsin mutations. In this test they obtained a reduced likelihood ratio of heterogeneity versus homogeneity, of 1.0. On the basis of these statistical analyses they have found no significant support for two adRP loci on chromosome 3q. Furthermore, using 40 CEPH families, they have localized the rhodopsin gene to the D3S47-D3S20 interval, with a maximum lod score (Z[sub m]) of 20 and have found that the order qter-D3S47-rhodopsin-D3S20-cen is significantly more likely than any other order. In addition, they have mapped (Z[sub m] = 30) the microsatellite marker D3S621 relative to other loci in this region of the genome. 27 refs., 3 figs., 3 tabs.

  11. Molecular genetics of X-linked retinitis pigmentosa: Progress towards cloning the RP3 gene

    SciTech Connect

    Fujita, R.; Yan, D.; McHenry, C.

    1994-09-01

    Our goal is to identify the X-linked retinitis pigmentosa (XLRP) gene RP3. The location of RP3 is genetically delimited to a region of 1 Mb, distal to DXS140, CYBB and tctex-1-like gene and proximal to the gene OTC. It is currently thought that RP3 is within 40 kb of the proximal deletion breakpoint of a patient BB. However, a more proximal location of the gene, closer to OTC, is not ruled out. We initiated the isolation of the genomic region between DXS140 to OTC in YACs. One of the clones from DXS140 region (55B) is 460 kb and spans about 200 kb at each side of BB patient`s proximal breakpoint. It contains CYBB, tctex-1-like genes and two additional CpG islands. The 55B clone has been covered by cosmid and phage subclones. Another YAC clone from the OTC region (OTCC) spans about 1 Mb and contains at least 5 CpG islands. In situ hybridization performed with OTCC showed its location in Xp21; however, several derivative cosmids map to chromosome 7, indicating that it is a chimeric YAC. No overlap is evident between 55B and OTCC. We have isolated the YAC end-sequences and isolation of clones to close the gap is in progress. Cosmids are being used for screening eye tissue cDNA libraries, mainly from retina. Screening is done by hybridization to replica filters or by cDNA enrichment methods. Several cDNA clones have been isolated and are being characterized. Exon-amplification is also being used with the cosmids and phages. Genetic analysis is being performed to determine RP3 patients from clinically indistinguishable RP2, located in Xp11.23-p11.4, and to reduce the genetic distance of current flanking markers. For this we are analyzing a number of XLRP families with established markers in the region and with new microsatellites.

  12. Evidence against a second autosomal dominant retinitis pigmentosa locus close to rhodopsin on chromosome 3q

    SciTech Connect

    Inglehearn, C.; Bhattacharya, S. ); Farrar, J.; Humphries, P. ); Denton, M. ); Gal, A. )

    1993-08-01

    In 1989 McWilliam et al. reported close linkage of the autosomal dominant retinitis pigmentosa (adRP) locus to chromosome 3q marker D3S47 in a large Irish pedigree (McWilliam et al 1989). Subsequent studies confirmed linkage in two other adRP families (Lester et al 1990; Olsson et al. 1990). Shortly afterward, utations in the rhodopsin (RHO) gene, mapping to 3q21-24, were implicated in disease causation, and it is now known that around one-third of adRP results from such mutations (Dryja et al. 1991; Sung et al. 1991; Inglchearn et al. 1992a). At that time, sequencing studies had failed to find rhodopsin mutations in the three families first linked to 3q. Several adRP families in which rhodopsin mutations had been found gave lod scores that, when pooled, had a peak of 4.47 at a theta of .12 (Inglehearn et al. 1992b). The apparent lack of mutations in families TCDM1, adRP3, and 20 together with the linkage data in these and the proved RHO-RP families, led to speculation that two adRP loci existed on chromosome 3q (Olsson et al. 1990; Inglehearn et al. 1992b). However this situation has been reversed by more recent analysis, since rhodopsin mutations have now been found in all three families. There is therefore no longer any evidence to support the hypothesis that a second adRP locus exists close to rhodopsin on chromosome 3q.

  13. Efficacy of valproic acid for retinitis pigmentosa patients: a pilot study

    PubMed Central

    Iraha, Satoshi; Hirami, Yasuhiko; Ota, Sachiko; Sunagawa, Genshiro A; Mandai, Michiko; Tanihara, Hidenobu; Takahashi, Masayo; Kurimoto, Yasuo

    2016-01-01

    Purpose The purpose of this study was to examine the efficacy and safety of valproic acid (VPA) use in patients with retinitis pigmentosa (RP). Patients and methods This was a prospective, interventional, noncomparative case study. In total, 29 eyes from 29 patients with RP whose best-corrected visual acuities (BCVAs) in logarithm of the minimum angle of resolution (logMAR) ranged from 1.0 to 0.16 with visual fields (VFs) of ≤10° (measured using Goldmann perimeter with I4) were recruited. The patients received oral supplementation with 400 mg of VPA daily for 6 months and were followed for an additional 6 months. BCVAs, VFs (measured with the Humphrey field analyzer central 10-2 program), and subjective questionnaires were examined before, during, and after the cessation of VPA supplementation. Results The changes in BCVA and VF showed statistically significant differences during the internal use of VPA, compared with after cessation (P=0.001). With VPA intake, BCVA in logMAR significantly improved from baseline to 6 months (P=0.006). The mean deviation value of the VF significantly improved from baseline to 1 month (P=0.001), 3 months (P=0.004), and 6 months (P=0.004). These efficacies, however, were reversed to the baseline levels after the cessation of VPA intake. There were no significant relations between the mean blood VPA concentrations of each patient and the changes in BCVA and VF. During the internal use of VPA, 15 of 29 patients answered “easier to see”, whereas blurred vision was registered in 21 of 29 patients on cessation. No systemic drug-related adverse events were observed. Conclusion While in use, oral intake of VPA indicated a short-term benefit to patients with RP. It is necessary to examine the effect of a longer VPA supplementation in a controlled study design. PMID:27536054

  14. The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice

    PubMed Central

    van Huet, Ramon A. C.; Pierrache, Laurence H.M.; Meester-Smoor, Magda A.; Klaver, Caroline C.W.; van den Born, L. Ingeborgh; Hoyng, Carel B.; de Wijs, Ilse J.; Collin, Rob W. J.; Hoefsloot, Lies H.

    2015-01-01

    Purpose To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). Methods We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon–intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort. Results The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1). Conclusions The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis. PMID:25999674

  15. Retinitis Pigmentosa Mutations in Bad Response to Refrigeration 2 (Brr2) Impair ATPase and Helicase Activity.

    PubMed

    Ledoux, Sarah; Guthrie, Christine

    2016-06-01

    Brr2 is an RNA-dependent ATPase required to unwind the U4/U6 snRNA duplex during spliceosome assembly. Mutations within the ratchet helix of the Brr2 RNA binding channel result in a form of degenerative human blindness known as retinitis pigmentosa (RP). The biochemical consequences of these mutations on Brr2's RNA binding, helicase, and ATPase activity have not yet been characterized. Therefore, we identified the largest construct of Brr2 that is soluble in vitro, which truncates the first 247 amino acids of the N terminus (Δ247-Brr2), to characterize the effects of the RP mutations on Brr2 activity. The Δ247-Brr2 RP mutants exhibit a gradient of severity of weakened RNA binding, reduced helicase activity, and reduced ATPase activity compared with wild type Δ247-Brr2. The globular C-terminal Jab1/Mpn1-like domain of Prp8 increases the ability of Δ247-Brr2 to bind the U4/U6 snRNA duplex at high pH and increases Δ247-Brr2's RNA-dependent ATPase activity and the extent of RNA unwinding. However, this domain of Prp8 does not differentially affect the Δ247-Brr2 RP mutants compared with the wild type Δ247-Brr2. When stimulated by Prp8, wild type Δ247-Brr2 is able to unwind long stable duplexes in vitro, and even the RP mutants capable of binding RNA with tight affinity are incapable of fully unwinding short duplex RNAs. Our data suggest that the RP mutations within the ratchet helix impair Brr2 translocation through RNA helices. PMID:27072132

  16. Autosomal Recessive Retinitis Pigmentosa with Early Macular Affectation Caused by Premature Truncation in PROM1

    PubMed Central

    Permanyer, Jon; Navarro, Rafael; Friedman, James; Pomares, Esther; Castro-Navarro, Joaquín; Marfany, Gemma; Swaroop, Anand

    2010-01-01

    Purpose. To identify the genetic basis of a large consanguineous Spanish pedigree affected with autosomal recessive retinitis pigmentosa (arRP) with premature macular atrophy and myopia. Methods. After a high-throughput cosegregation gene chip was used to exclude all known RP and Leber congenital amaurosis (LCA) candidates, genome-wide screening and linkage analysis were performed. Direct mutational screening identified the pathogenic mutation, and primers were designed to obtain the RT-PCR products for isoform characterization. Results. Mutational analysis detected a novel homozygous PROM1 mutation, c.869delG in exon 8 cosegregating with the disease. This variant causes a frameshift that introduces a premature stop codon, producing truncation of approximately two-thirds of the protein. Analysis of PROM1 expression in the lymphocytes of patients, carriers, and control subjects revealed an aberrant transcript that is degraded by the nonsense-mediated decay pathway, suggesting that the disease is caused by the absence of the PROM1 protein. Three (s2, s11 and s12) of the seven alternatively spliced isoforms reported in humans, accounted for 98% of the transcripts in the retina. Given that these three contained exon 8, no PROM1 isoform is expected in the affected retinas. Conclusions. A remarkable clinical finding in the affected family is early macular atrophy with concentric spared areas. The authors propose that the hallmark of PROM1 truncating mutations is early and severe progressive degeneration of both rods and cones and highlight this gene as a candidate of choice to prioritize in the molecular genetic study of patients with noncanonical clinical peripheral and macular affectation. PMID:20042663

  17. Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa

    PubMed Central

    Ramachandran, Rithambara; X. Cai, Cindy; Lee, Dongwon; C. Epstein, Benjamin; Locke, Kirsten G.; G. Birch, David; C. Hood, Donald

    2016-01-01

    Purpose We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). Methods A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. Results Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 μm) was close to 0 μm, and the 95% limits were between −284 and 323 μm, approximately ±1.1°. Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 μm, approximately 1.2°, for both test times. Conclusions While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. Translational Relevance For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under ±2.0°, are considerably smaller than the 6° spacing for the typically used static visual field. PMID:27226930

  18. Autosomal dominant retinitis pigmentosa: no evidence for nonallelic genetic heterogeneity on 3q.

    PubMed Central

    Kumar-Singh, R; Wang, H; Humphries, P; Farrar, G J

    1993-01-01

    Since the initial report of linkage of autosomal dominant retinitis pigmentosa (adRP) to the long arm of chromosome 3, several mutations in the gene encoding rhodopsin, which also maps to 3q, have been reported in adRP pedigrees. However, there has been some discussion as to the possibility of a second adRP locus on 3q. This suggestion has important diagnostic and research implications and must raise doubts about the usefulness of linked markers for reliable diagnosis of RP patients. In order to address this issue we have performed an admixture test (A-test) on 10 D3S47-linked adRP pedigrees and have found a likelihood ratio of heterogeneity versus homogeneity of 4.90. We performed a second A-test, combining the data from all families with known rhodopsin mutations. In this test we obtained a reduced likelihood ratio of heterogeneity versus homogeneity, of 1.0. On the basis of these statistical analyses we have found no significant support for two adRP loci on chromosome 3q. Furthermore, using 40 CEPH families, we have localized the rhodopsin gene to the D3S47-D3S20 interval, with a maximum lod score (Zm) of 20 and have found that the order qter-D3S47-rhodopsin-D3S20-cen is significantly more likely than any other order. In addition, we have mapped (Zm = 30) the microsatellite marker D3S621 relative to other loci in this region of the genome. PMID:8430695

  19. Prevalence of Mutations in eyeGENE Probands With a Diagnosis of Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Sullivan, Lori S.; Bowne, Sara J.; Reeves, Melissa J.; Blain, Delphine; Goetz, Kerry; NDifor, Vida; Vitez, Sally; Wang, Xinjing; Tumminia, Santa J.; Daiger, Stephen P.

    2013-01-01

    Purpose. To screen samples from patients with presumed autosomal dominant retinitis pigmentosa (adRP) for mutations in 12 disease genes as a contribution to the research and treatment goals of the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE). Methods. DNA samples were obtained from eyeGENE. A total of 170 probands with an intake diagnosis of adRP were tested through enrollment in eyeGENE. The 10 most common genes causing adRP (IMPDH1, KLHL7, NR2E3, PRPF3/RP18, PRPF31/RP11, PRPF8/RP13, PRPH2/RDS, RHO, RP1, and TOPORS) were chosen for PCR-based dideoxy sequencing, along with the two X-linked RP genes, RPGR and RP2. RHO, PRPH2, PRPF31, RPGR, and RP2 were completely sequenced, while only mutation hotspots in the other genes were analyzed. Results. Disease-causing mutations were identified in 52% of the probands. The frequencies of disease-causing mutations in the 12 genes were consistent with previous studies. Conclusions. The Laboratory for Molecular Diagnosis of Inherited Eye Disease at the University of Texas in Houston has thus far received DNA samples from 170 families with a diagnosis of adRP from the eyeGENE Network. Disease-causing mutations in autosomal genes were identified in 48% (81/170) of these families while mutations in X-linked genes accounted for an additional 4% (7/170). Of the 55 distinct mutations detected, 19 (33%) have not been previously reported. All diagnostic results were returned by eyeGENE to participating patients via their referring clinician. These genotyped samples along with their corresponding phenotypic information are also available to researchers who may request access to them for further study of these ophthalmic disorders. (ClinicalTrials.gov number, NCT00378742.) PMID:23950152

  20. Response to Drs. Shastry and Trese: Phenotype-genotype correlations in X-linked retinitis pigmentosa

    SciTech Connect

    Kaplan, J.; Munnich, A.

    1996-11-11

    Shastry and Trese recently reported on a large kindred with X-linked retinitis pigmentosa (XLRP) characterized by a loss of central vision and preserved peripheral function. In their report, the disease had an early onset with severe myopia and a loss of central vision, while night blindness occurred later. Genetic analysis suggested that the disease was linked to the RP2 locus, and the authors raised the question of whether other cases linked to RP2 could display a similar loss of central vision. Three years ago, we reported on 4 large XLRP pedigrees with a very early onset with severe myopia and early loss of visual acuity, while in 5 other families the disease started later with night blindness. We showed that the first clinical form was linked to RP2, while the second was linked to RP3. Thus, the major difference between the two forms concerns the initial symptom, information which can be obtained from the parents and patients after careful questioning. By contrast, in adult life, no difference in either severity of disease or aspect of the fundus was observed in our series, regardless of the clinical subtype of XLRP. Some months later, Jacobson et al. reported on a pedigree with an RP2 genotype, and their data support the notion that in XLRP of RP2 type 1, cone dysfunction takes place first, and as the disease advances both rods and cones are affected. We were very happy, therefore, to read that the study of Shastry and Trese fully confirmed our previous findings. 3 refs.

  1. Prp8 retinitis pigmentosa mutants cause defects in the transition between the catalytic steps of splicing.

    PubMed

    Mayerle, Megan; Guthrie, Christine

    2016-05-01

    Pre-mRNA splicing must occur with high fidelity and efficiency for proper gene expression. The spliceosome uses DExD/H box helicases to promote on-pathway interactions while simultaneously minimizing errors. Prp8 and Snu114, an EF2-like GTPase, regulate the activity of the Brr2 helicase, promoting RNA unwinding by Brr2 at appropriate points in the splicing cycle and repressing it at others. Mutations linked to retinitis pigmentosa (RP), a disease that causes blindness in humans, map to the Brr2 regulatory region of Prp8. Previous in vitro studies of homologous mutations inSaccharomyces cerevisiaeshow that Prp8-RP mutants cause defects in spliceosome activation. Here we show that a subset of RP mutations in Prp8 also causes defects in the transition between the first and second catalytic steps of splicing. Though Prp8-RP mutants do not cause defects in splicing fidelity, they result in an overall decrease in splicing efficiency. Furthermore, genetic analyses link Snu114 GTP/GDP occupancy to Prp8-dependent regulation of Brr2. Our results implicate the transition between the first and second catalytic steps as a critical place in the splicing cycle where Prp8-RP mutants influence splicing efficiency. The location of the Prp8-RP mutants, at the "hinge" that links the Prp8 Jab1-MPN regulatory "tail" to the globular portion of the domain, suggests that these Prp8-RP mutants inhibit regulated movement of the Prp8 Jab1/MPN domain into the Brr2 RNA binding channel to transiently inhibit Brr2. Therefore, in Prp8-linked RP, disease likely results not only from defects in spliceosome assembly and activation, but also because of defects in splicing catalysis. PMID:26968627

  2. Efficacy of Column Scatter Plots for Presenting Retinitis Pigmentosa Phenotypes in a Japanese Cohort

    PubMed Central

    Ogino, Ken; Oishi, Akio; Oishi, Maho; Gotoh, Norimoto; Morooka, Satoshi; Sugahara, Masako; Hasegawa, Tomoko; Miyata, Manabu; Yoshimura, Nagahisa

    2016-01-01

    Purpose We evaluated the efficacy of column scatter plots to describe genotype–phenotype correlations in a Japanese cohort with retinitis pigmentosa (RP). Methods Clinical records of 121 patients with RP with identified causative mutations were reviewed. Visual acuity, central and peripheral visual fields, electroretinography (ERG), lens status, and measurements of optical coherence tomography were evaluated according to causative genes using column scatter plots. Values for three common genes (EYS, USH2A, and RHO) were compared statistically. Results All patients with PDE6B, PRPH2, and RPGR mutations, those 55 years old or younger with RP1L1 and USH2A mutations, and those 45 years old or younger with EYS and RHO mutations retained visual acuity of at least 0.1. All patients with RPGR mutations showed at least −20 dB mean deviation. Goldmann perimeter measures of 4/6 patients with RHO mutations showed remaining peripheral visual fields. Dark-adapted 0.01 and 3.0 ERGs were extinguished for most genes. Half of the patients with RHO RP maintained cone responses in light-adapted 3.0 and 3.0 flicker ERG. All patients with PRPH2, those 55 years old or younger with USH2A and RP1L1, and those 45 years old or younger with PDE6B and EYS mutations maintained subfoveal ellipsoid zones. No differences were identified between EYS and USH2A or RHO and USH2A. Conclusions Column scatter plots enabled comparisons of the associated severities and illustration of the ophthalmological measurements for every RP causative gene. Translational Relevance Analysis of mutations in specific genes may be helpful for determining visual prognoses in the clinical setting. PMID:26966640

  3. Nonsense mutation in MERTK causes autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family

    PubMed Central

    Shahzadi, Amber; Riazuddin, S Amer; Ali, Shahbaz; Li, David; Khan, Shaheen N; Husnain, Tayyab; Akram, Javed; Sieving, Paul A; Hejtmancik, J Fielding; Riazuddin, Sheikh

    2012-01-01

    Background Retinitis pigmentosa (RP) is one of the most common ophthalmic disorders affecting one in approximately 5000 people worldwide. A nuclear family was recruited from the Punjab province of Pakistan to study the genetic basis of autosomal recessive RP. Methods All affected individuals underwent a thorough ophthalmic examination and the disease was characterised based upon results for fundus photographs and electroretinogram recordings. Genomic DNA was extracted from peripheral leucocytes. Exclusion studies were performed with short tandem repeat (STR) markers flanking reported autosomal recessive RP loci. Haplotypes were constructed and results were statistically evaluated. Results The results of exclusion analyses suggested that family PKRP173 was linked to chromosome 2q harbouring mer tyrosine kinase protooncogene (MERTK), a gene previously associated with autosomal recessive RP. Additional STR markers refined the critical interval and placed it in a 13.4 cM (17 Mb) region flanked by D2S293 proximally and D2S347 distally. Significant logarithm of odds (LOD) scores of 3.2, 3.25 and 3.18 at θ=0 were obtained with markers D2S1896, D2S2269 and D2S160. Sequencing of the coding exons of MERTK identified a mutation, c.718G→T in exon 4, which results in a premature termination of p.E240X that segregates with the disease phenotype in the family. Conclusion Our results strongly suggest that the nonsense mutation in MERTK, leading to premature termination of the protein, is responsible for RP phenotype in the affected individuals of the Pakistani family. PMID:20538656

  4. Efficient In Silico Identification of a Common Insertion in the MAK Gene which Causes Retinitis Pigmentosa

    PubMed Central

    Bujakowska, Kinga M.; White, Joseph; Place, Emily; Consugar, Mark; Comander, Jason

    2015-01-01

    Background Next generation sequencing (NGS) offers a rapid and comprehensive method of screening for mutations associated with retinitis pigmentosa and related disorders. However, certain sequence alterations such as large insertions or deletions may remain undetected using standard NGS pipelines. One such mutation is a recently-identified Alu insertion into the Male Germ Cell-Associated Kinase (MAK) gene, which is missed by standard NGS-based variant callers. Here, we developed an in silico method of searching NGS raw sequence reads to detect this mutation, without the need to recalculate sequence alignments or to screen every sample by PCR. Methods The Linux program grep was used to search for a 23 bp “probe” sequence containing the known junction sequence of the insert. A corresponding search was performed with the wildtype sequence. The matching reads were counted and further compared to the known sequences of the full wildtype and mutant genomic loci. (See https://github.com/MEEIBioinformaticsCenter/grepsearch.) Results In a test sample set consisting of eleven previously published homozygous mutants, detection of the MAK-Alu insertion was validated with 100% sensitivity and specificity. As a discovery cohort, raw NGS reads from 1,847 samples (including custom and whole exome selective capture) were searched in ~1 hour on a local computer cluster, yielding an additional five samples with MAK-Alu insertions and solving two previously unsolved pedigrees. Of these, one patient was homozygous for the insertion, one compound heterozygous with a missense change on the other allele (c. 46G>A; p.Gly16Arg), and three were heterozygous carriers. Conclusions Using the MAK-Alu grep program proved to be a rapid and effective method of finding a known, disease-causing Alu insertion in a large cohort of patients with NGS data. This simple approach avoids wet-lab assays or computationally expensive algorithms, and could also be used for other known disease

  5. Mutation Independent Rescue of a Novel Mouse Model of Retinitis Pigmentosa

    PubMed Central

    Greenwald, David L.; Cashman, Siobhan M.; Kumar-Singh, Rajendra

    2014-01-01

    Retinitis pigmentosa (RP) is the leading cause of inherited blindness in the developed world, affecting approximately 1 in 3,000 individuals. While there is currently no cure for RP, the genetic pathology has been well established. In this study we developed a novel mouse model of RP (huRhoP347S) expressing a pathogenic human rhodopsin gene with a Pro347Ser mutation on a rhodopsin knockout background. These mice undergo severe retinal degeneration at one month of age. In contrast to prior studies, this model was administered a gene therapy treatment at 19 days post natal. We evaluated several self-complementary adeno-associated virus serotypes for photoreceptor tropism including scAAV2/2, scAAV2/5, scAAV2/6.2 and scAAV2/9, and found that scAAV2/9 transduced photoreceptors with greater efficiency and expression than other vectors. We engineered a scAAV2/9 vector to contain a microRNA sequence specifically targeting the human rhodopsin gene and demonstrated its ability to silence rhodopsin by 60.2 ± 8.2% in vitro. In addition, we constructed a scAAV2/9 vector to contain a replacement “codon-modified” rhodopsin transgene (RhoR2) that was resistant to degradation by the microRNA. We found that delivery of the RhoR2 by scAAV2/9 is capable of restoring vision to rhodopsin knockout mice, and rescuing our novel transgenic huRhoP347S mouse model of dominant RP. Average a-wave responses of RhoR2-injected eyes were 1.8-fold higher than those of control-injected eyes. We found that delivery of the microRNA and replacement rhodopsin in a 1:2 ratio produced an average ERG a-wave response of 17.4 ± 2.9 μV compared to 6.5 ± 2.8 μV for eyes injected with negative control virus. PMID:22809998

  6. Molecular Genetics of FAM161A in North American Patients with Early-Onset Retinitis Pigmentosa

    PubMed Central

    Harper, Shyana; Weigel-DiFranco, Carol

    2014-01-01

    Retinitis pigmentosa (RP) is a hereditary disease that leads to the progressive degeneration of retinal photoreceptor cells and to blindness. It is caused by mutations in several distinct genes, including the ciliary gene FAM161A, which is associated with a recessive form of this disorder. Recent investigations have revealed that defects in FAM161A represent a rather prevalent cause of hereditary blindness in Israel and the Palestinian territories, whereas they seem to be rarely present within patients from Germany. Genetic or clinical data are currently not available for other countries. In this work, we screened a cohort of patients with recessive RP from North America to determine the frequency of FAM161A mutations in this ethnically-mixed population and to assess the phenotype of positive cases. Out of 273 unrelated patients, only 3 subjects had defects in FAM161A. A fourth positive patient, the sister of one of these index cases, was also identified following pedigree analysis. They were all homozygous for the p.T452Sfx3 mutation, which was previously reported as a founder DNA variant in the Israeli and Palestinian populations. Analysis of cultured lymphoblasts from patients revealed that mutant FAM161A transcripts were actively degraded by nonsense-mediated mRNA decay. Electroretinographic testing showed 30 Hz cone flicker responses in the range of 0.10 to 0.60 microvolts in all cases at their first visit (age 12 to 23) (lower norm  =  50 μV) and of 0.06 to 0.32 microvolts at their most recent examination (age 27 to 43), revealing an early-onset of this progressive disease. Our data indicate that mutations in FAM161A are responsible for 1% of recessive RP cases in North America, similar to the prevalence detected in Germany and unlike the data from Israel and the Palestinian territories. We also show that, at the molecular level, the disease is likely caused by FAM161A protein deficiency. PMID:24651477

  7. A Pro23His Mutation Alters Prenatal Rod Photoreceptor Morphology in a Transgenic Swine Model of Retinitis Pigmentosa

    PubMed Central

    Scott, Patrick A.; Fernandez de Castro, Juan P.; Kaplan, Henry J.; McCall, Maureen A.

    2014-01-01

    Purpose. Functional studies have detected deficits in retinal signaling in asymptomatic children from families with inherited autosomal dominant retinitis pigmentosa (RP). Whether retinal abnormalities are present earlier during gestation or shortly after birth in a subset of children with autosomal dominant RP is unknown and no appropriate animal RP model possessing visual function at birth has been available to examine this possibility. In a recently developed transgenic P23H (TgP23H) rhodopsin swine model of RP, we tracked changes in pre- and early postnatal retinal morphology, as well as early postnatal retinal function. Methods. Domestic swine inseminated with semen from a TgP23H miniswine founder produced TgP23H hybrid and wild type (Wt) littermates. Outer retinal morphology was assessed at light and electron microscopic levels between embryonic (E) and postnatal (P) day E85 to P3. Retinal function was evaluated using the full field electroretinogram at P3. Results. Embryonic TgP23H rod photoreceptors are malformed and their rhodopsin expression pattern is abnormal. Consistent with morphological abnormalities, rod-driven function is absent at P3. In contrast, TgP23H and Wt cone photoreceptor morphology (E85–P3) and cone-driven retinal function (P3) are similar. Conclusions. Prenatal expression of mutant rhodopsin alters the normal morphological and functional development of rod photoreceptors in TgP23H swine embryos. Despite this significant change, cone photoreceptors are unaffected. Human infants with similarly aggressive RP might never have rod vision, although cone vision would be unaffected. Such aggressive forms of RP in preverbal children would require early intervention to delay or prevent functional blindness. PMID:24618321

  8. Silencing of Tuberin Enhances Photoreceptor Survival and Function in a Preclinical Model of Retinitis Pigmentosa (An American Ophthalmological Society Thesis)

    PubMed Central

    Tsang, Stephen H.; Chan, Lawrence; Tsai, Yi-Ting; Wu, Wen-Hsuan; Hsu, Chun-Wei; Yang, Jin; Tosi, Joaquin; Wert, Katherine J.; Davis, Richard J.; Mahajan, Vinit B.

    2014-01-01

    Purpose: To assess the functional consequences of silencing of tuberin, an inhibitor of the mTOR signaling pathway, in a preclinical model of retinitis pigmentosa (RP) in order to test the hypothesis that insufficient induction of the protein kinase B (PKB)-regulated tuberin/mTOR self-survival pathway initiates apoptosis. Methods: In an unbiased genome-scale approach, kinase peptide substrate arrays were used to analyze self-survival pathways at the onset of photoreceptor degeneration. The mutant Pde6bH620Q/Pde6bH620Q at P14 and P18 photoreceptor outer segment (OS) lysates were labeled with P-ATP and hybridized to an array of 1,164 different synthetic peptide substrates. At this stage, OS of Pde6bH620Q/Pde6bH620Q rods are morphologically normal. In vitro kinase assays and immunohistochemistry were used to validate phosphorylation. Short hairpin RNA (shRNA) gene silencing was used to validate tuberin’s role in regulating survival. Results: At the onset of degeneration, 162 peptides were differentially phosphorylated. Protein kinases A, G, C (AGC kinases), and B exhibited increased activity in both peptide array and in vitro kinase assays. Immunohistochemical data confirmed altered phosphorylation patterns for phosphoinositide-dependent kinase-1 (PDK1), ribosomal protein S6 (RPS6), and tuberin. Tuberin gene silencing rescued photoreceptors from degeneration. Conclusions: Phosphorylation of tuberin and RPS6 is due to the upregulated activity of PKB. PKB/tuberin cell growth/survival signaling is activated before the onset of degeneration. Substrates of the AGC kinases in the PKB/tuberin pathway are phosphorylated to promote cell survival. Knockdown of tuberin, the inhibitor of the mTOR pathway, increased photoreceptor survival and function in a preclinical model of RP. PMID:25646031

  9. Identification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family

    PubMed Central

    Siemiatkowska, Anna M.; Astuti, Galuh D.N.; Arimadyo, Kentar; den Hollander, Anneke I.; Faradz, Sultana M.H.; Cremers, Frans P.M.

    2012-01-01

    Purpose The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP). Methods Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals was analyzed with Illumina 700k single nucleotide polymorphism (SNP) arrays, and homozygous regions were identified using PLINK software. Mutation analysis was performed with sequence analysis of the retinitis pigmentosa 1 (RP1) gene that resided in one of the homozygous regions. The frequency of the identified mutation in the Indonesian population was determined with TaqI restriction fragment length polymorphism analysis. Results A novel homozygous nonsense mutation in exon 4 of the RP1 gene, c.1012C>T (p.R338*), was identified in the proband and her two affected sisters. Unaffected family members either carried two wild-type alleles or were heterozygous carriers of the mutation. The mutation was not present in 184 Indonesian control samples. Conclusions Most of the previously reported RP1 mutations are inherited in an autosomal dominant mode, and appear to cluster in exon 4. Here, we identified a novel homozygous p.R338* mutation in exon 4 of RP1, and speculate on the mutational mechanisms of different RP1 mutations underlying dominant and recessive RP. PMID:23077400

  10. A Short N-terminal Domain of HDAC4 Preserves Photoreceptors and Restores Visual Function in Retinitis Pigmentosa

    PubMed Central

    Guo, Xinzheng; Wang, Shao-Bin; Xu, Hongping; Ribic, Adema; Mohns, Ethan J.; Zhou, Yu; Zhu, Xianjun; Biederer, Thomas; Crair, Michael C.; Chen, Bo

    2015-01-01

    Retinitis pigmentosa is a leading cause of inherited blindness, with no effective treatment currently available. Mutations primarily in genes expressed in rod photoreceptors lead to early rod death, followed by a slower phase of cone photoreceptor death. Rd1 mice provide an invaluable animal model to evaluate therapies for the disease. We previously reported that overexpression of histone deacetylase 4 (HDAC4) prolongs rod survival in rd1 mice. Here we report a key role of a short N-terminal domain of HDAC4 in photoreceptor protection. Expression of this domain suppresses multiple cell death pathways in photoreceptor degeneration, and preserves even more rd1 rods than the full length HDAC4 protein. Expression of a short N-terminal domain of HDAC4 in transgenic mice carrying the rd1 mutation also prolongs the survival of cone photoreceptors, and partially restores visual function. Our results may facilitate the design of a small protein therapy for some forms of retinitis pigmentosa. PMID:26272629

  11. Mutation analysis of pre-mRNA splicing genes in Chinese families with retinitis pigmentosa

    PubMed Central

    Pan, Xinyuan; Chen, Xue; Liu, Xiaoxing; Gao, Xiang; Kang, Xiaoli; Xu, Qihua; Chen, Xuejuan; Zhao, Kanxing; Zhang, Xiumei; Chu, Qiaomei; Wang, Xiuying

    2014-01-01

    Purpose Seven genes involved in precursor mRNA (pre-mRNA) splicing have been implicated in autosomal dominant retinitis pigmentosa (adRP). We sought to detect mutations in all seven genes in Chinese families with RP, to characterize the relevant phenotypes, and to evaluate the prevalence of mutations in splicing genes in patients with adRP. Methods Six unrelated families from our adRP cohort (42 families) and two additional families with RP with uncertain inheritance mode were clinically characterized in the present study. Targeted sequence capture with next-generation massively parallel sequencing (NGS) was performed to screen mutations in 189 genes including all seven pre-mRNA splicing genes associated with adRP. Variants detected with NGS were filtered with bioinformatics analyses, validated with Sanger sequencing, and prioritized with pathogenicity analysis. Results Mutations in pre-mRNA splicing genes were identified in three individual families including one novel frameshift mutation in PRPF31 (p.Leu366fs*1) and two known mutations in SNRNP200 (p.Arg681His and p.Ser1087Leu). The patients carrying SNRNP200 p.R681H showed rapid disease progression, and the family carrying p.S1087L presented earlier onset ages and more severe phenotypes compared to another previously reported family with p.S1087L. In five other families, we identified mutations in other RP-related genes, including RP1 p. Ser781* (novel), RP2 p.Gln65* (novel) and p.Ile137del (novel), IMPDH1 p.Asp311Asn (recurrent), and RHO p.Pro347Leu (recurrent). Conclusions Mutations in splicing genes identified in the present and our previous study account for 9.5% in our adRP cohort, indicating the important role of pre-mRNA splicing deficiency in the etiology of adRP. Mutations in the same splicing gene, or even the same mutation, could correlate with different phenotypic severities, complicating the genotype–phenotype correlation and clinical prognosis. PMID:24940031

  12. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

    PubMed Central

    Wang, Xia; Wang, Hui; Sun, Vincent; Tuan, Han-Fang; Keser, Vafa; Wang, Keqing; Ren, Huanan; Lopez, Irma; Zaneveld, Jacques E; Siddiqui, Sorath; Bowles, Stephanie; Khan, Ayesha; Salvo, Jason; Jacobson, Samuel G; Iannaccone, Alessandro; Wang, Feng; Birch, David; Heckenlively, John R; Fishman, Gerald A; Traboulsi, Elias I; Li, Yumei; Wheaton, Dianna; Koenekoop, Robert K; Chen, Rui

    2014-01-01

    Background Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments. Methods We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis. Results Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients. Conclusions We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis. PMID:23847139

  13. Application of Whole Exome Sequencing in Six Families with an Initial Diagnosis of Autosomal Dominant Retinitis Pigmentosa: Lessons Learned

    PubMed Central

    Fernandez-San Jose, Patricia; Liu, Yichuan; March, Michael; Pellegrino, Renata; Golhar, Ryan; Corton, Marta; Blanco-Kelly, Fiona; López-Molina, Maria Isabel; García-Sandoval, Blanca; Guo, Yiran; Tian, Lifeng; Liu, Xuanzhu; Guan, Liping; Zhang, Jianguo; Keating, Brendan; Xu, Xun

    2015-01-01

    This study aimed to identify the genetics underlying dominant forms of inherited retinal dystrophies using whole exome sequencing (WES) in six families extensively screened for known mutations or genes. Thirty-eight individuals were subjected to WES. Causative variants were searched among single nucleotide variants (SNVs) and insertion/deletion variants (indels) and whenever no potential candidate emerged, copy number variant (CNV) analysis was performed. Variants or regions harboring a candidate variant were prioritized and segregation of the variant with the disease was further assessed using Sanger sequencing in case of SNVs and indels, and quantitative PCR (qPCR) for CNVs. SNV and indel analysis led to the identification of a previously reported mutation in PRPH2. Two additional mutations linked to different forms of retinal dystrophies were identified in two families: a known frameshift deletion in RPGR, a gene responsible for X-linked retinitis pigmentosa and p.Ser163Arg in C1QTNF5 associated with Late-Onset Retinal Degeneration. A novel heterozygous deletion spanning the entire region of PRPF31 was also identified in the affected members of a fourth family, which was confirmed with qPCR. This study allowed the identification of the genetic cause of the retinal dystrophy and the establishment of a correct diagnosis in four families, including a large heterozygous deletion in PRPF31, typically considered one of the pitfalls of this method. Since all findings in this study are restricted to known genes, we propose that targeted sequencing using gene-panel is an optimal first approach for the genetic screening and that once known genetic causes are ruled out, WES might be used to uncover new genes involved in inherited retinal dystrophies. PMID:26197217

  14. Animals deficient in C2Orf71, an autosomal recessive retinitis pigmentosa-associated locus, develop severe early-onset retinal degeneration.

    PubMed

    Kevany, Brian M; Zhang, Ning; Jastrzebska, Beata; Palczewski, Krzysztof

    2015-05-01

    Genetic mapping was recently used to identify the underlying cause for a previously uncharacterized cohort of autosomal recessive retinitis pigmentosa cases. Genetic mapping of affected individuals resulted in the identification of an uncharacterized gene, C2Orf71, as the causative locus. However, initial homology searches failed to reveal similarities to any previously characterized protein or domain. To address this issue, we characterized the mouse homolog, BC027072. Immunohistochemistry with a custom polyclonal antibody showed staining localized to the inner segments (IS) of photoreceptor cells, as well as the outer segments (OS) of cone cells. A knockout mouse line (BC(-/-)) was generated and demonstrated that loss of this gene results in a severe, early-onset retinal degeneration. Histology and electron microscopy (EM) revealed disorganized OS as early as 3 weeks with complete loss by 24 weeks of age. EM micrographs displayed packets of cellular material containing OS discs or IS organelles in the OS region and abnormal retinal pigmented epithelium cells. Analyses of retinoids and rhodopsin levels showed <20% in BC(-/-) versus wild-type mice early in development. Electroretinograms demonstrated that affected mice were virtually non-responsive to light by 8 weeks of age. Lastly, RNAseq analysis of ocular gene expression in BC(-/-) mice revealed clues to the causes of the progressive retinal degenerations. Although its function remains unknown, this protein appears essential for normal OS development/maintenance and vision in humans and mice. RNAseq data are available in the GEO database under accession: GSE63810. PMID:25616964

  15. Identical Mutation in a Novel Retinal Gene Causes Progressive Rod-Cone Degeneration (prcd) in Dogs and Retinitis Pigmentosa in Man

    PubMed Central

    Zangerl, Barbara; Goldstein, Orly; Philp, Alisdair R.; Lindauer, Sarah J.P.; Pearce-Kelling, Susan E.; Mullins, Robert F.; Graphodatsky, Alexander S.; Ripoll, Daniel; Felix, Jeanette S.; Stone, Edwin M.; Acland, Gregory M.; Aguirre, Gustavo D.

    2014-01-01

    Progressive rod-cone degeneration (prcd) is a late-onset, autosomal recessive photoreceptor degeneration of dogs, and a homolog for some forms of human retinitis pigmentosa (RP). Previously, the disease relevant interval was reduced to a 106 Kb region on CFA9, and a common phenotype-specific haplotype was identified in all affected dogs from several different breeds, and breed varieties. Screening of a canine retinal EST library identified partial cDNAs for novel candidate genes in the disease relevant interval. The complete cDNA of one of these, PRCD, was cloned in dog, human and mouse. The gene codes for a 54 amino acid (aa) protein in dog and human, and 53 aa protein in the mouse; the first 24 aa, coded for by exon 1, are highly conserved in 14 vertebrate species. A homozygous mutation (TGC → TAC) in the second codon shows complete concordance with the disorder in 18 different dog breeds/breed varieties tested. The same homozygous mutation was identified in a human patient from Bangladesh with autosomal recessive (ar) RP. Expression studies support the predominant expression of this gene in the retina, with equal expression in the retinal pigment epithelium (RPE), photoreceptors and ganglion cell layers. This study provides strong evidence that a mutation in the novel gene, PRCD, is the cause of autosomal recessive retinal degeneration in both dogs and man. PMID:16938425

  16. The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa

    SciTech Connect

    Riess, O.; Weber, B.; Hayden, M.R. ); Noerremoelle, A. ); Musarella, M.A. )

    1992-10-01

    The finding of a mutation in the beta subunit of the cyclic GMP (cGMP) phosphodiesterase gene causing retinal degeneration in mice (the Pdeb gene) prompted a search for disease-causing mutations in the human phosphodiesterase gene (PDEB gene) in patients with retinitis pigmentosa. All 22 exons including 196 bp of the 5[prime] region of the PDEB gene have been assessed for mutations by using single-strand conformational polymorphism analysis in 14 patients from 13 unrelated families with autosomal recessive retinitis pigmentosa (ARRP). No disease-causing mutations were found in this group of affected individuals of seven different ancestries. However, a frequent intronic and two exonic polymorphisms (Leu[sup 489][yields]Gln and Gly[sup 842][yields]Gly) were identified. Segregation analysis using these polymorphic sites excludes linkage of ARRP to the PDEB gene in a family with two affected children. 43 refs., 3 figs., 2 tabs.

  17. Characterization of macular structure and function in two Swedish families with genetically identified autosomal dominant retinitis pigmentosa

    PubMed Central

    Abdulridha-Aboud, Wissam; Kjellström, Ulrika; Andréasson, Sten

    2016-01-01

    Purpose To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions These two families demonstrate the extreme inter- and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype. PMID:27212874

  18. Rhodopsin F45L Allele Does Not Cause Autosomal Dominant Retinitis Pigmentosa in a Large Caucasian Family

    PubMed Central

    Vincent, Andrea L.; Carroll, Joseph; Fishman, Gerald A.; Sauer, Alexandra; Sharp, Dianne; Summerfelt, Phyllis; Williams, Vesper; Dubis, Adam M.; Kohl, Susanne; Wong, Fulton

    2013-01-01

    Purpose To ascertain the potential pathogenicity of a retinitis pigmentosa (RP)-causing RHO F45L allele in a family affected by congenital achromatopsia (ACHM). Methods Case series/observational study that included two patients with ACHM and 24 extended family members. Molecular genetic analysis was performed to identify RHO F45L carrier status in the family and a control population. An adaptive optics scanning light ophthalmoscope (AOSLO) was used to image the photoreceptor mosaic and assess rod and cone structure. Spectral domain optical coherence tomography (SD-OCT) was used to examine retinal lamination. Comprehensive clinical testing included acuity, color vision, and dilated fundus examination. Electroretinography was used to assess rod and cone function. Results Five carriers of the RHO F45L allele alone (24–80 years) and three carriers in combination with a heterozygous CNGA3 mutant allele (10–64 years) were all free of the classic symptoms and signs of RP. In heterozygous carriers of both mutations, SD-OCT showed normal retinal thickness and intact outer retinal layers; rod and cone densities were within normal limits on AOSLO. The phenotype in two individuals affected with ACHM and harboring the RHO F45L allele was indistinguishable from that previously reported for ACHM. Conclusions The RHO F45L allele is not pathogenic in this large family; hence, the two ACHM patients would unlikely develop RP in the future. Translational Relevance The combined approach of comprehensive molecular analysis of individual genomes and noninvasive cellular resolution retinal imaging enhances the current repertoire of clinical diagnostic tools, giving a substantial impetus to personalized medicine. PMID:24049715

  19. Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

    PubMed

    Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

    2016-03-15

    Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. PMID:26740549

  20. Correlation of Outer Nuclear Layer Thickness With Cone Density Values in Patients With Retinitis Pigmentosa and Healthy Subjects

    PubMed Central

    Menghini, Moreno; Lujan, Brandon J.; Zayit-Soudry, Shiri; Syed, Reema; Porco, Travis C.; Bayabo, Kristine; Carroll, Joseph; Roorda, Austin; Duncan, Jacque L.

    2015-01-01

    Purpose. We studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP). Methods. Spectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5° intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r. Results. Cone densities averaged over the central 6° were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5° to 1.5° eccentricity was stronger (r = 0.67) than between 1.5° and 3.0° eccentricity (r = 0.23). Although cone densities were lower between 0.5° and 1.5° in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important. Conclusions. The ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.) PMID:25515570

  1. Rhodopsin mutations in a Scottish retinitis pigmentosa population, including a novel splice site mutation in intron four.

    PubMed Central

    Bell, C; Converse, C A; Hammer, H M; Osborne, A; Haites, N E

    1994-01-01

    Retinitis pigmentosa (RP) is the name given to a group of disorders, both clinically and genetically heterogeneous, that primarily affect the photoreceptor function of the eye. Mutations in the genes encoding for rhodopsin, RDS-peripherin, or the beta subunit of the cGMP phosphodiesterase enzyme can be responsible for the phenotype. In this study the rhodopsin gene has been screened for mutations in a panel of RP individuals and five different sequence changes have been detected to date in three dominantly inherited and two unclassified families. One of these, a base substitution in the 3'UTR, has not yet been confirmed as disease specific, while three missense substitutions have previously been reported and are likely to be responsible for the phenotype. The fifth change, a base substitution at the intron 4 acceptor splice site, represents a novel mutation and is assumed to be the causative mutation. Images PMID:7819178

  2. Whole exome sequencing identifies a novel NRL mutation in a Chinese family with autosomal dominant retinitis pigmentosa

    PubMed Central

    Gao, Meng; Zhang, Su; Liu, Chunjie; Qin, Yayun; Archacki, Stephen; Jin, Ling; Wang, Yong; Liu, Fei; Chen, Jiaxiang; Liu, Ying; Wang, Jiuxiang; Huang, Mi; Liao, Shengjie; Tang, Zhaohui; Guo, An Yuan; Liu, Mugen

    2016-01-01

    Purpose To investigate the genetic basis and its relationship to the clinical manifestations in a four generation Chinese family with autosomal dominant retinitis pigmentosa. Methods Ophthalmologic examinations including fundus photography, fundus autofluorescence imaging, fundus fluorescein angiography, optical coherence tomography, and a best-corrected visual acuity test were performed to define the clinical features of the patients. We extracted the genomic DNA from peripheral blood samples. The proband’s genomic DNA was submitted to the whole exome sequencing. Results Whole exome sequencing and the subsequent data analysis detected six candidate mutations in the proband of this pedigree. The novel c.146 C>T mutation in NRL was found to be the only mutation that co-segregated with the disease in this pedigree. This mutation resulted in a substitution of proline by a leucine at position 49 of NRL protein (p.P49L). Most importantly, the proline residue at position 49 of NRL is highly conserved from zebrafish to humans. The c.146 C>T mutation was not observed in 200 control individuals. What’s more, we performed the luciferase activity assay to prove that this mutation we detected alters the NRL protein function. Conclusions The c.146 C>T mutation in NRL gene causes autosomal dominant retinitis pigmentosa for this family. Our finding not only expands the mutation spectrum of NRL, but also demonstrates that whole-exome sequencing is a powerful strategy to detect causative genes and mutations in RP patients. This technique may provide a precise diagnosis for rare heterogeneous monogenic disorders such as RP. PMID:27081294

  3. Mutation analysis in 129 genes associated with other forms of retinal dystrophy in 157 families with retinitis pigmentosa based on exome sequencing

    PubMed Central

    Xu, Yan; Guan, Liping; Xiao, Xueshan; Zhang, Jianguo; Li, Shiqiang; Jiang, Hui; Jia, Xiaoyun; Yang, Jianhua; Guo, Xiangming; Yin, Ye; Wang, Jun

    2015-01-01

    Purpose Mutations in 60 known genes were previously identified by exome sequencing in 79 of 157 families with retinitis pigmentosa (RP). This study analyzed variants in 129 genes associated with other forms of hereditary retinal dystrophy in the same cohort. Methods Apart from the 73 genes previously analyzed, a further 129 genes responsible for other forms of hereditary retinal dystrophy were selected based on RetNet. Variants in the 129 genes determined by whole exome sequencing were selected and filtered by bioinformatics analysis. Candidate variants were confirmed by Sanger sequencing and validated by analysis of available family members and controls. Results A total of 90 candidate variants were present in the 129 genes. Sanger sequencing confirmed 83 of the 90 variants. Analysis of family members and controls excluded 76 of these 83 variants. The remaining seven variants were considered to be potential pathogenic mutations; these were c.899A>G, c.1814C>G, and c.2107C>T in BBS2; c.1073C>T and c.1669C>T in INPP5E; and c.3582C>G and c.5704–5C>G in CACNA1F. Six of these seven mutations were novel. The mutations were detected in five unrelated patients without a family history, including three patients with homozygous or compound heterozygous mutations in BBS2 and INPP5E, and two patients with hemizygous mutations in CACNA1F. None of the patients had mutations in the genes associated with autosome dominant retinal dystrophy. Conclusions Only a small portion of patients with RP, about 3% (5/157), had causative mutations in the 129 genes associated with other forms of hereditary retinal dystrophy. PMID:25999675

  4. Systematic Review of Randomized Clinical Trials on Safety and Efficacy of Pharmacological and Nonpharmacological Treatments for Retinitis Pigmentosa

    PubMed Central

    Sacchetti, Marta; Mantelli, Flavio; Merlo, Daniela; Lambiase, Alessandro

    2015-01-01

    Aims. Several treatments have been proposed to slow down progression of Retinitis pigmentosa (RP), a hereditary retinal degenerative condition leading to severe visual impairment. The aim of this study is to systematically review data from randomized clinical trials (RCTs) evaluating safety and efficacy of medical interventions for the treatment of RP. Methods. Randomized clinical trials on medical treatments for syndromic and nonsyndromic RP published up to December 2014 were included in the review. Visual acuity, visual field, electroretinogram, and adverse events were used as outcome measures. Results. The 19 RCTs included in this systematic review included trials on hyperbaric oxygen delivery, topical brimonidine tartrate, vitamins, docosahexaenoic acid, gangliosides, lutein, oral nilvadipine, ciliary neurotrophic factor, and valproic acid. All treatments proved safe but did not show significant benefit on visual function. Long term supplementation with vitamin A showed a significantly slower decline rate in electroretinogram amplitude. Conclusions. Although all medical treatments for RP appear safe, evidence emerging from RCTs is limited since they do not present comparable results suitable for quantitative statistical analysis. The limited number of RCTs, the poor clinical results, and the heterogeneity among studies negatively influence the strength of recommendations for the long term management of RP patients. PMID:26339504

  5. A novel mutation of the RP1 gene (Lys778ter) associated with autosomal dominant retinitis pigmentosa

    PubMed Central

    Dietrich, K; Jacobi, F K; Tippmann, S; Schmid, R; Zrenner, E; Wissinger, B; Apfelstedt-Sylla, E

    2002-01-01

    Background: Besides the three known genes (RHO, RDS/Peripherin, NRL) involved in autosomal dominant retinitis pigmentosa (adRP), a fourth gene, RP1, has been recently identified. Initial reports suggest that mutations in the RP1 gene are the second most frequent cause of adRP. The clinical findings were described in a family with adRP and a novel mutation in the RP1 gene. Method: Index patients from 15 independent families with adRP in which RHO mutations had been excluded in previous examinations were screened for mutations in the RP1 gene by means of direct DNA sequencing. Evaluation of the RP1 phenotype in patients included funduscopy, kinetic perimetry, dark adapted final threshold test, standard electroretinography and, in one case, multifocal electroretinography. Results: One novel nonsense mutation (Lys778ter) in one of these 15 patients was detected. Cosegregation of the mutation with the disease phenotype could be established in the index patient's family. The phenotype comprises variable expression of clinical disease probably including one case of incomplete penetrance, a onset of symptoms beginning in adulthood, and evidence of regionally varying retinal function loss. Conclusion: The Lys778ter mutation localises inside the critical region harbouring all mutations described so far. The ophthalmic findings support previous observations that variation of disease expression appears as a typical feature of the RP1 phenotype. PMID:11864893

  6. Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13).

    PubMed

    McKie, A B; McHale, J C; Keen, T J; Tarttelin, E E; Goliath, R; van Lith-Verhoeven, J J; Greenberg, J; Ramesar, R S; Hoyng, C B; Cremers, F P; Mackey, D A; Bhattacharya, S S; Bird, A C; Markham, A F; Inglehearn, C F

    2001-07-15

    Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration. PMID:11468273

  7. A Splice-Site Mutation in a Retina-Specific Exon of BBS8 Causes Nonsyndromic Retinitis Pigmentosa

    PubMed Central

    Riazuddin, S. Amer; Iqbal, Muhammad; Wang, Yue; Masuda, Tomohiro; Chen, Yuhng; Bowne, Sara; Sullivan, Lori S.; Waseem, Naushin H.; Bhattacharya, Shomi; Daiger, Stephen P.; Zhang, Kang; Khan, Shaheen N.; Riazuddin, Sheikh; Hejtmancik, J. Fielding; Sieving, Paul A.; Zack, Donald J.; Katsanis, Nicholas

    2010-01-01

    Tissue-specific alternative splicing is an important mechanism for providing spatiotemporal protein diversity. Here we show that an in-frame splice mutation in BBS8, one of the genes involved in pleiotropic Bardet-Biedl syndrome (BBS), is sufficient to cause nonsyndromic retinitis pigmentosa (RP). A genome-wide scan of a consanguineous RP pedigree mapped the trait to a 5.6 Mb region; subsequent systematic sequencing of candidate transcripts identified a homozygous splice-site mutation in a previously unknown BBS8 exon. The allele segregated with the disorder, was absent from controls, was completely invariant across evolution, and was predicted to lead to the elimination of a 10 amino acid sequence from the protein. Subsequent studies showed the exon to be expressed exclusively in the retina and enriched significantly in the photoreceptor layer. Importantly, we found this exon to represent the major BBS8 mRNA species in the mammalian photoreceptor, suggesting that the encoded 10 amino acids play a pivotal role in the function of BBS8 in this organ. Understanding the role of this additional sequence might therefore inform the mechanism of retinal degeneration in patients with syndromic BBS or other related ciliopathies. PMID:20451172

  8. A historical perspective on the early treatment of night blindness and the use of dubious and unproven treatment strategies for patients with retinitis pigmentosa.

    PubMed

    Fishman, Gerald A

    2013-01-01

    Retinitis pigmentosa (RP) is a form of inherited night blindness. Over decades, various dubious treatment strategies that lacked sufficient theoretically sound underpinnings were explored. Initially they were enthusiastically promoted and subsequently discredited. It is apparent that many were predicated on the erroneous assumption that the primary cause of RP was related to impairment of the retinal circulation. Herein, several of these strategies are reviewed and critiqued. Reasons why clinicians may have been deceived into overzealous interpretations of their treatment methods are explored. The examples disclosed should serve as a note of caution for current investigators to guard against self-deception when exploring newly developed treatment strategies. PMID:23911150

  9. Mislocalization and Degradation of Human P23H-Rhodopsin-GFP in a Knockin Mouse Model of Retinitis Pigmentosa

    PubMed Central

    Price, Brandee A.; Sandoval, Ivette M.; Chan, Fung; Simons, David L.; Wu, Samuel M.; Wensel, Theodore G.

    2011-01-01

    Purpose. To engineer a knockin mouse model that can be used to monitor the effects of treatments on degradation and mislocalization of proline-to-histidine change at codon 23 (P23H) rhodopsin, a common cause of autosomal dominant retinitis pigmentosa (ADRP). The goal was to introduce a gene that expressed rhodopsin at low levels to avoid rapid retinal degeneration, and with a readily visible tag to make it easy to distinguish from wild type rhodopsin. Methods. One copy of the endogenous mouse rhodopsin gene was replaced with a mutant human rhodopsin gene that encodes P23H-rhodopsin fused to enhanced green fluorescent protein (GFP) at its C terminus. The gene includes a LoxP site in the sequence corresponding to the 5′-untranslated region, which greatly reduces translation efficiency. Characterized are the resulting heterozygous and homozygous P23H-hRho-GFP mouse lines for mRNA and protein expression, P23H-rhodopsin localization in rod cells, effects on visual function, and retinal degeneration. Results. The retinas of heterozygous P23H-hRho-GFP mice are morphologically and functionally very similar to those of wild type mice, and they display little cell death over time. P23H-hRho-GFP mice transcribe the knockin gene as efficiently as the endogenous mouse allele, but they contain much less of the protein product than do knockin mice expressing nonmutant hRho-GFP, indicating that substantial degradation of P23H-rRho-GFP occurs in mouse rod cells. The remaining P23H-hRho-GFP mislocalizes to the inner segment and outer nuclear layer, with only approximately 20% in rod outer segments. Conclusions. P23H-hRho-GFP mice provide a valuable tool for evaluating the efficacy of potential therapies for ADRP that influence the levels or localization of P23H-rhodopsin. PMID:22110080

  10. X-linked dominant cone-rod degeneration: Linkage mapping of a new locus for retinitis pigmentosa (RP15) to Xp22.13-p22.11

    SciTech Connect

    McGuire, R.E.; Sullivan, L.S.; Daiger, S.P.

    1995-07-01

    Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and exluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10{sup 5}:1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol {open_quotes}RP15{close_quotes}. 17 refs., 2 figs., 4 tabs.

  11. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa

    PubMed Central

    Kijas, James W.; Cideciyan, Artur V.; Aleman, Tomas S.; Pianta, Michael J.; Pearce-Kelling, Susan E.; Miller, Brian J.; Jacobson, Samuel G.; Aguirre, Gustavo D.; Acland, Gregory M.

    2002-01-01

    Rhodopsin is the G protein-coupled receptor that is activated by light and initiates the transduction cascade leading to night (rod) vision. Naturally occurring pathogenic rhodopsin (RHO) mutations have been previously identified only in humans and are a common cause of dominantly inherited blindness from retinal degeneration. We identified English Mastiff dogs with a naturally occurring dominant retinal degeneration and determined the cause to be a point mutation in the RHO gene (Thr4Arg). Dogs with this mutant allele manifest a retinal phenotype that closely mimics that in humans with RHO mutations. The phenotypic features shared by dog and man include a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and a distinctive topographic pattern to the retinal degeneration. The canine disease offers opportunities to explore the basis of prolonged photoreceptor recovery after light in RHO mutations and determine whether there are links between the dysfunction and apoptotic retinal cell death. The RHO mutant dog also becomes the large animal needed for preclinical trials of therapies for a major subset of human retinopathies. PMID:11972042

  12. The synthetic progestin norgestrel acts to increase LIF levels in the rd10 mouse model of retinitis pigmentosa

    PubMed Central

    Byrne, Ashleigh M.; Roche, Sarah L.; Ruiz-Lopez, Ana M.; Jackson, Alice C. Wyse

    2016-01-01

    Purpose: Retinal degenerative conditions affect thousands of people worldwide. Retinitis pigmentosa (RP) is among the most common, but it is currently incurable. It is characterized by the progressive death of photoreceptor cells, eventually leading to blindness. Neurotrophic factors play an important role in such retinopathies, and much research has been performed on their use as treatments. Our group previously demonstrated the ability of the synthetic progestin norgestrel to rescue photoreceptors from cell death, the mechanism of which is believed to include upregulation of the neurotrophic factor basic fibroblast growth factor (bFGF). The objective of the present study was to investigate whether the protection provided by norgestrel is likely to be mediated by other neurotrophins. Methods: The 661W photoreceptor cells and retinal explants from P30 to P40 wild-type (wt) C57BL/6 mice were treated with norgestrel over time. Homozygous rd10/rd10 mice that mimic the human form of RP were fed either a control or a norgestrel-containing diet. Changes in neurotrophic factor expression in response to norgestrel were detected with real-time PCR, western blotting, or immunofluorescence staining. Using specific siRNA, leukemia inhibitory factor (Lif) expression was knocked down in 661W photoreceptor cells that were stressed by serum starvation. Cells were treated with norgestrel followed by measurement of cell viability with (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. Results: LIF, a potent neuroprotective cytokine, was found to be upregulated in response to norgestrel in vitro and in vivo. Upregulation of LIF in degenerating rd10 retinas coincided with preservation of the photoreceptor layer. We also found LIF was necessary for the norgestrel-mediated rescue of stressed photoreceptor cells from cell death in vitro. Conclusions: LIF was upregulated in response to norgestrel in all models studied and is necessary

  13. Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP)

    PubMed Central

    Sullivan, Lori S.; Bowne, Sara J.; Koboldt, Daniel C.; Blanton, Susan H.; Wheaton, Dianna K.; Avery, Cheryl E.; Cadena, Elizabeth D.; Koenekoop, Robert K.; Fulton, Robert S.; Wilson, Richard K.; Weinstock, George M.; Lewis, Richard A.; Birch, David G.

    2016-01-01

    Whole-genome linkage mapping identified a region on chromosome 10q21.3–q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites. PMID:26427411

  14. Towards an assistive peripheral visual prosthesis for long-term treatment of retinitis pigmentosa: evaluating mobility performance in immersive simulations

    NASA Astrophysics Data System (ADS)

    Zapf, Marc Patrick H.; Boon, Mei-Ying; Matteucci, Paul B.; Lovell, Nigel H.; Suaning, Gregg J.

    2015-06-01

    Objective. The prospective efficacy of a future peripheral retinal prosthesis complementing residual vision to raise mobility performance in non-end stage retinitis pigmentosa (RP) was evaluated using simulated prosthetic vision (SPV). Approach. Normally sighted volunteers were fitted with a wide-angle head-mounted display and carried out mobility tasks in photorealistic virtual pedestrian scenarios. Circumvention of low-lying obstacles, path following, and navigating around static and moving pedestrians were performed either with central simulated residual vision of 10° alone or enhanced by assistive SPV in the lower and lateral peripheral visual field (VF). Three layouts of assistive vision corresponding to hypothetical electrode array layouts were compared, emphasizing higher visual acuity, a wider visual angle, or eccentricity-dependent acuity across an intermediate angle. Movement speed, task time, distance walked and collisions with the environment were analysed as performance measures. Main results. Circumvention of low-lying obstacles was improved with all tested configurations of assistive SPV. Higher-acuity assistive vision allowed for greatest improvement in walking speeds—14% above that of plain residual vision, while only wide-angle and eccentricity-dependent vision significantly reduced the number of collisions—both by 21%. Navigating around pedestrians, there were significant reductions in collisions with static pedestrians by 33% and task time by 7.7% with the higher-acuity layout. Following a path, higher-acuity assistive vision increased walking speed by 9%, and decreased collisions with stationary cars by 18%. Significance. The ability of assistive peripheral prosthetic vision to improve mobility performance in persons with constricted VFs has been demonstrated. In a prospective peripheral visual prosthesis, electrode array designs need to be carefully tailored to the scope of tasks in which a device aims to assist. We posit that maximum

  15. Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP).

    PubMed

    Daiger, Stephen P; Sullivan, Lori S; Bowne, Sara J; Koboldt, Daniel C; Blanton, Susan H; Wheaton, Dianna K; Avery, Cheryl E; Cadena, Elizabeth D; Koenekoop, Robert K; Fulton, Robert S; Wilson, Richard K; Weinstock, George M; Lewis, Richard A; Birch, David G

    2016-01-01

    Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites. PMID:26427411

  16. Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa

    PubMed Central

    Rose, Anna M.; Shah, Amna Z.; Venturini, Giulia; Krishna, Abhay; Chakravarti, Aravinda; Rivolta, Carlo; Bhattacharya, Shomi S.

    2016-01-01

    PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation. PMID:26781568

  17. Crystal Structure of the C-terminal Domain of Splicing Factor Prp8 Carrying Retinitis Pigmentosa Mutants

    SciTech Connect

    Zhang,L.; Shen, J.; Guarnieri, M.; Heroux, A.; Yang, K.; Zhao, R.

    2007-01-01

    Prp8 is a critical pre-mRNA splicing factor. Prp8 is proposed to help form and stabilize the spliceosome catalytic core and to be an important regulator of spliceosome activation. Mutations in human Prp8 (hPrp8) cause a severe form of the genetic disorder retinitis pigmentosa, RP13. Understanding the molecular mechanism of Prp8's function in pre-mRNA splicing and RP13 has been hindered by its large size (over 2000 amino acids) and remarkably low-sequence similarity with other proteins. Here we present the crystal structure of the C-terminal domain (the last 273 residues) of Caenorhabditis elegans Prp8 (cPrp8). The core of the C-terminal domain is an / structure that forms the MPN (Mpr1, Pad1 N-terminal) fold but without Zn{sup 2+} coordination. We propose that the C-terminal domain is a protein interaction domain instead of a Zn{sup 2+}-dependent metalloenzyme as proposed for some MPN proteins. Mapping of RP13 mutants on the Prp8 structure suggests that these residues constitute a binding surface between Prp8 and other partner(s), and the disruption of this interaction provides a plausible molecular mechanism for RP13.

  18. Targeted Next-generation Sequencing Reveals Novel EYS Mutations in Chinese Families with Autosomal Recessive Retinitis Pigmentosa

    PubMed Central

    Chen, Xue; Liu, Xiaoxing; Sheng, Xunlun; Gao, Xiang; Zhang, Xiumei; Li, Zili; Li, Huiping; Liu, Yani; Rong, Weining; Zhao, Kanxing; Zhao, Chen

    2015-01-01

    EYS mutations demonstrate great genotypic and phenotypic varieties, and are one of the major causes for patients with autosomal recessive retinitis pigmentosa (ARRP). Here, we aim to determine the genetic lesions with phenotypic correlations in two Chinese families with ARRP. Medical histories and ophthalmic documentations were obtained from all participants from the two pedigrees. Targeted next-generation sequencing (NGS) on 189 genes was performed to screen for RP causative mutations in the two families. Two biallelic mutations in EYS, p.[R164*];[C2139Y] and p.[W2640*];[F2954S], were identified in the two families, respectively. EYS p.R164* and p.F2954S are novel alleles associated with RP, while p.C2139Y and p.W2640* are known mutations. Crystal structure modeling on the protein eyes shut homolog encoded by the EYS gene revealed abnormal hydrogen bonds generated by p.C2139Y and p.F2954S, which would likely affect the solubility and cause significant structural changes of the two mutated proteins. In conclusion, our study expands the genotypic spectrums for EYS mutations, and may provide novel insights into the relevant pathogenesis for RP. We also demonstrate targeted NGS approach as a valuable tool for genetic diagnosis. PMID:25753737

  19. Artificial vision by direct optic nerve electrode (AV-DONE) implantation in a blind patient with retinitis pigmentosa.

    PubMed

    Sakaguchi, Hirokazu; Kamei, Motohiro; Fujikado, Takashi; Yonezawa, Eiji; Ozawa, Motoki; Cecilia-Gonzalez, Carmen; Ustariz-Gonzalez, Orlando; Quiroz-Mercado, Hugo; Tano, Yasuo

    2009-01-01

    The purpose of this study was to evaluate the efficacy and safety of artificial vision by using a direct optic nerve electrode (AV-DONE) in a blind patient with retinitis pigmentosa (RP). This device, comprising three wire electrodes (0.05 mm in diameter), was implanted into the optic disc of a patient with RP with no light perception vision and the device was left implanted. Six months later, visual sensations were elicited by electrical stimulation through each electrode and the thresholds for the phosphene perception elicited by pulses of 0.25-ms duration/phase and a pulse frequency of 320 Hz were 30, 5, and 70 microA for each electrode. The phosphenes, which ranged in size from that of a match head to an apple, were round, oval, or linear, primarily yellow, and focally distributed. The area of the phosphenes changed when the electrical stimulation was supplied from different electrodes. No complications arose during the follow-up period. Localized visual sensations were produced in a blind patient with advanced RP, suggesting that our system could lead to the development of a useful visual prosthesis system. PMID:19894096

  20. Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa.

    PubMed

    Rose, Anna M; Shah, Amna Z; Venturini, Giulia; Krishna, Abhay; Chakravarti, Aravinda; Rivolta, Carlo; Bhattacharya, Shomi S

    2016-01-01

    PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation. PMID:26781568

  1. A new family linked to the RP13 locus for autosomal dominant retinitis pigmentosa on distal 17p.

    PubMed

    Tarttelin, E E; Plant, C; Weissenbach, J; Bird, A C; Bhattacharya, S S; Inglehearn, C F

    1996-06-01

    A form of autosomal dominant retinitis pigmentosa (ADRP) mapping to chromosome 17p has been reported in a single large South African family. We now report a new family with severe early onset ADRP which maps to 17p. Linkage and haplotype analysis in this family places the ADRP locus in the 5 cM interval between markers AFMc024za5 and D17S1845, confirming the data obtained in the South African family. The discovery of a second 17p linked family may imply that this is one of the more common loci for dominant RP. In addition, the confirmation of an RP diagnosis at this locus is of interest since loci for a dominant cone dystrophy and Leber's congenital amaurosis (LCA1) have recently been linked to the same markers. While the cone dystrophy locus may be allelic with RP, our data and that of Goliath et al show that distinct genes are responsible for dominant RP and Leber's congenital amaurosis on chromosome 17p. PMID:8782056

  2. Novel compound heterozygous mutation in the CNGA1 gene underlie autosomal recessive retinitis pigmentosa in a Chinese family

    PubMed Central

    Jin, Xin; Qu, Ling-Hui; Hou, Bao-Ke; Xu, Hai-Wei; Meng, Xiao-Hong; Pang, Chi-Pui; Yin, Zheng-Qin

    2016-01-01

    Retinitis pigmentosa (RP) describes a group of inherited retinopathies that are characterized by the progressive degeneration of photoreceptor neurons, which causes night blindness, a reduction in the peripheral visual field and decreased visual acuity. More than 50 RP-related genes have been identified. In the present study, we analysed a Chinese family with autosomal recessive RP. We identified a compound heterozygous mutation, c.265delC and c.1537G>A, in CNGA1 using targeted next-generation sequencing (NGS) of RP-causing genes. The mutations were validated in the family members by Sanger sequencing. The mutations co-segregated with the RP phenotype and were absent from ethnically-matched control chromosomes. The mutant (mut) CNGA1 p.(G513R) protein caused by the mis-sense novel mutation c.1537G>A was expressed in vitro. The mut CNGA1 p.(G513R) protein was largely retained inside the cell rather than being targeted to the plasma membrane, suggesting the absence of cGMP-gated cation channels in the plasma membrane would be deleterious to rod photoreceptors, leading lead to RP. PMID:26802146

  3. Unusual presentation: pulmonary hemosiderosis with celiac disease and retinitis pigmentosa in a child.

    PubMed

    Keskin, Ozlem; Keskin, Mehmet; Guler, Elif; Tutar, Ediz; Saygili, Oguzhan; Kucukosmanoglu, Ercan; Kor, Yilmaz; Celik, Haydar; Coskun, Enes

    2011-08-01

    Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by anemia, hemoptysis and recurrent alveolar hemorrhage. The combination of IPH and celiac disease (CD) is extremely rare. We report a 9-year-old boy with Lane-Hamilton syndrome, co-occurrence of pulmonary hemosiderosis with CD. This presentation is unique presentation because he has also retinal pigmentation. PMID:21337729

  4. WDR19: An ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome

    PubMed Central

    Coussa, RG; Otto, EA; Gee, H-Y; Arthurs, P; Ren, H; Lopez, I; Keser, V; Fu, Q; Faingold, R; Khan, A; Schwartzentruber, J; Majewski, J; Hildebrandtand, F; Koenekoop, RK

    2014-01-01

    Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ~500 arRP mutations in ~20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed ‘sub-clinical’ renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes. PMID:23683095

  5. Photoactivation-Induced Instability of Rhodopsin Mutants T4K and T17M in Rod Outer Segments Underlies Retinal Degeneration in X. laevis Transgenic Models of Retinitis Pigmentosa

    PubMed Central

    Tam, Beatrice M.; Noorwez, Syed M.; Kaushal, Shalesh; Kono, Masahiro

    2014-01-01

    Retinitis pigmentosa (RP) is an inherited neurodegenerative disease involving progressive vision loss, and is often linked to mutations in the rhodopsin gene. Mutations that abolish N-terminal glycosylation of rhodopsin (T4K and T17M) cause sector RP in which the inferior retina preferentially degenerates, possibly due to greater light exposure of this region. Transgenic animal models expressing rhodopsin glycosylation mutants also exhibit light exacerbated retinal degeneration (RD). In this study, we used transgenic Xenopus laevis to investigate the pathogenic mechanism connecting light exposure and RD in photoreceptors expressing T4K or T17M rhodopsin. We demonstrate that increasing the thermal stability of these rhodopsins via a novel disulfide bond resulted in significantly less RD. Furthermore, T4K or T17M rhodopsins that were constitutively inactive (due to lack of the chromophore-binding site or dietary deprivation of the chromophore precursor vitamin A) induced less toxicity. In contrast, variants in the active conformation accumulated in the ER and caused RD even in the absence of light. In vitro, T4K and T17M rhodopsins showed reduced ability to regenerate pigment after light exposure. Finally, although multiple amino acid substitutions of T4 abolished glycosylation at N2 but were not toxic, similar substitutions of T17 were not tolerated, suggesting that the carbohydrate moiety at N15 is critical for cell viability. Our results identify a novel pathogenic mechanism in which the glycosylation-deficient rhodopsins are destabilized by light activation. These results have important implications for proposed RP therapies, such as vitamin A supplementation, which may be ineffective or even detrimental for certain RP genotypes. PMID:25274813

  6. Photoactivation-induced instability of rhodopsin mutants T4K and T17M in rod outer segments underlies retinal degeneration in X. laevis transgenic models of retinitis pigmentosa.

    PubMed

    Tam, Beatrice M; Noorwez, Syed M; Kaushal, Shalesh; Kono, Masahiro; Moritz, Orson L

    2014-10-01

    Retinitis pigmentosa (RP) is an inherited neurodegenerative disease involving progressive vision loss, and is often linked to mutations in the rhodopsin gene. Mutations that abolish N-terminal glycosylation of rhodopsin (T4K and T17M) cause sector RP in which the inferior retina preferentially degenerates, possibly due to greater light exposure of this region. Transgenic animal models expressing rhodopsin glycosylation mutants also exhibit light exacerbated retinal degeneration (RD). In this study, we used transgenic Xenopus laevis to investigate the pathogenic mechanism connecting light exposure and RD in photoreceptors expressing T4K or T17M rhodopsin. We demonstrate that increasing the thermal stability of these rhodopsins via a novel disulfide bond resulted in significantly less RD. Furthermore, T4K or T17M rhodopsins that were constitutively inactive (due to lack of the chromophore-binding site or dietary deprivation of the chromophore precursor vitamin A) induced less toxicity. In contrast, variants in the active conformation accumulated in the ER and caused RD even in the absence of light. In vitro, T4K and T17M rhodopsins showed reduced ability to regenerate pigment after light exposure. Finally, although multiple amino acid substitutions of T4 abolished glycosylation at N2 but were not toxic, similar substitutions of T17 were not tolerated, suggesting that the carbohydrate moiety at N15 is critical for cell viability. Our results identify a novel pathogenic mechanism in which the glycosylation-deficient rhodopsins are destabilized by light activation. These results have important implications for proposed RP therapies, such as vitamin A supplementation, which may be ineffective or even detrimental for certain RP genotypes. PMID:25274813

  7. Essential and synergistic roles of RP1 and RP1L1 in rod photoreceptor axoneme and retinitis pigmentosa

    PubMed Central

    Yamashita, Tetsuji; Liu, Jiewu; Gao, Jiangang; LeNoue, Sean; Wang, Changguan; Kaminoh, Jack; Bowne, Sara J.; Sullivan, Lori S.; Daiger, Stephen P.; Zhang, Kang; Fitzgerald, Malinda E.C.; Kefalov, Vladimir J.; Zuo, Jian

    2009-01-01

    Retinitis pigmentosa 1 (RP1) is a common inherited retinopathy with variable onset and severity. The RP1 gene encodes a photoreceptor-specific, microtubule-associated ciliary protein containing the doublecortin (DCX) domain. Here we show that another photoreceptor-specific Rp1-like protein (Rp1L1) in mice is also localized to the axoneme of outer segments (OS) and connecting cilia in rod photoreceptors, overlapping with Rp1. Rp1L1−/− mice display scattered OS disorganization, reduced electroretinogram amplitudes, and progressive photoreceptor degeneration, less severe and slower than in Rp1−/− mice. In single rods of Rp1L1−/−, photosensitivity is reduced, similar to that of Rp1−/−. While individual heterozygotes are normal, double heterozygotes of Rp1 and Rp1L1 exhibit abnormal OS morphology and reduced single rod photosensitivity and dark currents. The electroretinogram amplitudes of double heterozygotes are more reduced than those of individual heterozygotes combined. In support, Rp1L1 interacts with Rp1 in transfected cells and in retina pull-down experiments. Interestingly, phototransduction kinetics are normal in single rods and whole retinas of individual or double Rp1 and Rp1L1 mutant mice. Together, Rp1 and Rp1L1 play essential and synergistic roles in affecting photosensitivity and OS morphogenesis of rod photoreceptors. Our findings suggest that mutations in RP1L1 could underlie retinopathy or modify RP1 disease expression in humans. PMID:19657028

  8. A recombination outside the BB deletion refines the location of the X linked retinitis pigmentosa locus RP3.

    PubMed Central

    Fujita, R.; Bingham, E.; Forsythe, P.; McHenry, C.; Aita, V.; Navia, B. A.; Dry, K.; Segal, M.; Devoto, M.; Bruns, G.; Wright, A. F.; Ott, J.; Sieving, P. A.; Swaroop, A.

    1996-01-01

    Genetic loci for X-linked retinitis pigmentosa (XLRP) have been mapped between Xp11.22 and Xp22.13 (RP2, RP3, RP6, and RP15). The RP3 gene, which is responsible for the predominant form of XLRP in most Caucasian populations, has been localized to Xp21.1 by linkage analysis and the map positions of chromosomal deletions associated with the disease. Previous linkage studies have suggested that RP3 is flanked by the markers DXS1110 (distal) and OTC (proximal). Patient BB was thought to have RP because of a lesion at the RP3 locus, in addition to chronic granulomatous disease, Duchenne muscular dystrophy (DMD), mild mental retardation, and the McLeod phenotype. This patient carried a deletion extending approximately 3 Mb from DMD in Xp21.3 to Xp21.1, with the proximal breakpoint located approximately 40 kb centromeric to DXS1110. The RP3 gene, therefore, is believed to reside between DXS1110 and the proximal breakpoint of the BB deletion. In order to refine the location of RP3 and to ascertain patients with RP3, we have been analyzing several XLRP families for linkage to Xp markers. Linkage analysis in an American family of 27 individuals demonstrates segregation of XLRP with markers in Xp21.1, consistent with the RP3 subtype. One affected mate shows a recombination event proximal to DXS1110. Additional markers within the DXS1110-OTC interval show that the crossover is between two novel polymorphic markers, DXS8349 and M6, both of which are present in BB DNA and lie centromeric to the proximal breakpoint. This recombination places the XLRP mutation in this family outside the BB deletion and redefines the location of RP3. PMID:8659520

  9. A recombination outside the BB deletion refines the location of the X-linked retinitis pigmentosa locus RP3

    SciTech Connect

    Fujita, R.; Bingham, E.; Forsythe, P.; McHenry, C.

    1996-07-01

    Genetic loci for X-linked retinitis pigmentosa (XLRP) have been mapped between Xp11.22 and Xp22.13 (RP2, RP3, RP6, and RP15). The RP3 gene, which is responsible for the predominant form of XLRP in most Caucasian populations, has been localized to Xp21.1 by linkage analysis and the map positions of chromosomal deletions associated with the disease. Previous linkage studies have suggested that RP3 is flanked by the markers DXS1110 (distal) and OTC (proximal). Patient BB was though to have RP because of a lesion at the RP3 locus, in addition to chronic granulomatous disease, Duchenne muscular dystrophy (DMD), mild mental retardation, and the McLeod phenotype. This patient carried a deletion extending {approximately}3 Mb from DMD in Xp21.3 to Xp21.1, with the proximal breakpoint located {approximately}40 kb centromeric to DXS1110. The RP3 gene, therefore, is believed to reside between DXS1110 and the proximal breakpoint of the BB deletion. In order to refine the location of RP3 and to ascertain patients with RP3, we have been analyzing several XLRP families for linkage to Xp markers. Linkage analysis in an American family of 27 individuals demonstrates segregation of XLRP with markers in Xp21.1, consistent with the RP3 subtype. One affected male shows a recombination event proximal to DXS1110. Additional markers within the DXS1110-OTC interval show that the crossover is between two novel polymorphic markers, DXS8349 and M6, both of which are present in BB DNA and lie centromeric to the proximal breakpoint. This recombination places the XLRP mutation in this family outside the BB deletion and redefines the location of RP3. 22 refs., 3 figs., 2 tabs.

  10. Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families

    PubMed Central

    Khan, Shahid Y.; Ali, Shahbaz; Naeem, Muhammad Asif; Khan, Shaheen N.; Husnain, Tayyab; Butt, Nadeem H.; Qazi, Zaheeruddin A.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

    2015-01-01

    Purpose This study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin. Methods Ophthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1. Results A large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028–1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408–2A>G. In silico analysis suggested that these

  11. TSC but not PTEN loss in starving cones of retinitis pigmentosa mice leads to an autophagy defect and mTORC1 dissociation from the lysosome.

    PubMed

    Venkatesh, A; Ma, S; Punzo, C

    2016-01-01

    Understanding the mechanisms that contribute to secondary cone photoreceptor loss in retinitis pigmentosa (RP) is critical to devise strategies to prolong vision in this neurodegenerative disease. We previously showed that constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1), by loss of its negative regulator the tuberous sclerosis complex protein 1 (Tsc1; also known as Hamartin), was sufficient to promote robust survival of nutrient-stressed cones in two mouse models of RP by improving glucose uptake and utilization. However, while cone protection remained initially stable for several weeks, eventually cone loss resumed. Here we show that loss of Tsc1 in the cones of RP mice causes a defect in autophagy, leading to the accumulation of ubiquitinated aggregates. We demonstrate that this defect was not due to an inhibition of autophagy initiation, but due to an accumulation of autolysosomes, suggesting a defect in the end-stage of the process causing an amino-acid shortage in cones, thereby hampering long-term cone survival. Because cells with TSC loss fail to completely inhibit mTORC1 and properly activate autophagy in the absence of amino acids, we sporadically administered the mTORC1 inhibitor rapamycin, which was sufficient to correct the defects seen in cones, further enhancing the efficiency of cone survival mediated by Tsc1 loss. Concordantly, activation of mTORC1 by loss of the phosphatase and tensin homolog (Pten) did not affect autophagy and amino-acid metabolism, leading to a more sustained long-term protection of cones. As loss of Pten, which in cones results in less robust mTORC1 activation when compared with loss of Tsc1, still affords long-term cone survival, therapeutic interventions with mTORC1 activators or gene therapy with selected mTORC1 targets that improve glucose metabolism are potential strategies to delay vision loss in patients with RP. PMID:27362797

  12. The retinitis pigmentosa-mutated RP2 protein exhibits exonuclease activity and translocates to the nucleus in response to DNA damage

    SciTech Connect

    Yoon, Jung-Hoon; Qiu Junzhuan; Cai Sheng; Chen Yuan; Cheetham, Michael E.; Shen Binghui; Pfeifer, Gerd P. . E-mail: gpfeifer@coh.org

    2006-05-01

    Retinitis pigmentosa (RP) is a genetically heterogeneous disease characterized by degeneration of the retina. Mutations in the RP2 gene are linked to the second most frequent form of X-linked retinitis pigmentosa. RP2 is a plasma membrane-associated protein of unknown function. The N-terminal domain of RP2 shares amino acid sequence similarity to the tubulin-specific chaperone protein co-factor C. The C-terminus consists of a domain with similarity to nucleoside diphosphate kinases (NDKs). Human NDK1, in addition to its role in providing nucleoside triphosphates, has recently been described as a 3' to 5' exonuclease. Here, we show that RP2 is a DNA-binding protein that exhibits exonuclease activity, with a preference for single-stranded or nicked DNA substrates that occur as intermediates of base excision repair pathways. Furthermore, we show that RP2 undergoes re-localization into the nucleus upon treatment of cells with DNA damaging agents inducing oxidative stress, most notably solar simulated light and UVA radiation. The data suggest that RP2 may have previously unrecognized roles as a DNA damage response factor and 3' to 5' exonuclease.

  13. Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Bhootada, Yogesh; Kotla, Pravallika; Zolotukhin, Sergei; Gorbatyuk, Oleg; Bebok, Zsuzsanna; Athar, Mohammad; Gorbatyuk, Marina

    2016-01-01

    T17M rhodopsin expression in rod photoreceptors leads to severe retinal degeneration and is associated with the activation of ER stress related Unfolded Protein Response (UPR) signaling. Here, we show a novel role of a UPR transcription factor, ATF4, in photoreceptor cellular pathology. We demonstrated a pro-death role for ATF4 overexpression during autosomal dominant retinitis pigmentosa (ADRP). Based on our results in ATF4 knockout mice and adeno-associated viral (AAV) delivery of ATF4 to the retina, we validated a novel therapeutic approach targeting ATF4 over the course of retinal degeneration. In T17M rhodopsin retinas, we observed ATF4 overexpression concomitantly with reduction of p62 and elevation of p53 levels. These molecular alterations, together with increased CHOP and caspase-3/7 activity, possibly contributed to the mechanism of photoreceptor cell loss. Conversely, ATF4 knockdown retarded retinal degeneration in 1-month-old T17M Rhodopsin mice and promoted photoreceptor survival, as measured by scotopic and photopic ERGs and photoreceptor nuclei row counts. Similarly, ATF4 knockdown also markedly delayed retinal degeneration in 3-month-old ADRP animals. This delay was accompanied by a dramatic decrease in UPR signaling, the launching of anti-oxidant defense, initiation of autophagy, and improvement of rhodopsin biosynthesis which together perhaps combat the cellular stress associated with T17M rhodopsin. Our data indicate that augmented ATF4 signals during retinal degeneration plays a cytotoxic role by triggering photoreceptor cell death. Future ADRP therapy regulating ATF4 expression can be developed to treat retinal degenerative disorders associated with activated UPR. PMID:27144303

  14. Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.

    PubMed

    Bhootada, Yogesh; Kotla, Pravallika; Zolotukhin, Sergei; Gorbatyuk, Oleg; Bebok, Zsuzsanna; Athar, Mohammad; Gorbatyuk, Marina

    2016-01-01

    T17M rhodopsin expression in rod photoreceptors leads to severe retinal degeneration and is associated with the activation of ER stress related Unfolded Protein Response (UPR) signaling. Here, we show a novel role of a UPR transcription factor, ATF4, in photoreceptor cellular pathology. We demonstrated a pro-death role for ATF4 overexpression during autosomal dominant retinitis pigmentosa (ADRP). Based on our results in ATF4 knockout mice and adeno-associated viral (AAV) delivery of ATF4 to the retina, we validated a novel therapeutic approach targeting ATF4 over the course of retinal degeneration. In T17M rhodopsin retinas, we observed ATF4 overexpression concomitantly with reduction of p62 and elevation of p53 levels. These molecular alterations, together with increased CHOP and caspase-3/7 activity, possibly contributed to the mechanism of photoreceptor cell loss. Conversely, ATF4 knockdown retarded retinal degeneration in 1-month-old T17M Rhodopsin mice and promoted photoreceptor survival, as measured by scotopic and photopic ERGs and photoreceptor nuclei row counts. Similarly, ATF4 knockdown also markedly delayed retinal degeneration in 3-month-old ADRP animals. This delay was accompanied by a dramatic decrease in UPR signaling, the launching of anti-oxidant defense, initiation of autophagy, and improvement of rhodopsin biosynthesis which together perhaps combat the cellular stress associated with T17M rhodopsin. Our data indicate that augmented ATF4 signals during retinal degeneration plays a cytotoxic role by triggering photoreceptor cell death. Future ADRP therapy regulating ATF4 expression can be developed to treat retinal degenerative disorders associated with activated UPR. PMID:27144303

  15. Increased Risk of Acute Angle Closure in Retinitis Pigmentosa: A Population-Based Case-Control Study

    PubMed Central

    Ko, Yu-Chieh; Liu, Chia-Jen; Hwang, De-Kuang; Chen, Tzeng-Ji; Liu, Catherine J.

    2014-01-01

    Purpose To investigate the association between retinitis pigmentosa (RP) and acute angle closure during a 15-year follow-up period. Methods Using the Taiwan Longitudinal Health Insurance Database 2000, we identified 382 RP patients based on the diagnostic code of RP (International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) 362.74) made during 1996–2010, excluding subjects under age of 20 years at diagnosis or subjects undergoing lens extraction before the index date. The control group included 3820 randomly selected non-RP subjects matched with the RP patients in age, gender and the index date of diagnosis. The incidence of acute angle closure during the study period was observed based on an ICD-9-CM code of 365.22. Cochran-Mantel-Haenszel test was used to determine the odds ratio (OR) of having acute angle closure in RP patients. Results The mean age at the diagnosis of RP was 51.1years (standard deviation [SD] 16.7). Acute angle closure occurred in 5 RP patients (1.3%) and in 15 controls (0.4%). The mean age with the acute angle closure was 53.3 years (SD 8.0) in RP patients and 64.6 years (SD 8.4) in controls (P = 0.015). After adjusting for age, gender and comorbid disorders, RP patients had 3.64-fold (95% confidence interval [CI], 1.29–10.25, P<0.001) greater odds of having acute angle closure. After stratification for gender and age, the risk of acute angle closure in RP was higher in patients under age of 60 years (adjusted OR 11.84; 95% CI, 2.84–49.48) and male patients (adjusted OR 19.36; 95% CI, 3.43–109.40)(both P = 0.001). Conclusions RP patients had increased risk of acute angle closure than controls. Contrary to the fact that angle closure disease is more prevalent in elderly females in general population, acute angle closure attack occurred earlier in life and the risk was higher in males among RP patients. PMID:25222486

  16. Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7

    PubMed Central

    Van Schil, Kristof; Karlstetter, Marcus; Aslanidis, Alexander; Dannhausen, Katharina; Azam, Maleeha; Qamar, Raheel; Leroy, Bart P.; Depasse, Fanny; Langmann, Thomas; De Baere, Elfride

    2016-01-01

    The aim of this study was to unravel the molecular pathogenesis of an unusual retinitis pigmentosa (RP) phenotype observed in a Turkish consanguineous family. Homozygosity mapping revealed two candidate genes, SAMD7 and RHO. A homozygous RHO mutation c.448G > A, p.E150K was found in two affected siblings, while no coding SAMD7 mutations were identified. Interestingly, four non-coding homozygous variants were found in two SAMD7 genomic regions relevant for binding of the retinal transcription factor CRX (CRX-bound regions, CBRs) in these affected siblings. Three variants are located in a promoter CBR termed CBR1, while the fourth is located more downstream in CBR2. Transcriptional activity of these variants was assessed by luciferase assays and electroporation of mouse retinal explants with reporter constructs of wild-type and variant SAMD7 CBRs. The combined CBR2/CBR1 variant construct showed significantly decreased SAMD7 reporter activity compared to the wild-type sequence, suggesting a cis-regulatory effect on SAMD7 expression. As Samd7 is a recently identified Crx-regulated transcriptional repressor in retina, we hypothesize that these SAMD7 variants might contribute to the retinal phenotype observed here, characterized by unusual, recognizable pigment deposits, differing from the classic spicular intraretinal pigmentation observed in other individuals homozygous for p.E150K, and typically associated with RP in general. PMID:26887858

  17. Two novel PRPF31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa

    PubMed Central

    Dong, Bing; Chen, Jieqiong; Zhang, Xiaohui; Pan, Zhe; Bai, Fengge

    2013-01-01

    Objective To identify the causative mutations in two Chinese families with retinitis pigmentosa (RP), and to describe the associated phenotype. Methods Individuals from two unrelated families underwent full ophthalmic examinations. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Linkage analysis was performed on the known genetic loci for autosomal dominant retinitis pigmentosa with a panel of polymorphic markers in the two families, and then all coding exons of the PRP31 premessenger ribonucleic acid processing factor 31 homolog (PRPF31) gene were screened for mutations with direct sequencing of PCR-amplified DNA fragments. Allele-specific PCR was used to validate a substitution in all available family members and 100 normal controls. A large deletion was detected with real-time quantitative PCR (RQ-PCR) using a panel of primers from regions around the PRPF31 gene. Long-range PCR, followed by DNA sequencing, was used to define the breakpoints. Results Clinical examination and pedigree analysis revealed two four-generation families (RP24 and RP106) with autosomal dominant retinitis pigmentosa. A significant two-point linkage odd disequilibrium score was generated at marker D19S926 (Zmax=3.55, θ=0) for family RP24 and D19S571 (Zmax=3.21, θ=0) for family RP106, and further linkage and haplotype studies confined the disease locus to chromosome 19q13.42 where the PRPF31 gene is located. Mutation screening of the PRPF31 gene revealed a novel deletion c.1215delG (p.G405fs+7X) in family RP106. The deletion cosegregated with the family’s disease phenotype, but was not found in 100 normal controls. No disease-causing mutation was detected in family RP24 with PCR-based sequencing analysis. RQ-PCR and long-range PCR analysis revealed a complex insertion-deletion (indel) in the patients of family RP24. The deletion is more than 19 kb and encompasses part of the PRPF31 gene (exons 1–3), together with three adjacent

  18. Dominant Retinitis Pigmentosa, p.Gly56Arg Mutation in NR2E3: Phenotype in a Large Cohort of 24 Cases

    PubMed Central

    Lopez Martinez, Miguel Angel; Lopez-Molina, Maria Isabel; Riveiro-Alvarez, Rosa; Fernandez-San Jose, Patricia; Avila-Fernandez, Almudena; Corton, Marta; Millan, Jose M.; García Sandoval, Blanca; Ayuso, Carmen

    2016-01-01

    Importance This research is the single largest NR2E3 genotype-phenotype correlation study performed to date in autosomal dominant Retinitis Pigmentosa. Objective The aim of this study is to analyse the frequency of the p.Gly56Arg mutation in NR2E3 for the largest cohort of autosomal dominant Retinitis Pigmentosa patients to date and its associated phenotype. Patients and Methods A cohort of 201 unrelated Spanish families affected by autosomal dominant Retinitis Pigmentosa. The p.Gly56Arg mutation in the NR2E3 (NM_014249.2) gene was analysed in 201 families. In the 24 cases where the mutation had been detected, a haplotype analysis linked to the p.Gly56Arg families was performed, using four extragenic polymorphic markers D15S967, D15S1050, D15S204 and D15S188. Phenotype study included presence and age of onset of night blindness, visual field loss and cataracts; and an ophthalmoscopic examination after pupillary dilation and electroretinogram for the 24 cases. Results Seven of the 201 analyzed families were positive for the p.Gly56Arg, leading to a prevalence of 3.5%. Clinical data were available for 24 subjects. Night blindness was the first noticeable symptom (mean 15.9 years). Visual field loss onset was variable (23.3 ± 11.9 years). Loss of visual acuity appeared late in the disease´s evolution. Most of the patients with cataracts (50%) presented it from the third decade of life. Fundus changes showed inter and intrafamiliar variability, but most of the patients showed typical RP changes and it was common to find macular affectation (47.4%). Electroretinogram was impaired from the beginning of the disease. Two families shared a common haplotype. Additionally, all patients shared a 104Kb region between D15S1050 and the NR2E3 gene. Conclusions This study highlights the importance of p.Gly56Arg in the NR2E3 gene as a common mutation associated with adRP, and provides new clues to its phenotype, which can allow for a better clinical management and genetic

  19. Accounting for disagreements on average cone loss rates in retinitis pigmentosa with a new kinetic model: Its relevance for clinical trials.

    PubMed

    Baumgartner, W A; Baumgartner, A M

    2016-04-01

    Since 1985, at least nine studies of the average rate of cone loss in retinitis pigmentosa (RP) populations have yielded conflicting average rate constant values (-k), differing by 90-160%. This is surprising, since, except for the first two investigations, the Harvard or Johns Hopkins' protocols used in these studies were identical with respect to: use of the same exponential decline model, calculation of average -k from individual patient k values, monitoring patients over similarly large time frames, and excluding data exhibiting floor and ceiling effects. A detailed analysis of Harvard's and Hopkins' protocols and data revealed two subtle differences: (i) Hopkins' use of half-life t0.5 (or t(1/e)) for expressing patient cone-loss rates rather than k as used by Harvard; (ii) Harvard obtaining substantially more +k from improving fields due to dormant-cone recovery effects and "small -k" values than Hopkins' ("small -k" is defined as less than -0.040 year(-1)), e.g., 16% +k, 31% small -k, vs. Hopkins' 3% and 6% respectively. Since t0.5=0.693/k, it follows that when k=0, or is very small, t0.5 (or t(1/e)) is respectively infinity or a very large number. This unfortunate mathematical property (which also prevents t0.5 (t(1/e)) histogram construction corresponding to -k to +k) caused Hopkins' to delete all "small -k" and all +k due to "strong leverage". Naturally this contributed to Hopkins' larger average -k. Difference (ii) led us to re-evaluate the Harvard/Hopkins' exponential unchanging -k model. In its place we propose a model of increasing biochemical stresses from dying rods on cones during RP progression: increasing oxidative stresses and trophic factor deficiencies (e.g., RdCVF), and RPE malfunction. Our kinetic analysis showed rod loss to follow exponential kinetics with unchanging -k due to constant genetic stresses, thereby providing a theoretical basis for Clarke et al.'s empirical observation of such kinetics with eleven animal models of RP. In

  20. TIMP-1 affects the spatial distribution of dendritic processes of second-order neurons in a rat model of Retinitis Pigmentosa.

    PubMed

    Shin, Jung-A; Eom, Yun Sung; Yu, Wan-Qing; Grzywacz, Norberto M; Craft, Cheryl Mae; Lee, Eun-Jin

    2015-11-01

    Retinitis Pigmentosa (RP) is an inherited disorder that may lead to blindness. In the rhodopsin S334ter-line-3 rat model of RP, the death of rods induces spatial rearrangement of cones into regular ring mosaics. Using this model, we discovered that the ring mosaics are restored to a homogeneous distribution upon application of tissue inhibitor of metalloproteinase-1 (TIMP-1). In this study, we further investigated the cone migration and spatial distribution of second-order neurons and their connections to cones in the presence or absence of TIMP-1 using immunohistochemistry to identify retinal neurons and their connections with cones. M-opsin cell bodies and their outer segments were evaluated to determine whether TIMP-1 delays the degeneration of outer segments of cones. We observed that during cone rearrangement into ring mosaics in RP retina, dendritic processes of second-order neurons undergo remodeling to maintain their synaptic connections with the cones in the rings. TIMP-1 treatment induced the cones to rearrange and dendritic processes of second-order neurons to return to a more homogeneous spatial distribution. In addition, TIMP-1 treatment protected the outer segments of cones at later stages of retinal degeneration. Our findings clearly demonstrate that despite their dramatic spatial rearrangement, cones and second-order neuron processes maintain their synaptic connections before and after TIMP-1 treatment. PMID:26277580

  1. Light Induces Ultrastructural Changes in Rod Outer and Inner Segments, Including Autophagy, in a Transgenic Xenopus laevis P23H Rhodopsin Model of Retinitis Pigmentosa

    PubMed Central

    Bogéa, Tami H.; Wen, Runxia H.; Moritz, Orson L.

    2015-01-01

    Purpose We previously reported a transgenic Xenopus laevis model of retinitis pigmentosa in which tadpoles express the bovine form of P23H rhodopsin (bP23H) in rod photoreceptors. In this model, retinal degeneration was dependent on light exposure. Here, we investigated ultrastructural changes that occurred in the rod photoreceptors of these retinas when exposed to light. Methods Tadpoles expressing bP23H in rods were transferred from constant darkness to a 12-hour light:12-hour dark (12L:12D) regimen. For comparison, transgenic tadpoles expressing an inducible form of caspase 9 (iCasp9) were reared in a 12L:12D regimen, and retinal degeneration was induced by administration of the drug AP20187. Tadpoles were euthanized at various time points, and eyes were processed for confocal light and transmission electron microscopy. Results We observed defects in outer and inner segments of rods expressing bP23H that were aggravated by light exposure. Rod outer segments exhibited vesiculations throughout and were rapidly phagocytosed by the retinal pigment epithelium. In rod inner segments, we observed autophagic compartments adjacent to the endoplasmic reticulum and extensive vesiculation at later time points. These defects were not found in rods expressing iCasp9, which completely degenerated within 36 hours after drug administration. Conclusions Our results indicate that ultrastructural defects in outer and inner segment membranes of bP23H expressing rods differ from those observed in drug-induced apoptosis. We suggest that light-induced retinal degeneration caused by P23H rhodopsin occurs via cell death with autophagy, which may represent an attempt to eliminate the mutant rhodopsin and/or damaged cellular compartments from the secretory pathway. PMID:26720441

  2. Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa.

    PubMed

    Angius, Andrea; Uva, Paolo; Buers, Insa; Oppo, Manuela; Puddu, Alessandro; Onano, Stefano; Persico, Ivana; Loi, Angela; Marcia, Loredana; Höhne, Wolfgang; Cuccuru, Gianmauro; Fotia, Giorgio; Deiana, Manila; Marongiu, Mara; Atalay, Hatice Tuba; Inan, Sibel; El Assy, Osama; Smit, Leo M E; Okur, Ilyas; Boduroglu, Koray; Utine, Gülen Eda; Kılıç, Esra; Zampino, Giuseppe; Crisponi, Giangiorgio; Crisponi, Laura; Rutsch, Frank

    2016-07-01

    Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1) is a very rare autosomal-recessive disorder characterized by a complex phenotype with high neonatal lethality, associated with the following main clinical features: hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold since early childhood. CS/CISS1 can be caused by mutations in cytokine receptor-like factor 1 (CRLF1). However, the physiopathological role of CRLF1 is still poorly understood. A subset of CS/CISS1 cases remain yet genetically unexplained after CRLF1 sequencing. In five of them, exome sequencing and targeted Sanger sequencing identified four homozygous disease-causing mutations in kelch-like family member 7 (KLHL7), affecting the Kelch domains of the protein. KLHL7 encodes a BTB-Kelch-related protein involved in the ubiquitination of target proteins for proteasome-mediated degradation. Mono-allelic substitutions in other domains of KLHL7 have been reported in three families affected by a late-onset form of autosomal-dominant retinitis pigmentosa. Retinitis pigmentosa was also present in two surviving children reported here carrying bi-allelic KLHL7 mutations. KLHL7 mutations are thus associated with a more severe phenotype in recessive than in dominant cases. Although these data further support the pathogenic role of KLHL7 mutations in a CS/CISS1-like phenotype, they do not explain all their clinical manifestations and highlight the high phenotypic heterogeneity associated with mutations in KLHL7. PMID:27392078

  3. Learning about Retinitis Pigmentosa

    MedlinePlus

    ... for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues ...

  4. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.

    PubMed

    Cai, Xue; Conley, Shannon M; Nash, Zack; Fliesler, Steven J; Cooper, Mark J; Naash, Muna I

    2010-04-01

    The purpose of the present study was to test the therapeutic efficiency and safety of compacted-DNA nanoparticle-mediated gene delivery into the subretinal space of a juvenile mouse model of retinitis pigmentosa. Nanoparticles containing the mouse opsin promoter and wild-type mouse Rds gene were injected subretinally into mice carrying a haploinsufficiency mutation in the retinal degeneration slow (rds(+ or -)) gene at postnatal day (P)5 and 22. Control mice were either injected with saline, injected with uncompacted naked plasmid DNA carrying the Rds gene, or remained untreated. Rds mRNA levels peaked at postinjection day 2 to 7 (PI-2 to PI-7) for P5 injections, stabilized at levels 2-fold higher than in uninjected controls for both P5 and P22 injections, and remained elevated at the latest time point examined (PI-120). Rod function (measured by electroretinography) showed modest but statistically significant improvement compared with controls after both P5 and P22 injections. Cone function in nanoparticle-injected eyes reached wild-type levels for both ages of injections, indicating full prevention of cone degeneration. Ultrastructural examination at PI-120 revealed significant improvement in outer segment structures in P5 nanoparticle-injected eyes, while P22 injection had a modest structural improvement. There was no evidence of macrophage activation or induction of IL-6 or TNF-alpha mRNA in P5 or P22 nanoparticle-dosed eyes at either PI-2 or PI-30. Thus, compacted-DNA nanoparticles can efficiently and safely drive gene expression in both mitotic and postmitotic photoreceptors and retard degeneration in this model. These findings, using a clinically relevant treatment paradigm, illustrate the potential for application of nanoparticle-based gene replacement therapy for treatment of human retinal degenerations.-Cai, X., Conley, S. M., Nash, Z., Fliesler, S. J., Cooper, M. J., Naash, M. I. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA

  5. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa.

    PubMed

    Zabel, Matthew K; Zhao, Lian; Zhang, Yikui; Gonzalez, Shaimar R; Ma, Wenxin; Wang, Xu; Fariss, Robert N; Wong, Wai T

    2016-09-01

    Retinitis pigmentosa (RP), a disease characterized by the progressive degeneration of mutation-bearing photoreceptors, is a significant cause of incurable blindness in the young worldwide. Recent studies have found that activated retinal microglia contribute to photoreceptor demise via phagocytosis and proinflammatory factor production, however mechanisms regulating these contributions are not well-defined. In this study, we investigate the role of CX3CR1, a microglia-specific receptor, in regulating microglia-mediated degeneration using the well-established rd10 mouse model of RP. We found that in CX3CR1-deficient (CX3CR1(GFP/GFP) ) rd10 mice microglial infiltration into the photoreceptor layer was significantly augmented and associated with accelerated photoreceptor apoptosis and atrophy compared with CX3CR1-sufficient (CX3CR1(GFP/+) ) rd10 littermates. CX3CR1-deficient microglia demonstrated increased phagocytosis as evidenced by (1) having increased numbers of phagosomes in vivo, (2) an increased rate of phagocytosis of fluorescent beads and photoreceptor cellular debris in vitro, and (3) increased photoreceptor phagocytosis dynamics on live cell imaging in retinal explants, indicating that CX3CR1 signaling in microglia regulates the phagocytic clearance of at-risk photoreceptors. We also found that CX3CR1 deficiency in retinal microglia was associated with increased expression of inflammatory cytokines and microglial activation markers. Significantly, increasing CX3CL1-CX3CR1 signaling in the rd10 retina via exogenous intravitreal delivery of recombinant CX3CL1 was effective in (1) decreasing microglial infiltration, phagocytosis and activation, and (2) improving structural and functional features of photoreceptor degeneration. These results indicate that CX3CL1-CX3CR1 signaling is a molecular mechanism capable of modulating microglial-mediated degeneration and represents a potential molecular target in therapeutic approaches to RP. GLIA 2016

  6. Assistive peripheral phosphene arrays deliver advantages in obstacle avoidance in simulated end-stage retinitis pigmentosa: a virtual-reality study

    NASA Astrophysics Data System (ADS)

    Zapf, Marc Patrick H.; Boon, Mei-Ying; Lovell, Nigel H.; Suaning, Gregg J.

    2016-04-01

    Objective. The prospective efficacy of peripheral retinal prostheses for guiding orientation and mobility in the absence of residual vision, as compared to an implant for the central visual field (VF), was evaluated using simulated prosthetic vision (SPV). Approach. Sighted volunteers wearing a head-mounted display performed an obstacle circumvention task under SPV. Mobility and orientation performance with three layouts of prosthetic vision were compared: peripheral prosthetic vision of higher visual acuity (VA) but limited VF, of wider VF but limited VA, as well as centrally restricted prosthetic vision. Learning curves using these layouts were compared fitting an exponential model to the mobility and orientation measures. Main results. Using peripheral layouts, performance was superior to the central layout. Walking speed with both higher-acuity and wider-angle layouts was 5.6% higher, and mobility errors reduced by 46.4% and 48.6%, respectively, as compared to the central layout. The wider-angle layout yielded the least number of collisions, 63% less than the higher-acuity and 73% less than the central layout. Using peripheral layouts, the number of visual-scanning related head movements was 54.3% (higher-acuity) and 60.7% (wider-angle) lower, as compared to the central layout, and the ratio of time standing versus time walking was 51.9% and 61.5% lower, respectively. Learning curves did not differ between layouts, except for time standing versus time walking, where both peripheral layouts achieved significantly lower asymptotic values compared to the central layout. Significance. Beyond complementing residual vision for an improved performance, peripheral prosthetic vision can effectively guide mobility in the later stages of retinitis pigmentosa (RP) without residual vision. Further, the temporal dynamics of learning peripheral and central prosthetic vision are similar. Therefore, development of a peripheral retinal prosthesis and early implantation to

  7. Reshaping the Cone-Mosaic in a Rat Model of Retinitis Pigmentosa: Modulatory Role of ZO-1 Expression in DL-Alpha-Aminoadipic Acid Reshaping

    PubMed Central

    Shin, Jung-A; Nair, Divya; Grzywacz, Sara X. Z.; Grzywacz, Norberto M.; Craft, Cheryl Mae; Lee, Eun-Jin

    2016-01-01

    In S334ter-line-3 rat model of Retinitis Pigmentosa (RP), rod cell death induces the rearrangement of cones into mosaics of rings while the fibrotic processes of Müller cells remodel to fill the center of the rings. In contrast, previous work established that DL-alpha-aminoadipic-acid (AAA), a compound that transiently blocks Müller cell metabolism, abolishes these highly structured cone rings. Simultaneously, adherens-junction associated protein, Zonula occludens-1 (ZO-1) expression forms in a network between the photoreceptor segments and Müller cells processes. Thus, we hypothesized that AAA treatment alters the cone mosaic rings by disrupting the distal sealing formed by these fibrotic processes, either directly or indirectly, by down regulating the expression of ZO-1. Therefore, we examined these processes and ZO-1 expression at the outer retina after intravitreal injection of AAA and observed that AAA treatment transiently disrupts the distal glial sealing in RP retina, plus induces cones in rings to become more homogeneous. Moreover, ZO-1 expression is actively suppressed after 3 days of AAA treatment, which coincided with cone ring disruption. Similar modifications of glial sealing and cone distribution were observed after injection of siRNA to inhibit ZO-1 expression. These findings support our hypothesis and provide additional information about the critical role played by ZO-1 in glial sealing and shaping the ring mosaic in RP retina. These studies represent important advancements in the understanding of retinal degeneration’s etiology and pathophysiology. PMID:26977812

  8. Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population

    SciTech Connect

    Van Soest, S.; Ingeborgh Van Den Born, L.; Bergen, A.A.B.

    1994-08-01

    Linkage analysis was carried out in a large family segregating for autosomal recessive retinitis pigmentosa (arRP), originating from a genetically isolated population in The Netherlands. Within the family, clinical heterogeneity was observed, with a major section of the family segregating arRP with characteristic para-arteriolar preservation of the retinal pigment epithelium (PPRPE). In the remainder of the arRP patients no PPRPE was found. Initially, all branches of the family were analyzed jointly, and linkage was found between the marker F13B, located at 1q31-q32.1, and RP12 ({Zeta}{sub max} = 4.99 at 8% recombination). Analysis of linkage heterogeneity between five branches of the family yielded significant evidence for nonallelic genetic heterogeneity within this family, coinciding with the observed clinical differences. Multipoint analysis, carried out in the branches that showed linkage, favored the locus order 1cen-D1S158-(F13B, RP12)-D1S53-1qter ({Zeta}{sub max} = 9.17). The finding of a single founder allele associated with the disease phenotype supports this localization. This study reveals that even in a large family, apparently segregating for a single disease entity, genetic heterogeneity can be detected and resolved successfully. 35 refs., 5 figs.

  9. Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele.

    PubMed Central

    McGee, T L; Devoto, M; Ott, J; Berson, E L; Dryja, T P

    1997-01-01

    A subset of families with autosomal dominant retinitis pigmentosa (RP) display reduced penetrance with some asymptomatic gene carriers showing no retinal abnormalities by ophthalmic examination or by electroretinography. Here we describe a study of three families with reduced-penetrance RP. In all three families the disease gene appears to be linked to chromosome 19q13.4, the region containing the RP11 locus, as defined by previously reported linkage studies based on five other reduced-penetrance families. Meiotic recombinants in one of the newly identified RP11 families and in two of the previously reported families serve to restrict the disease locus to a 6-cM region bounded by markers D19S572 and D19S926. We also compared the disease status of RP11 carriers with the segregation of microsatellite alleles within 19q13.4 from the noncarrier parents in the newly reported and the previously reported families. The results support the hypothesis that wild-type alleles at the RP11 locus or at a closely linked locus inherited from the noncarrier parents are a major factor influencing the penetrance of pathogenic alleles at this locus. PMID:9345108

  10. Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11) and association with a unique bimodal expressivity phenotype.

    PubMed Central

    Al-Maghtheh, M.; Vithana, E.; Tarttelin, E.; Jay, M.; Evans, K.; Moore, T.; Bhattacharya, S.; Inglehearn, C. F.

    1996-01-01

    Retinitis pigmentosa (RP) is the name given to a heterogeneous group of retinal degenerations mapping to at least 16 loci. The autosomal dominant form (ARP), accounting for approximately 25% of cases, can be caused by mutations in two genes, rhodopsin and peripherin/RDS, and by at least six other loci identified by linkage analysis. The RP11 locus for adRP has previously been mapped to chromosome 19q13.4 in a large English family. This linkage has been independently confirmed in a Japanese family, and we now report three additional unrelated linked U.K. families, suggesting that this is a major locus for RP. Linkage analysis in the U.K. families refines the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibit incomplete penetrance; some obligate gene carriers remain asymptomatic throughout their lives, whereas symptomatic individuals experience night blindness and visual field loss in their teens and are generally registered as blind by their 30s. This "bimodal expressivity" contrasts with the variable-expressivity RP mapping to chromosome 7p (RP9) in another family, which has implications for diagnosis and counseling of RP11 families. These results may also imply that a proportion of sporadic RP, previously assumed to be recessive, might result from mutations at this locus. PMID:8808602

  11. Identification of a Novel Heterozygous Missense Mutation in the CACNA1F Gene in a Chinese Family with Retinitis Pigmentosa by Next Generation Sequencing

    PubMed Central

    Tania, Mousumi; Wang, Hui; Khan, Md. Asaduzzaman; Duan, Chengxia; Zhu, Li; Chen, Rui; Lv, Hongbin

    2015-01-01

    Background. Retinitis pigmentosa (RP) is an inherited retinal degenerative disease, which is clinically and genetically heterogeneous, and the inheritance pattern is complex. In this study, we have intended to study the possible association of certain genes with X-linked RP (XLRP) in a Chinese family. Methods. A Chinese family with RP was recruited, and a total of seven individuals were enrolled in this genetic study. Genomic DNA was isolated from peripheral leukocytes, and used for the next generation sequencing (NGS). Results. The affected individual presented the clinical signs of XLRP. A heterozygous missense mutation (c.1555C>T, p.R519W) was identified by NGS in exon 13 of the CACNA1F gene on X chromosome, and was confirmed by Sanger sequencing. It showed perfect cosegregation with the disease in the family. The mutation at this position in the CACNA1F gene of RP was found novel by database searching. Conclusion. By using NGS, we have found a novel heterozygous missense mutation (c.1555C>T, p.R519W) in CACNA1F gene, which is probably associated with XLRP. The findings might provide new insights into the cause and diagnosis of RP, and have implications for genetic counseling and clinical management in this family. PMID:26075273

  12. Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11), and association with a unique bimodal expressivity phenotype

    SciTech Connect

    Al-Maghtheh, M.; Vithana, E.; Tarttelin, E.; Evans, K.

    1996-10-01

    Retinitis pigmentosa (RP) is the name given to a heterogeneous group of retinal degenerations mapping to at least 16 loci. The autosomal dominant form (adRP), accounting for {approximately}25% of cases, can be caused by mutations in two genes, rhodopsin and peripherin/RDS, and by at least six other loci identified by linkage analysis. The RP11 locus for adRP has previously been mapped to chromosome 19q13.4 in a large English family. This linkage has been independently confirmed in a Japanese family, and we now report three additional unrelated linked U.K. families, suggesting that this is a major locus for RP. Linkage analysis in the U.K. families refines the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibit incomplete penetrance; some obligate gene carriers remain asymptomatic throughout their lives, whereas symptomatic individuals experience night blindness and visual field loss in their teens and are generally registered as blind by their 30s. This {open_quotes}bimodal expressivity{close_quotes} contrasts with the variable-expressivity RP mapping to chromosome 7p (RP9) in another family, which has implications for diagnosis and counseling of RP11 families. These results may also imply that a proportion of sporadic RP, previously assumed to be recessive, might result from mutations at this locus. 27 refs., 3 figs., 1 tab.

  13. A novel mutation (ASn244Lys) in the peripherin/RDS gene causing autosomal dominant retinitis pigmentosa associated with bull's eye maculopathy detected by nonradioisotopic SSCP

    SciTech Connect

    Kikawa, Emi; Nakazawa, Mitsuru; Chida, Yasushi; Shiono, Takashi; Tamai, Makota )

    1994-03-01

    Retinitis pigmentosa (RP) is characterized by night blindness, an eventual loss of visual field, a diminished response on the electroretinogram, and pigmentary retinal degeneration. These features are primarily explained by the degeneration of photoreceptors. The recent development of the molecular genetic approach has enabled the identification of genes responsible for parts of autosomal dominant RP (ADRP). Rhodopsin and peripherin/RDS genes, in particular, have been successfully shown to cosegregate with ADRP. The authors, therefore, screened 42 unrelated Japanese patients with ADRP to search for mutations in the peripherin/RDS gene. The method we employed for screening was a nonradioisotopic modification of single-strand conformation polymorphism. Among 42 unrelated patients with ADRP, the DNA from one patient (SY) showed an abnormal pattern in exon 2 on SSCP. The DNA fragments were then amplified from affected and nonaffected members of the same family as SY. The alteration in the DNA sequence that was commonly found in the affected members of the family was identified as a heterozygous transversional change of C to A at the third nucleotide in codon 244, resulting in the amino acid replacement of asparagine residue with lysine residue. None of unaffected family members or 30 normal control individuals had this alteration.

  14. Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population.

    PubMed

    Zhou, Yu; Saikia, Bibhuti B; Jiang, Zhilin; Zhu, Xiong; Liu, Yuqing; Huang, Lulin; Kim, Ramasamy; Yang, Yin; Qu, Chao; Hao, Fang; Gong, Bo; Tai, Zhengfu; Niu, Lihong; Yang, Zhenglin; Sundaresan, Periasamy; Zhu, Xianjun

    2015-10-01

    Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 50 genes. To identify genetic mutations underlying autosomal recessive RP (arRP), we performed whole-exome sequencing study on two consanguineous marriage Indian families (RP-252 and RP-182) and 100 sporadic RP patients. Here we reported novel mutation in FAM161A in RP-252 and RP-182 with two patients affected with RP in each family. The FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. By whole-exome sequencing we identified several homozygous genomic regions, one of which included the recently identified FAM161A gene mutated in RP28-linked arRP. Sequencing analysis revealed the presence of a novel homozygous frameshift mutation p.R592FsX2 in both patients of family RP-252 and family RP-182. In 100 sporadic Indian RP patients, this novel homozygous frameshift mutation p.R592FsX2 was identified in one sporadic patient ARRP-S-I-46 by whole-exome sequencing and validated by Sanger sequencing. Meanwhile, this homozygous frameshift mutation was absent in 1000 ethnicity-matched control samples screened by direct Sanger sequencing. In conclusion, we identified a novel homozygous frameshift mutations of RP28-linked RP gene FAM161A in Indian population. PMID:26246154

  15. A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases

    PubMed Central

    Duno, Morten; Batbayli, Mustafa; Vilhelmsen, Kaj; Rosenberg, Thomas

    2011-01-01

    Purpose The aim of the study was to elucidate the genetic background of retinitis pigmentosa (RP) in a Faroe Islands population, a genetic isolate in the North Atlantic Ocean. Methods Blood samples were collected from subjects diagnosed with RP and their families. DNA from affected individuals underwent single nucleotide polymorphism microarray analysis and homozygosity mapping followed by sequence analysis of candidate genes. Results We identified 25 cases of nonsyndromic RP corresponding to a prevalence of 1 in 1,900. Single nucleotide polymorphism analysis revealed a homozygous region on chromosome 2q, common to patients in four families, which harbored the RP gene MER tyrosine kinase protooncogene (MERTK). A deletion of 91 kb was identified in seven patients, representing 30% of the analyzed Faroese cases of nonsyndromic RP. The clinical course of six patients who were homozygous for the deletion showed onset in the first decade followed by a rapid deterioration of both rod and cone photoreceptor function. Early macular involvement was present, in accordance with that of other reported patients with MERTK mutations. Conclusions Previous studies have shown a frequency of less than 1% of MERTK mutations in RP patients. The 91-kb deletion encompassing exons 1–7 of MERTK is a common founder mutation in the Faroe Islands, responsible for around 30% of RP, and together with mutations in protocadherin 21 (PCDH21) accounts for more than half of the retinal dystrophy cases. PMID:21677792

  16. Prurigo pigmentosa.

    PubMed

    Cox, N H

    1987-07-01

    Prurigo pigmentosa is a rare dermatosis which is most common in Japan. Although the histological features are non-specific, the clinical appearance is striking and is dominated by gross reticular pigmentation. A Chinese patient with prurigo pigmentosa is described. PMID:3651331

  17. Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations

    PubMed Central

    Jiao, K; Sahaboglu, A; Zrenner, E; Ueffing, M; Ekström, P A R; Paquet-Durand, F

    2016-01-01

    Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6aV685M/R562W mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies. PMID:27551530

  18. Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23).

    PubMed

    Webb, Tom R; Parfitt, David A; Gardner, Jessica C; Martinez, Ariadna; Bevilacqua, Dalila; Davidson, Alice E; Zito, Ilaria; Thiselton, Dawn L; Ressa, Jacob H C; Apergi, Marina; Schwarz, Nele; Kanuga, Naheed; Michaelides, Michel; Cheetham, Michael E; Gorin, Michael B; Hardcastle, Alison J

    2012-08-15

    X-linked retinitis pigmentosa (XLRP) is genetically heterogeneous with two causative genes identified, RPGR and RP2. We previously mapped a locus for a severe form of XLRP, RP23, to a 10.71 Mb interval on Xp22.31-22.13 containing 62 genes. Candidate gene screening failed to identify a causative mutation, so we adopted targeted genomic next-generation sequencing of the disease interval to determine the molecular cause of RP23. No coding variants or variants within or near splice sites were identified. In contrast, a variant deep within intron 9 of OFD1 increased the splice site prediction score 4 bp upstream of the variant. Mutations in OFD1 cause the syndromic ciliopathies orofaciodigital syndrome-1, which is male lethal, Simpson-Golabi-Behmel syndrome type 2 and Joubert syndrome. We tested the effect of the IVS9+706A>G variant on OFD1 splicing in vivo. In RP23 patient-derived RNA, we detected an OFD1 transcript with the insertion of a cryptic exon spliced between exons 9 and 10 causing a frameshift, p.N313fs.X330. Correctly spliced OFD1 was also detected in patient-derived RNA, although at reduced levels (39%), hence the mutation is not male lethal. Our data suggest that photoreceptors are uniquely susceptible to reduced expression of OFD1 and that an alternative disease mechanism can cause XLRP. This disease mechanism of reduced expression for a syndromic ciliopathy gene causing isolated retinal degeneration is reminiscent of CEP290 intronic mutations that cause Leber congenital amaurosis, and we speculate that reduced dosage of correctly spliced ciliopathy genes may be a common disease mechanism in retinal degenerations. PMID:22619378

  19. Urticaria pigmentosa

    MedlinePlus

    ... pigmentosa. Discuss these with your health care provider. Bee stings may also cause a bad allergic reaction ... epinephrine kit to use if you get a bee sting. When to Contact a Medical Professional Call ...

  20. Whole-exome sequencing identifies a novel homozygous frameshift mutation in the PROM1 gene as a causative mutation in two patients with sporadic retinitis pigmentosa.

    PubMed

    Liu, Sanmei; Xie, Lan; Yue, Jun; Ma, Tao; Peng, Chunyan; Qiu, Biyuan; Yang, Zhenglin; Yang, Jiyun

    2016-06-01

    Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited retinal diseases caused by the loss of photoreceptors. The present study aimed to identify the gene mutations responsible for RP in two patients diagnosed with sporadic RP using next-generation sequencing technology. For this purpose, two patients with sporadic RP and family members (namely parents and siblings) were recruited into this study and underwent a complete ophthalmological assessment. Whole-exome sequencing (WES) was performed on genomic DNA samples isolated from peripheral leukocytes which had been obtained from the two patients diagnosed with sporadic RP. WES data were annotated and filtered against four public databases and one in-house database. Subsequently, Sanger sequencing was performed in order to determine whether any of the candidate variants co-segregated with the disease phenotype in the families. A homozygous frameshift mutation, c.1445dupT (p.F482fs) in exon 12 of the PROM1 gene (MIM: 604365), satisfied a recessive inheritance model and showed complete co-segregation of the mutation with the disease phenotype in the families. The same mutation was not detected in the 200 ethnically-matched control samples by Sanger sequencing. The novel homozygous mutation c.1445dupT (p.F482fs) in the PROM1 gene was identified as a causative mutation for RP. Thus, the identification of this mutation has further expanded the existing spectrum of PROM1 mutations in patients with RP, thereby assisting in the molecular diagnosis of RP and enhancing our understanding of genotype-phenotype correlations in order to provide effective genetic counseling. PMID:27082927

  1. Characterisation of the canine rod-cone dysplasia type one gene (rod photoreceptor cGMP phosphodiesterase beta subunit (PDEB)) - a model for human retinitis pigmentosa

    SciTech Connect

    Clements, P.J.M.; Gregory, C.Y.; Petersen-Jones, S.M.

    1994-09-01

    Rod-cone dysplasia type one (rod-1) is an early onset, autosomal recessive retinal dystrophy segregating in the Irish setter breed. It is a model for certain forms of human autosomal recessive retinitis pigmentosa (arRP) caused by mutations in the same gene, PDEB. We confirmed the codon 807 Trp to Stop mutation and were the first to show cosegregation of the mutant allele with disease in a pedigree. We believe that this currently represents the best animal model available for some aspects of arRP, since canine tissues are relatively easy to access compared to human and yet the canine eye is of comparable size, unlike that of the rd mouse. This facilitates therapeutic intervention particularly at the subretinal level. In order to more fully investigate this model we have been characterizing the PDEB gene in the normal dog. Using PCR we have partially mapped the intron/exon structure, demonstrating a very high degree of evolutionary conservation with the mouse and human genes. RT-PCR has been used to reveal expression in a variety of neural and non-neural tissues. A PCR product spanning exons 19 to 22 (which also contains the site for the rcd-1 mutation) is detected in retina but also in tissues such as visual cortex, cerebral cortex, cerebellum, lateral geniculate nucleus, adrenal gland, lung, kidney and ovary. All of these tissues gave a negative result with primers for rds/peripherin, a gene which is expressed in rods and cones. This raises interesting questions about the regulation of PDEB transcripts which is initially being investigated by Northern analysis. In addition, anchored PCR techniques have generated upstream genomic sequences and we are currently mapping the 5{prime} extent of the mRNA transcript in the retina. This will facilitate the analysis of potential upstream promoter elements involved in directing expression.

  2. Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population

    PubMed Central

    Gamundi, María José; Hernan, Imma; Martínez-Gimeno, María; Maseras, Miquel; García-Sandoval, Blanca; Ayuso, Carmen; Antiñolo, Guillermo; Baiget, Montserrat; Carballo, Miguel

    2006-01-01

    Background Retinitis pigmentosa (RP), a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness. Mutations in the photoreceptor-specific gene RP1 account for 3–10% of cases of autosomal dominant RP (adRP). Most of these mutations are clustered in a 500 bp region of exon 4 of RP1. Methods Denaturing gradient gel electrophoresis (DGGE) analysis and direct genomic sequencing were used to evaluate the 5' coding region of exon 4 of the RP1 gene for mutations in 150 unrelated index adRP patients. Ophthalmic and electrophysiological examination of RP patients and relatives according to pre-existing protocols were carried out. Results Three novel disease-causing mutations in RP1 were detected: Q686X, K705fsX712 and K722fsX737, predicting truncated proteins. One novel missense mutation, Thr752Met, was detected in one family but the mutation does not co-segregate in the family, thereby excluding this amino acid variation in the protein as a cause of the disease. We found the Arg677Ter mutation, previously reported in other populations, in two independent families, confirming that this mutation is also present in a Spanish population. Conclusion Most of the mutations reported in the RP1 gene associated with adRP are expected to encode mutant truncated proteins that are approximately one third or half of the size of wild type protein. Patients with mutations in RP1 showed mild RP with variability in phenotype severity. We also observed several cases of non-penetrant mutations. PMID:16597330

  3. Whole-exome sequencing identifies a novel homozygous frameshift mutation in the PROM1 gene as a causative mutation in two patients with sporadic retinitis pigmentosa

    PubMed Central

    LIU, SANMEI; XIE, LAN; YUE, JUN; MA, TAO; PENG, CHUNYAN; QIU, BIYUAN; YANG, ZHENGLIN; YANG, JIYUN

    2016-01-01

    Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited retinal diseases caused by the loss of photoreceptors. The present study aimed to identify the gene mutations responsible for RP in two patients diagnosed with sporadic RP using next-generation sequencing technology. For this purpose, two patients with sporadic RP and family members (namely parents and siblings) were recruited into this study and underwent a complete ophthalmological assessment. Whole-exome sequencing (WES) was performed on genomic DNA samples isolated from peripheral leukocytes which had been obtained from the two patients diagnosed with sporadic RP. WES data were annotated and filtered against four public databases and one in-house database. Subsequently, Sanger sequencing was performed in order to determine whether any of the candidate variants co-segregated with the disease phenotype in the families. A homozygous frameshift mutation, c.1445dupT (p.F482fs) in exon 12 of the PROM1 gene (MIM: 604365), satisfied a recessive inheritance model and showed complete co-segregation of the mutation with the disease phenotype in the families. The same mutation was not detected in the 200 ethnically-matched control samples by Sanger sequencing. The novel homozygous mutation c.1445dupT (p.F482fs) in the PROM1 gene was identified as a causative mutation for RP. Thus, the identification of this mutation has further expanded the existing spectrum of PROM1 mutations in patients with RP, thereby assisting in the molecular diagnosis of RP and enhancing our understanding of genotype-phenotype correlations in order to provide effective genetic counseling. PMID:27082927

  4. Confirmation of the genetic heterogeneity of retinitis pigmentosa: Linkage analyses of the beta-subunit of rod phosphodiesterase (PDEB) in ten families

    SciTech Connect

    Kojis, T.L.; Heinzmann, C.; Bateman, J.B.

    1994-09-01

    Mutations in the gene for the {beta}-subunit of the human rod photoreceptor cGMP phosphodiesterase (PDEB) are responsible for some recessively inherited cases of retinitis pigmentosa (RP). The gene has been localized to human chromosome 4p16.3, near the Huntington disease locus (IT15), by in situ hybridization, somatic cell hybrid and linkage mapping. We previously identified and characterized RFLPs within PDEB, which we have used to establish the linkage relationships with nine other chromosome 4p16 markers in the CEPH v.6.0 database; the most likely locus order is D4S90-[PDEB-D4S115-D4S43]-[D4S95-D4S125]-IT15-[D4S126-D4S412]-D4S10. Using a combination of PDEB RFLPs and microsatellite variation in these linked marker loci, we analyzed ten families manifesting autosomal forms of RP for linkage to the PDEB reigon. PDEB was excluded as the disease-causing gene in three autosomal dominant (AD) RP families using PDEB RFLPs. While linkage to PDEB itself could not be ruled out, tight linkage to two closely linked markers (D4S115 and D4S43) was excluded in two additional AD and in three of five autosomal recessive (AR) RP families. Our data provide further evidence for the genetic heterogeneity in families with autosomal forms of RP.

  5. Linkage to D3S47 (C17) in one large autosomal dominant retinitis pigmentosa family and exclusion in another: confirmation of genetic heterogeneity.

    PubMed Central

    Lester, D H; Inglehearn, C F; Bashir, R; Ackford, H; Esakowitz, L; Jay, M; Bird, A C; Wright, A F; Papiha, S S; Bhattacharya, S S

    1990-01-01

    Recently Dryja and his co-workers observed a mutation in the 23d codon of the rhodopsin gene in a proportion of autosomal dominant retinitis pigmentosa (ADRP) patients. Linkage analysis with a rhodopsin-linked probe C17 (D3S47) was carried out in two large British ADRP families, one with diffuse-type (D-type) RP and the other with regional-type (R-type) RP. Significantly positive lod scores (lod score maximum [Zmax] = +5.58 at recombination fraction [theta] = .0) were obtained between C17 and our D-type ADRP family showing complete penetrance. Sequence and oligonucleotide analysis has, however, shown that no point mutation at the 23d codon exists in affected individuals in our complete-penetrance pedigree, indicating that another rhodopsin mutation is probably responsible for ADRP in this family. Significantly negative lod scores (Z less than -2 at theta = .045) were, however, obtained between C17 and our R-type family which showed incomplete penetrance. Previous results presented by this laboratory also showed no linkage between C17 and another large British R-type ADRP family with incomplete penetrance. This confirms genetic heterogeneity. Some types of ADRP are being caused by different mutations in the rhodopsin locus (3q21-24) or another tightly linked gene in this region, while other types of ADRP are the result of mutations elsewhere in the genome. Images Figure 2 Figure 3 Figure 4 PMID:2393026

  6. RHO Mutations (p.W126L and p.A346P) in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Akahori, Masakazu; Itabashi, Takeshi; Nishino, Jo; Yoshitake, Kazutoshi; Ikeo, Kazuho; Tsuneoka, Hiroshi

    2014-01-01

    Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP). Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling. PMID:25485142

  7. Minor Xp21 chromosome deletion in a male associated with expression of duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome

    PubMed Central

    Francke, Uta; Ochs, Hans D.; de Martinville, Bérengère; Giacalone, Joseph; Lindgren, Valerie; Distèche, Christine; Pagon, Roberta A.; Hofker, Marten H.; van Ommen, Gert-Jan B.; Pearson, Peter L.; Wedgwood, Ralph J.

    1985-01-01

    We are reporting a male patient who suffered from chronic granulomatous disease associated with cytochrome b−245 deficiency and McLeod red cell phenotype, Duchenne muscular dystrophy, and retinitis pigmentosa. On cytogenetic analysis, he seemed to have a very subtle interstitial deletion of part of band Xp21. Since it was impossible to know whether this material was truly deleted or inserted elsewhere in the genome, somatic cell and molecular studies were carried out. In somatic cell hybrids, the deleted X chromosome was isolated on a Chinese hamster background. Southern blot analysis with 20 single-copy probes, that had been mapped to the X short arm, led to the discovery of one (probe 754) that is missing from this patient's X chromosome and also from his total DNA. This proves that he, indeed, has a deletion rather than a balanced insertion. The results provide cytological mapping information for the X-linked phenotypes present in this patient. Furthermore, probe 754 recognizes a restriction fragment length polymorphism of high frequency that makes it the most powerful probe currently available for linkage studies with X-linked muscular dystrophy. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5 PMID:4039107

  8. Missense mutations at homologous positions in the fourth and fifth laminin A G-like domains of eyes shut homolog cause autosomal recessive retinitis pigmentosa

    PubMed Central

    Khan, Muhammad Imran; Collin, Rob W.J.; Arimadyo, Kentar; Micheal, Shazia; Azam, Maleeha; Qureshi, Nadeem; Faradz, Sultana M.H.; den Hollander, Anneke I.; Qamar, Raheel

    2010-01-01

    Purpose To describe two novel mutations in the eyes shut homolog (EYS) gene in two families with autosomal recessive retinitis pigmentosa (arRP) from Pakistan and Indonesia. Methods Genome-wide linkage and homozygosity mapping were performed using single nucleotide polymorphism microarray analysis in affected members of the two arRP families. Sequence analysis was performed to identify genetic changes in protein coding exons of EYS. Results In the Indonesian and Pakistani families, homozygous regions encompassing the EYS gene at 6q12 were identified, with maximum LOD scores of 1.8 and 3.6, respectively. Novel missense variants in the EYS gene (p.D2767Y and p.D3028Y) were found in the Pakistani and Indonesian families, respectively, that co-segregate with the disease phenotype. Interestingly, the missense variants are located at the same homologous position within the fourth and fifth laminin A G-like domains of EYS. Conclusions To date, mostly protein-truncating mutations have been described in EYS, while only few patients have been described with pathogenic compound heterozygous missense mutations. The mutations p.D2767Y and p.D3028Y described in this study affect highly conserved residues at homologous positions in laminin A G-like domains and support the notion that missense mutations in EYS can cause arRP. PMID:21179430

  9. Cone Photoreceptors Develop Normally in the Absence of Functional Rod Photoreceptors in a Transgenic Swine Model of Retinitis Pigmentosa

    PubMed Central

    Fernandez de Castro, Juan P.; Scott, Patrick A.; Fransen, James W.; Demas, James; DeMarco, Paul J.; Kaplan, Henry J.; McCall, Maureen A.

    2014-01-01

    Purpose. Human and swine retinas have morphological and functional similarities. In the absence of primate models, the swine is an attractive model to study retinal function and disease, with its cone-rich visual streak, our ability to manipulate their genome, and the differences in susceptibility of rod and cone photoreceptors to disease. We characterized the normal development of cone function and its subsequent decline in a P23H rhodopsin transgenic (TgP23H) miniswine model of autosomal dominant RP. Methods. Semen from TgP23H miniswine 53-1 inseminated domestic swine and produced TgP23H and Wt hybrid littermates. Retinal function was evaluated using ERGs between postnatal days (P) 14 and 120. Retinal ganglion cell (RGC) responses were recorded to full-field stimuli at several intensities. Retinal morphology was assessed using light and electron microscopy. Results. Scotopic retinal function matures in Wt pigs up to P60, but never develops in TgP23H pigs. Wt and TgP23H photopic vision matures similarly up to P30 and diverges at P60 where TgP23H cone vision declines. There are fewer TgP23H RGCs with visually evoked responses at all ages and their response to light is compromised. Photoreceptor morphological changes mirror these functional changes. Conclusions. Lack of early scotopic function in TgP23H swine suggests it as a model of an aggressive form of RP. In this mammalian model of RP, normal cone function develops independent of rod function. Therefore, its retina represents a system in which therapies to rescue cones can be developed to prolong photopic visual function in RP patients. PMID:24618325

  10. Structure-Function Modeling of Optical Coherence Tomography and Standard Automated Perimetry in the Retina of Patients with Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Smith, Travis B.; Parker, Maria; Steinkamp, Peter N.; Weleber, Richard G.; Smith, Ning; Wilson, David J.

    2016-01-01

    Purpose To assess relationships between structural and functional biomarkers, including new topographic measures of visual field sensitivity, in patients with autosomal dominant retinitis pigmentosa. Methods Spectral domain optical coherence tomography line scans and hill of vision (HOV) sensitivity surfaces from full-field standard automated perimetry were semi-automatically aligned for 60 eyes of 35 patients. Structural biomarkers were extracted from outer retina b-scans along horizontal and vertical midlines. Functional biomarkers were extracted from local sensitivity profiles along the b-scans and from the full visual field. These included topographic measures of functional transition such as the contour of most rapid sensitivity decline around the HOV, herein called HOV slope for convenience. Biomarker relationships were assessed pairwise by coefficients of determination (R2) from mixed-effects analysis with automatic model selection. Results Structure-function relationships were accurately modeled (conditional R2>0.8 in most cases). The best-fit relationship models and correlation patterns for horizontally oriented biomarkers were different than vertically oriented ones. The structural biomarker with the largest number of significant functional correlates was the ellipsoid zone (EZ) width, followed by the total photoreceptor layer thickness. The strongest correlation observed was between EZ width and HOV slope distance (marginal R2 = 0.85, p<10−10). The mean sensitivity defect at the EZ edge was 7.6 dB. Among all functional biomarkers, the HOV slope mean value, HOV slope mean distance, and maximum sensitivity along the b-scan had the largest number of significant structural correlates. Conclusions Topographic slope metrics show promise as functional biomarkers relevant to the transition zone. EZ width is strongly associated with the location of most rapid HOV decline. PMID:26845445

  11. Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Kojis, T.L.; Heinzmann, C.; Ngo, J.T.

    1996-02-01

    In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families. 39 refs., 4 figs., 3 tabs.

  12. Characterization and mapping of the human rhodopsin kinase gene and screening of the gene for mutations in patients with retinitis pigmentosa

    SciTech Connect

    Khani, S.C.; Lin, D.; Magovcevic, I.

    1994-09-01

    Rhodopsin kinase (RK) is a cytosolic enzyme in rod photoreceptors that initiates the deactivation of the phototransductions cascade by phosphorylating photoactivated rhodopsin. Although the cDNA sequence of bovine RK has been determined previously, no human cDNA or genomic sequence has thus far been available for genetic studies. In order to investigate the possible role of this candidate gene in retinitis pigmentosa (RP) and allied diseases, we have isolated and characterized human cDNA and genomic clones derived from the RK locus. The coding sequence of the human gene is 1692 nucleotides in length and is split into seven exons. The human and the bovine sequence show 84% identity at the nucleotide level and 92% identity at the amino acid level. Thus far, the intronic sequences flanking each exon except for one have been determined. We have also mapped the human RK gene to chromosome 13q34 using fluorescence in situ hybridization. To our knowledge, no RP gene has as yet been linked to this region. However, since the substrate for RK (rhodopsin) and other members of the phototransduction cascade have been implicated in the pathogenesis of RP, it is conceivable that defects in RK can also cause some forms of this disease. We are evaluating this possibility by screening DNA from 173 patients with autosomal recessive RP and 190 patients with autosomal dominant RP. So far, we have found 11 patients with variant bands. In one patient with autosomal dominant RP we discovered the missense change Ser536Leu. Cosegregation studies and further sequencing of the variant bands are currently underway.

  13. Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa.

    PubMed Central

    Kojis, T. L.; Heinzmann, C.; Flodman, P.; Ngo, J. T.; Sparkes, R. S.; Spence, M. A.; Bateman, J. B.; Heckenlively, J. R.

    1996-01-01

    In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families. PMID:8571961

  14. Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa

    PubMed Central

    Wert, Katherine J.; Sancho-Pelluz, Javier; Tsang, Stephen H.

    2014-01-01

    Deficiencies in rod-specific cyclic guanosine monophosphate (cGMP) phosphodiesterase-6 (PDE6) are the third most common cause of autosomal recessive retinitis pigmentosa (RP). Previously, viral gene therapy approaches on pre-clinical models with mutations in PDE6 have demonstrated that the photoreceptor cell survival and visual function can be rescued when the gene therapy virus is delivered into the subretinal space before the onset of disease. However, no studies have currently been published that analyze rescue effects after disease onset, a time when human RP patients are diagnosed by a clinician and would receive the treatment. We utilized the AAV2/8(Y733F)-Rho-Pde6α gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6αD670G. These mice were previously shown to have long-term photoreceptor cell rescue when this gene therapy virus was delivered before the onset of disease. Now, we have determined that subretinal transduction of this rod-specific transgene at post-natal day (P) 21, when approximately half of the photoreceptor cells have undergone degeneration, is more efficient in rescuing cone than rod photoreceptor function long term. Therefore, AAV2/8(Y733F)-Rho-Pde6α is an effective gene therapy treatment that can be utilized in the clinical setting, in human patients who have lost portions of their peripheral visual field and are in the mid-stage of disease when they first present to an eye-care professional. PMID:24101599

  15. Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa.

    PubMed

    Wert, Katherine J; Sancho-Pelluz, Javier; Tsang, Stephen H

    2014-01-15

    Deficiencies in rod-specific cyclic guanosine monophosphate (cGMP) phosphodiesterase-6 (PDE6) are the third most common cause of autosomal recessive retinitis pigmentosa (RP). Previously, viral gene therapy approaches on pre-clinical models with mutations in PDE6 have demonstrated that the photoreceptor cell survival and visual function can be rescued when the gene therapy virus is delivered into the subretinal space before the onset of disease. However, no studies have currently been published that analyze rescue effects after disease onset, a time when human RP patients are diagnosed by a clinician and would receive the treatment. We utilized the AAV2/8(Y733F)-Rho-Pde6α gene therapy virus and injected it into a pre-clinical model of RP with a mutation within the alpha subunit of PDE6: Pde6α(D670G). These mice were previously shown to have long-term photoreceptor cell rescue when this gene therapy virus was delivered before the onset of disease. Now, we have determined that subretinal transduction of this rod-specific transgene at post-natal day (P) 21, when approximately half of the photoreceptor cells have undergone degeneration, is more efficient in rescuing cone than rod photoreceptor function long term. Therefore, AAV2/8(Y733F)-Rho-Pde6α is an effective gene therapy treatment that can be utilized in the clinical setting, in human patients who have lost portions of their peripheral visual field and are in the mid-stage of disease when they first present to an eye-care professional. PMID:24101599

  16. The Effect of TIMP-1 on the Cone Mosaic in the Retina of the Rat Model of Retinitis Pigmentosa

    PubMed Central

    Ji, Yerina; Yu, Wan-Qing; Eom, Yun Sung; Bruce, Farouk; Craft, Cheryl Mae; Grzywacz, Norberto M.; Lee, Eun-Jin

    2015-01-01

    Purpose. The array of photoreceptors found in normal retinas provides uniform and regular sampling of the visual space. In contrast, cones in retinas of the S334ter-line-3 rat model for RP migrate to form a mosaic of rings, leaving large holes with few or no photoreceptors. Similar mosaics appear in human patients with other forms of retinal dystrophy. In the current study, we aimed to investigate the effect of tissue inhibitor of metalloproteinase-1 (TIMP-1) on the mosaic of cones in S334ter-line-3 rat retinas. We focused on TIMP-1 because it is one of the regulators of the extracellular matrix important for cellular migration. Methods. Immunohistochemistry was performed to reveal M-opsin cone cells (M-cone) and the results were quantified to test statistically whether or not TIMP-1 restores the mosaics to normal. In particular, the tests focused on the Voronoi and nearest-neighbor distance analyses. Results. Our tests indicated that TIMP-1 led to significant disruption of the M-opsin cone rings in S334ter-line-3 rat retinas and resulted in almost complete homogeneous mosaics. In addition, TIMP-1 induced the M-cone spatial distribution to become closer to random with decreased regularity in S334ter-line-3 rat retinas. Conclusions. These findings confirm that TIMP-1 induced M-cone mosaics in S334ter-line-3 to gain homogeneity without reaching the degree of regularity seen in normal retinal mosaics. Even if TIMP-1 fails to promote regularity, the effects of this drug on homogeneity appear to be so dramatic that TIMP-1 may be a potential therapeutic agent. TIMP-1 improves sampling of the visual field simply by causing homogeneity. PMID:25515575

  17. Photoreceptor Rescue by an Abbreviated Human RPGR Gene in a Murine Model of X-linked Retinitis Pigmentosa

    PubMed Central

    Pawlyk, Basil S.; Adamian, Michael; Sun, Xun; Bulgakov, Oleg V.; Shu, Xinhua; Smith, Alexander J.; Berson, Eliot L.; Ali, Robin R.; Khani, Shahrokh; F.Wright, Alan; Sandberg, Michael A.; Li, Tiansen

    2015-01-01

    The X-linked RP3 gene codes for the ciliary protein RPGR and accounts for over 10% of inherited retinal degenerations. The critical RPGR-ORF15 splice variant contains a highly repetitive purine-rich linker region that renders it unstable and difficult to adapt for gene therapy. To test the hypothesis that the precise length of the linker region is not critical for function, we evaluated whether AAV-mediated replacement gene therapy with a human ORF15 variant containing in-frame shortening of the linker region could reconstitute RPGR function in vivo. We delivered human RPGR-ORF15 replacement genes with deletion of most (314-codons, “short form”) or 1/3 (126-codons, “long form”) of the linker region to Rpgr null mice. Human RPGR-ORF15 expression was detected post-treatment with both forms of ORF15 transgenes. However, only the long form correctly localized to the connecting cilia and led to significant functional and morphological rescue of rods and cones. Thus the highly repetitive region of RPGR is functionally important but that moderate shortening of its length, which confers the advantage of added stability, preserves its function. These findings provide a theoretical basis for optimizing replacement gene design in clinical trials for X-linked RP3. PMID:26348595

  18. Retinal Detachment due to CrossFit Training Injury.

    PubMed

    Joondeph, Stephanie A; Joondeph, Brian C

    2013-01-01

    The purpose of this paper is to describe a traumatic retinal detachment occurring as a result of CrossFit training using an elastic exercise band. The patient sustained an ocular injury from an elastic band during CrossFit training, resulting in a giant retinal dialysis and retinal detachment, which were successfully repaired. Trainers and athletes need to be aware of the potential for ocular injury from elastic exercise bands and take appropriate precautions. PMID:24106626

  19. Retinal Detachment due to CrossFit Training Injury

    PubMed Central

    Joondeph, Stephanie A.; Joondeph, Brian C.

    2013-01-01

    The purpose of this paper is to describe a traumatic retinal detachment occurring as a result of CrossFit training using an elastic exercise band. The patient sustained an ocular injury from an elastic band during CrossFit training, resulting in a giant retinal dialysis and retinal detachment, which were successfully repaired. Trainers and athletes need to be aware of the potential for ocular injury from elastic exercise bands and take appropriate precautions. PMID:24106626

  20. Mutation in the splicing factor Hprp3p linked to retinitis pigmentosa impairs interactions within the U4/U6 snRNP complex

    PubMed Central

    Gonzalez-Santos, Juana Maria; Cao, Huibi; Duan, Rongqi Cathleen; Hu, Jim

    2015-01-01

    Mutations in PRPF3, a gene encoding the essential pre-mRNA splicing factor Hprp3p, have been identified in patients with autosomal dominant retinitis pigmentosa type 18 (RP18). Patients with RP18 have one of two single amino acid substitutions, Pro493Ser or Thr494Met, at the highly conserved Hprp3p C-terminal region. Pro493Ser occurs sporadically, whereas Thr494Met is observed in several unlinked RP families worldwide. The latter mutation also alters a potential recognition motif for phosphorylation by casein kinase II (CKII). To understand the molecular basis of RP18, we examined the consequences of Thr494Met mutation on Hprp3p molecular interactions with components of the U4/U6.U5 small nuclear ribonucleoprotein particles (snRNPs) complex. Since numerous mutations causing human diseases change pre-mRNA splice sites, we investigated whether Thr494Met substitution affects the processing of PRPF3 mRNA. We found that Thr494Met does not affect PRPF3 mRNA processing, indicating that the mutation may exert its effect primarily at the protein level. We used small hairpin RNAs to specifically silence the endogenous PRPF3 while simultaneously expressing HA-tagged Thr494Met. We demonstrated that the C-but not N-terminal region of Hprp3p is indeed phosphorylated by CKII in vitro and in cells. CKII-mediated Hprp3p phosphorylation was significantly reduced by Thr494Met mutation. Consequently, the Hprp3p C-terminal region is rendered partially defective in its association with itself, Hprp4p, and U4/U6 snRNA. Our findings provide new insights into the biology of Hprp3p and suggest that the loss of Hprp3p phosphorylation at Thr494 is a key step for initiating Thr494Met aberrant interactions within U4/U6 snRNP complex and that these are likely linked to the RP18 phenotype. PMID:17932117

  1. Long-term outcomes in patients undergoing vitrectomy for retinal detachment due to viral retinitis

    PubMed Central

    Almeida, David RP; Chin, Eric K; Tarantola, Ryan M; Tegins, Elizabeth O; Lopez, Christopher A; Boldt, Herbert Culver; Gehrs, Karen M; Sohn, Elliott H; Russell, Stephen R; Folk, James C; Mahajan, Vinit B

    2015-01-01

    Purpose To determine the outcomes in patients with rhegmatogenous retinal detachment (RRD) secondary to viral retinitis. Patients and methods This was a retrospective, consecutive, noncomparative, interventional case series of 12 eyes in ten patients with RRD secondary to viral retinitis. Results of vitreous or aqueous biopsy, effect of antiviral therapeutics, time to retinal detachment, course of visual acuity, and anatomic and surgical outcomes were investigated. Results There were 1,259 cases of RRD during the study period, with 12 cases of RRD secondary to viral retinitis (prevalence of 0.95%). Follow-up was available for a mean period of 4.4 years. Varicella zoster virus was detected in six eyes, herpes simplex virus in two eyes, and cytomegalovirus in two eyes. Eight patients were treated with oral valacyclovir and two patients with intravenous acyclovir. Lack of optic nerve involvement correlated with improved final visual acuity of 20/100 or greater. Pars plana vitrectomy (n=12), silicone-oil tamponade (n=11), and scleral buckling (n=10) provided successful anatomic retinal reattachment in all cases, with no recurrent retinal detachment and no cases of hypotony during the follow-up period. Conclusion Varicella zoster virus was the most frequent cause of viral retinitis, and lack of optic nerve involvement was predictive of a favorable visual acuity prognosis. Vitrectomy with silicone-oil tamponade and scleral buckle placement provided stable anatomical outcomes. PMID:26229423

  2. Retinal arteriolar occlusions due to cytomegalovirus retinitis in elderly patients without HIV

    PubMed Central

    2013-01-01

    Background Five of 7 (71%) elderly immunocompetent patients with cytomegalovirus retinitis had retinal arteriolar occlusions versus 2 of 8 (25%) elderly immunocompromised patients and 1 of 19 (5%) younger HIV-infected patients. Compared to HIV-infected patients, elderly patients were more likely to have occlusive events, neovascularization or hemorrhage, and underlying vasculopathy. The purpose of this study is to report the novel finding of extensive retinal arteriolar occlusions and neovascularization in immunocompetent patients with cytomegalovirus retinitis. This is a retrospective observational cohort study of cytomegalovirus retinitis (CMVR) in a university setting. Seven patients were elderly but not immunocompromised, 8 were elderly and iatrogenically immunocompromised, and 16 were HIV-infected. All patients underwent polymerase chain reaction testing of intraocular fluid. Primary outcome measure was visual acuity. Secondary outcome measures were vascular occlusions, ischemic complications, and response to treatment. Results Mean age was 73, 70, and 41 years for immunocompetent, immunocompromised, and HIV-infected patients, respectively. Diabetes and vascular disease were common in the elderly. Vision loss to less than 5/200 occurred in 50% of the immunocompetent elderly patients, and 17% of CMV eyes in immunocompromised and HIV patients. Occlusion of the entire retinal vasculature occurred in 4/7 (57%) of immunocompetent patients despite lack of Zone I involvement, and rubeosis occurred in three, disc neovascularization in one, and vitreous hemorrhage in two patients. Vascular occlusive events were less common in immunocompromised patients and rare in the HIV-infected. Conclusions CMVR in non-HIV-infected elderly patients is associated with retinal arteriolar occlusions. An intact host immune response may increase damage to retinal vessels. Prompt diagnosis may avert catastrophic vision loss. PMID:23514532

  3. A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome

    PubMed Central

    Hulleman, John D.; Nguyen, Annie; Ramprasad, V.L.; Murugan, Sakthivel; Gupta, Ravi; Mahindrakar, Avinash; Angara, Ravi; Sankurathri, Chandrasekhar

    2016-01-01

    Purpose To identify the causative mutation in two siblings from a consanguineous family in India with retinitis pigmentosa (RP) and polydactyly without other findings of Bardet-Biedl syndrome (BBS). We also performed functional characterization of the mutant protein to explore its role in this limited form of BBS. Methods The siblings underwent a thorough ophthalmological examination, including retinal optical coherence tomography (OCT) imaging, and an extensive physical examination with abdominal ultrasonography to characterize the disease phenotype. Next-generation sequencing (NGS) using a panel targeting retinal degeneration genes was performed on genomic DNA samples from the siblings and parents. Upon identification of the causative mutation, functional characterization was accomplished by performing protein–protein interaction studies in human embryonic kidney (HEK-293T) and human adult retinal pigmented epithelium (ARPE-19) cells. Results The two siblings showed signs of RP and polydactyly. The patients did not have truncal obesity, renal anomalies, hydrometrocolpos, congenital heart disease, or overt cognitive defects. NGS identified a homozygous c.1184A>G mutation in the MKKS/BBS6 gene in both patients resulting in a p.H395R substitution in the MKKS/BBS6 protein. This mutant protein decreased the interaction of MKKS/BBS6 with BBS12 but did so to a different extent in the HEK-293T versus ARPE-19 cells. Nonetheless, the effect of the H395R variant on disrupting interactions with BBS12 was not as profound as other reported MKKS/BBS6 mutations associated with syndromic RP. Conclusions We identified a novel H395R substitution in MKKS/BBS6 that results in a unique phenotype of only RP and polydactyly. Our observations reaffirm the notion that mutations in MKKS/BBS6 cause phenotypic heterogeneity and do not always result in classic MKKS or BBS findings. PMID:26900326

  4. Mouse Slc9a8 Mutants Exhibit Retinal Defects Due to Retinal Pigmented Epithelium Dysfunction

    PubMed Central

    Jadeja, Shalini; Barnard, Alun R.; McKie, Lisa; Cross, Sally H.; White, Jacqueline K.; Robertson, Morag; Budd, Peter S.; MacLaren, Robert E.; Jackson, Ian J.

    2015-01-01

    Purpose. As part of a large scale systematic screen to determine the effects of gene knockout mutations in mice, a retinal phenotype was found in mice lacking the Slc9a8 gene, encoding the sodium/hydrogen ion exchange protein NHE8. We aimed to characterize the mutant phenotype and the role of sodium/hydrogen ion exchange in retinal function. Methods. Detailed histology characterized the pathological consequences of Slc9a8 mutation, and retinal function was assessed by electroretinography (ERG). A conditional allele was used to identify the cells in which NHE8 function is critical for retinal function, and mutant cells analyzed for the effect of the mutation on endosomes. Results. Histology of mutant retinas reveals a separation of photoreceptors from the RPE and infiltration by macrophages. There is a small reduction in photoreceptor length and a mislocalization of visual pigments. The ERG testing reveals a deficit in rod and cone pathway function. The RPE shows abnormal morphology, and mutation of Slc9a8 in only RPE cells recapitulates the mutant phenotype. The NHE8 protein localizes to endosomes, and mutant cells have much smaller recycling endosomes. Conclusions. The NHE8 protein is required in the RPE to maintain correct regulation of endosomal volume and/or pH which is essential for the cellular integrity and subsequent function of RPE. PMID:25736793

  5. The cell stress machinery and retinal degeneration.

    PubMed

    Athanasiou, Dimitra; Aguilà, Monica; Bevilacqua, Dalila; Novoselov, Sergey S; Parfitt, David A; Cheetham, Michael E

    2013-06-27

    Retinal degenerations are a group of clinically and genetically heterogeneous disorders characterised by progressive loss of vision due to neurodegeneration. The retina is a highly specialised tissue with a unique architecture and maintaining homeostasis in all the different retinal cell types is crucial for healthy vision. The retina can be exposed to a variety of environmental insults and stress, including light-induced damage, oxidative stress and inherited mutations that can lead to protein misfolding. Within retinal cells there are different mechanisms to cope with disturbances in proteostasis, such as the heat shock response, the unfolded protein response and autophagy. In this review, we discuss the multiple responses of the retina to different types of stress involved in retinal degenerations, such as retinitis pigmentosa, age-related macular degeneration and glaucoma. Understanding the mechanisms that maintain and re-establish proteostasis in the retina is important for developing new therapeutic approaches to fight blindness. PMID:23684651

  6. Hard Retinal exudates and visual loss due to papilledema

    SciTech Connect

    Rush, J.A.

    1982-02-01

    Bilateral papilledema developed in a patient with a cystic, grade 3 astrocytoma of the right frontal lobe. Despite successful neurosurgical treatment, /sup 60/Co radiotherapy, and oral corticosteroid therapy, progressive visual loss occurred. At examination one year later, visual activity was 20/200 and 20/70, and extensive lipid exudates in the peripapillary retina and central macula of each eye were noted. Retinal lipid exudates rarely complicate the course of surviving patients who had papilledema from intracranial tumor; physicians involved in the multispecialty care of such patients should be aware of the possible ocular residuals of persistent papilledema in an otherwise successfully treated patient.

  7. The retinal ciliopathies.

    PubMed

    Adams, N A; Awadein, Ahmed; Toma, Hassanain S

    2007-09-01

    While the functions of many of the proteins located in or associated with the photoreceptor cilia are poorly understood, disruption of the function of these proteins may result in a wide variety of phenotypes ranging from isolated retinal degeneration to more pleiotropic phenotypes. Systemic findings include neurosensory hearing loss, developmental delay, situs-inversus, infertility, disorders of limb and digit development, obesity, kidney disease, liver disease, and respiratory disease. The concept of "retinal ciliopathies" brings to attention the importance of further molecular analysis of this organelle as well as provides a potential common target for therapies for these disorders. The retinal ciliopathies include retinitis pigmentosa, macular degeneration, cone-dystrophy, cone-rod dystrophy, Leber congenital amaurosis, as well as retinal degenerations associated with Usher syndrome, primary ciliary dyskinesia, Senior-Loken syndrome, Joubert syndrome, Bardet-Biedl syndrome, Laurence-Moon syndrome, McKusick-Kaufman syndrome, and Biemond syndrome. Mutations for these disorders have been found in retinitis pigmentosa-1 (RP1), retinitis pigmentosa GTPase regulator (RPGR), retinitis pigmentosa GTPase regulator interacting protein (RPGR-IP), as well as the Usher, Bardet-Biedl, and nephronophthisis genes. Other systemic disorders associated with retinal degenerations that may also involve ciliary abnormalities include: Alstrom, Edwards-Sethi, Ellis-van Creveld, Jeune, Meckel-Gruber, Orofaciodigital Type 9, and Gurrieri syndromes. Understanding these conditions as ciliopathies may help the ophthalmologist to recognize associations between seemingly unrelated diseases and have a high degree of suspicion that a systemic finding may be present. PMID:17896309

  8. Retinal Prosthesis

    PubMed Central

    Weiland, James D.; Humayun, Mark S.

    2015-01-01

    Retinal prosthesis have been translated from the laboratory to the clinical over the past two decades. Currently, two devices have regulatory approval for the treatment of retinitis pigmentosa. These devices provide partial sight restoration and patients use this improved vision in their everyday lives. Improved mobility and object detection are some of the more notable findings from the clinical trials. However, significant vision restoration will require both better technology and improved understanding of the interaction between electrical stimulation and the retina. This paper reviews the recent clinical trials, highlights technology breakthroughs that will contribute to next generation of retinal prostheses. PMID:24710817

  9. Prurigo Pigmentosa: Literature Review.

    PubMed

    Beutler, Bryce D; Cohen, Philip R; Lee, Robert A

    2015-12-01

    Prurigo pigmentosa, also referred to as Nagashima's disease, is a rare inflammatory skin condition of unknown etiology. It typically presents as pruritic erythematous papules, papulovesicles, and vesicles appearing in a reticular pattern on the back, chest, or neck. The histological features of prurigo pigmentosa vary according to the stage of the disease. Early-stage disease is characterized by a superficial perivascular infiltrate of neutrophils; spongiosis and necrotic keratinocytes commonly appear in later stages. The etiology of prurigo pigmentosa has yet to be determined. Oral minocycline is usually the first-line therapy for prurigo pigmentosa. However, doxycycline, macrolide antibiotics, and/or dapsone (diaminodiphenyl sulfone) may be indicated for some patients. We describe the key features of prurigo pigmentosa, including the epidemiology, clinical and histologic presentation, differential diagnosis, postulated pathogenesis, and treatment options for this condition. PMID:26334426

  10. Retinal Macroglial Responses in Health and Disease

    PubMed Central

    de Hoz, Rosa; Rojas, Blanca; Ramírez, Ana I.; Salazar, Juan J.; Gallego, Beatriz I.; Triviño, Alberto; Ramírez, José M.

    2016-01-01

    Due to their permanent and close proximity to neurons, glial cells perform essential tasks for the normal physiology of the retina. Astrocytes and Müller cells (retinal macroglia) provide physical support to neurons and supplement them with several metabolites and growth factors. Macroglia are involved in maintaining the homeostasis of extracellular ions and neurotransmitters, are essential for information processing in neural circuits, participate in retinal glucose metabolism and in removing metabolic waste products, regulate local blood flow, induce the blood-retinal barrier (BRB), play fundamental roles in local immune response, and protect neurons from oxidative damage. In response to polyetiological insults, glia cells react with a process called reactive gliosis, seeking to maintain retinal homeostasis. When malfunctioning, macroglial cells can become primary pathogenic elements. A reactive gliosis has been described in different retinal pathologies, including age-related macular degeneration (AMD), diabetes, glaucoma, retinal detachment, or retinitis pigmentosa. A better understanding of the dual, neuroprotective, or cytotoxic effect of macroglial involvement in retinal pathologies would help in treating the physiopathology of these diseases. The extensive participation of the macroglia in retinal diseases points to these cells as innovative targets for new drug therapies. PMID:27294114

  11. Changes in aberrations and retinal image quality due to tear film dynamics.

    PubMed

    Li, Kaccie Y; Yoon, Geunyoung

    2006-12-11

    A reliable and objective method to measure aberration changes due to the tear film is essential in improving clinical assessment of the tear film and in vivo retinal imaging. The tear film of 11 subjects are studied by acquiring continuous wavefront measurements in real-time with a customized Shack-Hartmann wavefront sensor. The device has a high resolution lenslet array (190 mum) and a topographer unit with an infrared pupil illuminator (940 nm). A Fourier transform reconstructor algorithm [1] was used to estimate the eyes' wavefront aberrations from slope measurements. Increasing irregularities in the tear film produced observable wavefront variations. The temporal behavior of tear induced aberrations and retinal image quality was evaluated by the root mean squared (RMS) error of the residual wavefront and the volume modulation transfer function (MTF). Similar trends were observed from both metrics. Our analysis demonstrates the applicability of the SH wavefront sensor to assessing the dynamics of the human tear film. PMID:19529690

  12. Transcorneal Electrical Stimulation Therapy for Retinal Disease

    ClinicalTrials.gov

    2012-05-03

    Retinitis Pigmentosa; Macula Off; Primary Open Angle Glaucoma; Hereditary Macular Degeneration; Treated Retina Detachment; Retinal Artery Occlusion; Retinal Vein Occlusion; Non-Arthritic-Anterior-Ischemic Optic-Neuropathy; Hereditary Autosomal Dominant Optic Atrophy; Dry Age Related Macular Degeneration; Ischemic Macula Edema

  13. [Application of retinal oximeter in ophthalmology].

    PubMed

    Li, Jing; Ma, Jianmin; Wang, Ningli

    2015-11-01

    Retinal oximeter is a new machine which has been used in the diagnose, treatment and research of several ophthalmic diseases for recent years. It allows ophthalmologists to gain retinal oxygen saturation directly. Therefore, retinal oximeter might be useful for ophthalmologists to understand ophthalmic diseases more deeper and clarify the impact of ischemia on retinal function. It has been reported in the literatures that retinal oximeter has potentially useful diagnostic and therapeutic indications in various eye diseases such as diabetic retinopathy, central retinal vein and artery occlusion, retinitis pigmentosa, glaucomatous optic neuropathy, et al. In this thesis, the application of retinal oximeter in ophthalmology is reviewed. PMID:26850588

  14. Inherited Retinal Degenerative Disease Registry

    ClinicalTrials.gov

    2016-03-21

    Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

  15. Long-term follow-up of vitrectomy, with or without 360° encircling buckle, for rhegmatogenous retinal detachment due to inferior retinal breaks

    PubMed Central

    Ghoraba, Hamouda Hamdy; Zaky, Adel Galal; Ellakwa, Amin Faisal

    2016-01-01

    Objective The aim of this study was to report and compare the anatomic and functional results of primary vitrectomy with and without 360° encircling scleral buckle (SB) for the treatment of rhegmatogenous retinal detachment (RRD) due to inferior retinal break(s). Background A variety of options, including SB, pars plana vitrectomy (PPV) with or without SB, and pneumatic retinopexy have been described as methods to repair RRDs. The use of additional SB with vitrectomy for RRD associated with inferior breaks has been a recent controversy after the introduction of transconjunctival cannula systems. Patients and methods A retrospective, interventional, comparative case study was performed. In this study, we reviewed 105 consecutive patients who underwent vitrectomy for primary RRD with inferior retinal break(s) at the vitreoretinal center, performed by a single surgeon. Ninety four patients (94 eyes) were followed up for at least 4 months after silicon oil removal (SOR), and were analyzed. They were divided into two groups: group I included 50 patients who underwent PPV alone + silicon oil (SO); and group II included 44 patients who underwent PPV with 360° SB + SO. The essential parameters were single-operation success rate (SOSR) before SOR, incidence of retinal redetachment after SOR, and final visual acuity. Results SOSR was obtained in 89 eyes (47 [94%] in group I and 42 [95.5%] in group II). From overall 59 phakic retinal detachments (RDs), SOSR was obtained in 56 eyes (30 in group I [93.8%] and 26 in group II [96.3%]) while from overall 35 aphakic or pseudophakic RDs, SOSR was obtained in 33 eyes (17 in group I [94.4%] and 16 in group II [94.1%]). Retinal redetachments after SOR occurred in three patients in group I and two patients in group II. Visual acuity improvement was greater in group I than in group II before SOR. Conclusion Both surgical procedures had similar reattachment rates. The addition of 360° SB to PPV + SO might not have additional benefits

  16. Argus II retinal prosthesis system: An update.

    PubMed

    Rachitskaya, Aleksandra V; Yuan, Alex

    2016-09-01

    This review focuses on a description of the Argus II retinal prosthesis system (Argus II; Second Sight Medical Products, Sylmar, CA) that was approved for humanitarian use by the FDA in 2013 in patients with retinitis pigmentosa with bare or no light perception vision. The article describes the components of Argus II, the studies on the implant, and future directions. PMID:26855177

  17. Evaluation of the effectiveness and safety of glucocorticoids intravitreal implant therapy in macular edema due to retinal vein occlusion

    PubMed Central

    Michalska-Małecka, Katarzyna; Gaborek, Aneta; Nowak, Mariusz; Halat, Tomasz; Pawłowska, Mariola; Śpiewak, Dorota

    2016-01-01

    The purpose of this study was to evaluate the impact of intravitreal dexamethasone implant (Ozurdex) on macular morphology and functions in eyes with macular edema (ME) secondary to retinal vein occlusion. Efficacy outcomes of the treatment were best-corrected visual acuity (BCVA) and central retinal thickness (CRT). Safety outcomes were intraocular pressure and cornea endothelial cell density. The study was conducted by the prospective analysis on 36 patients (17 women and 19 men) aged 28–77 years (the average age was 58±15 years) treated with the injection of dexamethasone implant because of the persistent ME at the Department of Ophthalmology and Ophthalmology Outpatient Clinic of the University Centre of Ophthalmology and Oncology in Katowice. The studied group included 16 patients with central retinal vein occlusion (16 eyes), and 20 patients with branch retinal vein occlusion (20 eyes). We found a significant increase of BCVA after first, second, and third month of treatment. Six months after the treatment, BCVA decreased, although not significantly compared with the value obtained in the third month. Two months after the intravitreal implantation of dexamethasone delivery system, CRT was 338±163 μm and was significantly lower compared with pretreatment value. Between third and sixth month after the treatment, we found insignificant increase of CRT compared with thickness observed in second month. Two months after the treatment, we found an increase in intraocular pressure in 36% of cases and a further decrease during the final visit 6 months after the treatment. During the treatment, there were no significant differences in endothelial cell density in branch retinal vein occlusion and central retinal vein occlusion. We found the intravitreal dexamethasone implant to be safe, well tolerated, and likely to lead to fast morphological and functional improvement of the macula and visual rehabilitation in patients with ME due to retinal vein occlusion. PMID

  18. Myosin7a Deficiency Results in Reduced Retinal Activity Which Is Improved by Gene Therapy

    PubMed Central

    Colella, Pasqualina; Sommella, Andrea; Marrocco, Elena; Di Vicino, Umberto; Polishchuk, Elena; Garrido, Marina Garcia; Seeliger, Mathias W.; Polishchuk, Roman; Auricchio, Alberto

    2013-01-01

    Mutations in MYO7A cause autosomal recessive Usher syndrome type IB (USH1B), one of the most frequent conditions that combine severe congenital hearing impairment and retinitis pigmentosa. A promising therapeutic strategy for retinitis pigmentosa is gene therapy, however its pre-clinical development is limited by the mild retinal phenotype of the shaker1 (sh1−/−) murine model of USH1B which lacks both retinal functional abnormalities and degeneration. Here we report a significant, early-onset delay of sh1−/− photoreceptor ability to recover from light desensitization as well as a progressive reduction of both b-wave electroretinogram amplitude and light sensitivity, in the absence of significant loss of photoreceptors up to 12 months of age. We additionally show that subretinal delivery to the sh1−/− retina of AAV vectors encoding the large MYO7A protein results in significant improvement of sh1−/− photoreceptor and retinal pigment epithelium ultrastructural anomalies which is associated with improvement of recovery from light desensitization. These findings provide new tools to evaluate the efficacy of experimental therapies for USH1B. In addition, although AAV vectors expressing large genes might have limited clinical applications due to their genome heterogeneity, our data show that AAV-mediated MYO7A gene transfer to the sh1−/− retina is effective. PMID:23991031

  19. Measurement of Retinal Blood Flow Rate in Diabetic Rats: Disparity Between Techniques Due to Redistribution of Flow

    PubMed Central

    Leskova, Wendy; Watts, Megan N.; Carter, Patsy R.; Eshaq, Randa S.; Harris, Norman R.

    2013-01-01

    Purpose. Reports of altered retinal blood flow in experimental models of type I diabetes have provided contrasting results, which leads to some confusion as to whether flow is increased or decreased. The purpose of our study was to evaluate early diabetes-induced changes in retinal blood flow in diabetic rats, using two distinctly different methods. Methods. Diabetes was induced by injection of streptozotocin (STZ), and retinal blood flow rate was measured under anesthesia by a microsphere infusion technique, or by an index of flow based on the mean circulation time between arterioles and venules. Measurements in STZ rats were compared to age-matched nondiabetic controls. In addition, the retinal distribution of fluorescently-labeled red blood cells (RBCs) was viewed by confocal microscopy in excised flat mounts. Results. Retinal blood flow rate was found to decrease by approximately 33% in the STZ rats compared to controls (P < 0.001) as assessed by the microsphere technique. However, in striking contrast, the mean circulation time through the retina was found to be almost 3× faster in the STZ rats (P < 0.01). This contradiction could be explained by flow redistribution through the superficial vessels of the diabetic retina, with this possibility supported by our observation of significantly fewer RBCs flowing through the deeper capillaries. Conclusions. We conclude that retinal blood flow rate is reduced significantly in the diabetic rat, with a substantial decrease of flow through the capillaries due to shunting of blood through the superficial layer, allowing rapid transit from arterioles to venules. PMID:23572104

  20. Sectorial loss of retinal ganglion cells in inherited photoreceptor degeneration is due to RGC death

    PubMed Central

    García-Ayuso, Diego; Salinas-Navarro, Manuel; Nadal-Nicolás, Francisco Manuel; Ortín-Martínez, Arturo; Agudo-Barriuso, Marta; Vidal-Sanz, Manuel; Villegas-Pérez, María P

    2014-01-01

    Aims To investigate the cause of retinal ganglion cell (RGC) loss in dystrophic aged Royal College of Surgeons (RCS) rats. Methods RCS-p+ (dystrophic) female rats of postnatal times (P365, P450 and P540) and age-matched RCS-p1 rdy+ (non-dystrophic) rats were used. In whole-mounted retinas, RGCs were doubly labelled with Fluorogold (FG) retrogradely transported from the superior colliculi and Brn3a immunohistochemistry. RGC axons were labelled with anti-neurofilament antibodies. Automatic image analysis techniques allowed quantification of the total population of RGCs per retina and construction of isodensity maps to investigate RGC topology. Results Dystrophic retinas showed at all times studied wedge-shaped sectors devoid of FG+ and Brn3a+ RGCs. These sectors were also devoid of neurofilament-labelled axons. The total number of FG+RGC and Brn3a+RGC per retina was significantly smaller in dystrophic rats at P540, revealing RGC death at this age. The total number of FG+RGCs was smaller than those of Brn3a+RGCs at P540, indicating a disturbance of the retrograde axonal transport at this age. Conclusions RGC double labelling documents that sectorial RGC loss in aged dystrophic RCS rats is mainly due to RGC death, although a deficit of the retrograde axonal transport exists also at the more advanced ages. PMID:24326325

  1. The clinical features of retinal disease due to a dominant mutation in RPE65

    PubMed Central

    Hull, Sarah; Mukherjee, Rajarshi; Holder, Graham E.; Moore, Anthony T.

    2016-01-01

    Purpose To present a detailed phenotypic and molecular study of two families with autosomal dominant RPE65-related retinal dystrophy. Methods Five patients from two families were ascertained from the retinal clinics of a tertiary referral center. Phenotyping included retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of exon 13 of RPE65 and its intron–exon boundaries was performed on all reported patients and segregation confirmed in available relatives. The main outcome measures were the results of an ophthalmic examination and investigation and molecular genetic analysis. Results Four affected patients from two families presented with nyctalopia and central visual disturbance in adulthood progressing to severe visual loss by the fifth to eighth decades. The patients had extensive chorioretinal atrophy with a relatively preserved anterior retina. In the second family, one patient had bilateral, vitelliform-like foveal lesions consistent with adult onset vitelliform macular dystrophy and no peripheral retinal changes. These unrelated families were both heterozygous for c.1430A>G (p.Asp477Gly). One unaffected family member also tested positive for this mutation but had good vision at age 80 years. Conclusions Autosomal dominant retinal dystrophy resembling choroideremia can arise from a heterozygous mutation in RPE65. It may manifest with mild disease or be non-penetrant. Awareness of these unusual presentations can facilitate targeted molecular investigation. PMID:27307694

  2. Retinal Ganglion Cell Atrophy in Homonymous Hemianopia due to Acquired Occipital Lesions Observed Using Cirrus High-Definition-OCT

    PubMed Central

    Yamashita, Tsutomu; Miki, Atsushi; Goto, Katsutoshi; Araki, Syunsuke; Takizawa, Go; Ieki, Yoshiaki; Kiryu, Junichi; Tabuchi, Akio; Iguchi, Yasuyuki; Kimura, Kazumi; Yagita, Yoshiki

    2016-01-01

    Purpose. To report a reduction in macular ganglion cell layer and inner plexiform layer (GCL+IPL) thickness and circumpapillary retinal nerve fiber layer (cpRNFL) thickness using spectral-domain optical coherence tomography in patients with homonymous hemianopia due to posterior cerebral artery (PCA) stroke. Methods. Seven patients with PCA stroke were examined using Cirrus high-definition-OCT. The GCL+IPL thicknesses were divided into the hemianopic and unaffected sides. The relationship between the time after stroke and the GCL+IPL thicknesses in the hemianopic side was evaluated. Results. The average thicknesses of the GCL+IPL were 64.6 and 82.0 μm on the hemianopic and unaffected sides, respectively, and the measurement was significantly thinner on the former side (p = 0.018). A regression analysis revealed a negative linear relationship (R2 = 0.574, p = 0.049) between the time after stoke and the GCL+IPL thicknesses on the hemianopic side. The supratemporal and inferotemporal cpRNFL thicknesses in the eyes ipsilateral to the stroke showed a significant reduction. Conclusion. Our findings confirmed our previous observations that the degeneration of retinal ganglion cells can occur after PCA stroke. GCL+IPL thinning was demonstrated in the hemiretinae corresponding to the affected hemifields. Also, it is suggested that the retinal changes observed are progressive. PMID:27274865

  3. Color Doppler imaging of retinal diseases.

    PubMed

    Dimitrova, Galina; Kato, Satoshi

    2010-01-01

    Color Doppler imaging (CDI) is a widely used method for evaluating ocular circulation that has been used in a number of studies on retinal diseases. CDI assesses blood velocity parameters by using ultrasound waves. In ophthalmology, these assessments are mainly performed on the retrobulbar blood vessels: the ophthalmic, the central retinal, and the short posterior ciliary arteries. In this review, we discuss CDI use for the assessment of retinal diseases classified into the following: vascular diseases, degenerations, dystrophies, and detachment. The retinal vascular diseases that have been investigated by CDI include diabetic retinopathy, retinal vein occlusions, retinal artery occlusions, ocular ischemic conditions, and retinopathy of prematurity. Degenerations and dystrophies included in this review are age-related macular degeneration, myopia, and retinitis pigmentosa. CDI has been used for the differential diagnosis of retinal detachment, as well as the evaluation of retrobulbar circulation in this condition. CDI is valuable for research and is a potentially useful diagnostic tool in the clinical setting. PMID:20385332

  4. [Intrinsically Photosensitive Retinal Ganglion Cells].

    PubMed

    Skorkovská, K; Skorkovská, Š

    2015-06-01

    Recently discovered intrinsically photosensitive melanopsin-containing retinal ganglion cells contribute to circadian photoentrainment and pupillary constriction; recent works have also brought new evidence for their accessory role in the visual system in humans. Pupil light reaction driven by individual photoreceptors can be isolated by means of the so called chromatic pupillography. The use of chromatic stimuli to elicit different pupillary responses may become an objective clinical pupil test in the detection of retinal diseases and in assessing new therapeutic approaches particularly in hereditary retinal degenerations like retinitis pigmentosa. In advanced stages of disease, the pupil light reaction is even more sensitive than standard electroretinography for detecting residual levels of photoreceptor activity. This review summarizes current knowledge on intrinsically photosensitive retinal cells and highlights its possible implications for clinical practice. PMID:26201360

  5. Automatic detection of referral patients due to retinal pathologies through data mining.

    PubMed

    Quellec, Gwenolé; Lamard, Mathieu; Erginay, Ali; Chabouis, Agnès; Massin, Pascale; Cochener, Béatrice; Cazuguel, Guy

    2016-04-01

    With the increased prevalence of retinal pathologies, automating the detection of these pathologies is becoming more and more relevant. In the past few years, many algorithms have been developed for the automated detection of a specific pathology, typically diabetic retinopathy, using eye fundus photography. No matter how good these algorithms are, we believe many clinicians would not use automatic detection tools focusing on a single pathology and ignoring any other pathology present in the patient's retinas. To solve this issue, an algorithm for characterizing the appearance of abnormal retinas, as well as the appearance of the normal ones, is presented. This algorithm does not focus on individual images: it considers examination records consisting of multiple photographs of each retina, together with contextual information about the patient. Specifically, it relies on data mining in order to learn diagnosis rules from characterizations of fundus examination records. The main novelty is that the content of examination records (images and context) is characterized at multiple levels of spatial and lexical granularity: 1) spatial flexibility is ensured by an adaptive decomposition of composite retinal images into a cascade of regions, 2) lexical granularity is ensured by an adaptive decomposition of the feature space into a cascade of visual words. This multigranular representation allows for great flexibility in automatically characterizing normality and abnormality: it is possible to generate diagnosis rules whose precision and generalization ability can be traded off depending on data availability. A variation on usual data mining algorithms, originally designed to mine static data, is proposed so that contextual and visual data at adaptive granularity levels can be mined. This framework was evaluated in e-ophtha, a dataset of 25,702 examination records from the OPHDIAT screening network, as well as in the publicly-available Messidor dataset. It was successfully

  6. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration

    PubMed Central

    Shirai, Hiroshi; Mandai, Michiko; Matsushita, Keizo; Kuwahara, Atsushi; Yonemura, Shigenobu; Nakano, Tokushige; Assawachananont, Juthaporn; Kimura, Toru; Saito, Koichi; Terasaki, Hiroko; Eiraku, Mototsugu; Sasai, Yoshiki; Takahashi, Masayo

    2016-01-01

    Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host–graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications. PMID:26699487

  7. Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene.

    PubMed

    Bisserbe, A; Tertian, G; Buffet, C; Turhan, A; Lambotte, O; Nasser, G; Alvin, P; Tardieu, M; Riant, F; Bergametti, F; Tournier-Lasserve, E; Denier, C

    2015-05-01

    Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures. PMID:25843205

  8. The Pop out of Scene-Relative Object Movement against Retinal Motion Due to Self-Movement

    ERIC Educational Resources Information Center

    Rushton, Simon K.; Bradshaw, Mark F.; Warren, Paul A.

    2007-01-01

    An object that moves is spotted almost effortlessly; it "pops out." When the observer is stationary, a moving object is uniquely identified by retinal motion. This is not so when the observer is also moving; as the eye travels through space all scene objects change position relative to the eye producing a complicated field of retinal motion.…

  9. neuroBi: A Highly Configurable Neurostimulator for a Retinal Prosthesis and Other Applications

    PubMed Central

    Slater, Kyle D.; Nelson, Timothy S.; Blamey, Peter J.; Mcdermott, Hugh J.

    2015-01-01

    To evaluate the efficacy of a suprachoroidal retinal prosthesis, a highly configurable external neurostimulator is required. In order to meet functional and safety specifications, it was necessary to develop a custom device. A system is presented which can deliver charge-balanced, constant-current biphasic pulses, with widely adjustable parameters, to arbitrary configurations of output electrodes. This system is shown to be effective in eliciting visual percepts in a patient with approximately 20 years of light perception vision only due to retinitis pigmentosa, using an electrode array implanted in the suprachoroidal space of the eye. The flexibility of the system also makes it suitable for use in a number of other emerging clinical neurostimulation applications, including epileptic seizure suppression and closed-loop deep brain stimulation. Clinical trial registration number NCT01603576 (www.clinicaltrials.gov). PMID:27170910

  10. Xeroderma pigmentosa in siblings: cystosarcoma phylloides in a case of xeroderma pigmentosa.

    PubMed

    Ramachandra, L; Rajagopal Shenoi, K; Santhosh Pai, U

    2002-01-01

    Xeroderma pigmentosa is a rare autosomal recessive disorder with numerous oculocutaneous neoplasms, neurological abnormalities and extremely rarely associated with neoplasms of organs other than the skin and the eyes. Here we report two cases of xeroderma pigmentosa with numerous oculocutaneous malignancies in siblings born to a consanguinously married normal parents. One of these patients had a cystosarcoma phylloides in association with xeroderma pigmentosa, hitherto not reported in literature. PMID:17656927

  11. High-Resolution Opto-Electronic Retinal Prosthesis: Physical Limitations and Design

    NASA Astrophysics Data System (ADS)

    Palanker, D.; Vankov, A.; Huie, P.; Butterwick, A.; Chan, I.; Marmor, M. F.; Blumenkranz, M. S.

    Electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa (RP). However, current retinal implants provide very low resolution (just a few electrodes), whereas many more pixels would be required for a functional restoration of sight.

  12. Implantable multilayer microstrip antenna for retinal prosthesis: antenna testing.

    PubMed

    Permana, Hans; Fang, Qiang; Rowe, Wayne S T

    2012-01-01

    Retinal prosthesis has come to a more mature stage and become a very strategic answer to Retinitis Pigmentosa (RP) and Age-related Macular Degeneration (AMD) diseases. In a retinal prosthesis system, wireless link holds a great importance for the continuity of the system. In this paper, an implantable multilayer microstrip antenna was proposed for the retinal prosthesis system. Simulations were performed in High Frequency Structure Simulator (HFSS) with the surrounding material of air and Vitreous Humor fluid. The fabricated antenna was measured for characteristic validation in free space. The results showed that the real antenna possessed similar return loss and radiation pattern, while there was discrepancy with the gain values. PMID:23366231

  13. Reprogramming of adult rod photoreceptors prevents retinal degeneration

    PubMed Central

    Montana, Cynthia L.; Kolesnikov, Alexander V.; Shen, Susan Q.; Myers, Connie A.; Kefalov, Vladimir J.; Corbo, Joseph C.

    2013-01-01

    A prime goal of regenerative medicine is to direct cell fates in a therapeutically useful manner. Retinitis pigmentosa is one of the most common degenerative diseases of the eye and is associated with early rod photoreceptor death followed by secondary cone degeneration. We hypothesized that converting adult rods into cones, via knockdown of the rod photoreceptor determinant Nrl, could make the cells resistant to the effects of mutations in rod-specific genes, thereby preventing secondary cone loss. To test this idea, we engineered a tamoxifen-inducible allele of Nrl to acutely inactivate the gene in adult rods. This manipulation resulted in reprogramming of rods into cells with a variety of cone-like molecular, histologic, and functional properties. Moreover, reprogramming of adult rods achieved cellular and functional rescue of retinal degeneration in a mouse model of retinitis pigmentosa. These findings suggest that elimination of Nrl in adult rods may represent a unique therapy for retinal degeneration. PMID:23319618

  14. Retinal Dystrophy Due to Paternal Isodisomy for Chromosome 1 or Chromosome 2, with Homoallelism for Mutations in RPE65 or MERTK, Respectively

    PubMed Central

    Thompson, Debra A.; McHenry, Christina L.; Li, Yun; Richards, Julia E.; Othman, Mohammad I.; Schwinger, Eberhard; Vollrath, Douglas; Jacobson, Samuel G.; Gal, Andreas

    2002-01-01

    Uniparental disomy (UPD) is a rare condition in which a diploid offspring carries a chromosomal pair from a single parent. We now report the first two cases of UPD resulting in retinal degeneration. We identified an apparently homozygous loss-of-function mutation of RPE65 (1p31) in one retinal dystrophy patient and an apparently homozygous loss-of-function mutation of MERTK (2q14.1) in a second retinal dystrophy patient. In both families, the gene defect was present in the patient’s heterozygous father but not in the patient's mother. Analysis of haplotypes in each nuclear kindred, by use of DNA polymorphisms distributed along both chromosomal arms, indicated the absence of the maternal allele for all informative markers tested on chromosome 1 in the first patient and on chromosome 2 in the second patient. Our results suggest that retinal degeneration in these individuals is due to apparently complete paternal isodisomy involving reduction to homoallelism for RPE65 or MERTK loss-of-function alleles. Our findings provide evidence for the first time, in the case of chromosome 2, and confirm previous observations, in the case of chromosome 1, that there are no paternally imprinted genes on chromosomes 1 and 2 that have a major effect on phenotype. PMID:11727200

  15. New mouse primary retinal degeneration (rd-3)

    SciTech Connect

    Chang, B.; Hawes, N.L.; Roderick, T.H. ); Heckenlively, J.R. )

    1993-04-01

    A new mouse retinal degeneration that appears to be an excellent candidate for modeling human retinitis pigmentosa is reported. In this degeneration, called rd-3, differentiation proceeds postnatally through 2 weeks, and photoreceptor degeneration starts by 3 weeks. The rod photoreceptor loss is essentially complete by 5 weeks, whereas remnant cone cells are seen through 7 weeks. This is the only mouse homozygous retinal degeneration reported to date in which photoreceptors are initially normal. Crosses with known mouse retinal degenerations rd, Rds, nr, and pcd are negative for retinal degeneration in offspring, and linkage analysis places rd-3 on mouse chromosome 1 at 10 [+-]2.5 cM distal to Akp-1. Homology mapping suggests that the homologous human locus should be on chromosome 1q. 32 refs., 3 figs., 3 tabs.

  16. ASIC Design and Data Communications for the Boston Retinal Prosthesis

    PubMed Central

    Shire, Douglas B.; Ellersick, William; Kelly, Shawn K.; Doyle, Patrick; Priplata, Attila; Drohan, William; Mendoza, Oscar; Gingerich, Marcus; McKee, Bruce; Wyatt, John L.; Rizzo, Joseph F.

    2016-01-01

    We report on the design and testing of a custom application-specific integrated circuit (ASIC) that has been developed as a key component of the Boston retinal prosthesis. This device has been designed for patients who are blind due to age-related macular degeneration or retinitis pigmentosa. Key safety and communication features of the low-power ASIC are described, as are the highly configurable neural stimulation current waveforms that are delivered to its greater than 256 output electrodes. The ASIC was created using an 0.18 micron Si fabrication process utilizing standard 1.8 volt CMOS transistors as well as 20 volt lightly doped drain FETs. The communication system receives frequency-shift keyed inputs at 6.78 MHz from an implanted secondary coil, and transmits data back to the control unit through a lower-bandwidth channel that employs load-shift keying. The design’s safety is ensured by on-board electrode voltage monitoring, stimulus charge limits, error checking of data transmitted to the implant, and comprehensive self-test and performance monitoring features. Each stimulus cycle is initiated by a transmitted word with a full 32-bit error check code. Taken together, these features allow researchers to safely and wirelessly tailor retinal stimulation and vision recovery for each patient. PMID:23365888

  17. Urticaria pigmentosa-like disease in a dog.

    PubMed

    Pariser, Marlene S; Gram, Dunbar W

    2015-03-01

    Urticaria pigmentosa is a rare dermatologic syndrome in humans, cats, and dogs. This report documents a case of canine urticaria pigmentosa-like disease with unusual features and no C-kit mutation. PMID:25750443

  18. Urticaria pigmentosa-like disease in a dog

    PubMed Central

    Pariser, Marlene S.; Gram, Dunbar W.

    2015-01-01

    Urticaria pigmentosa is a rare dermatologic syndrome in humans, cats, and dogs. This report documents a case of canine urticaria pigmentosa-like disease with unusual features and no C-kit mutation. PMID:25750443

  19. Retrobulbar optic neuritis and meningoencephalitis following progressive outer retinal necrosis due to CMV in a patient with AIDS.

    PubMed

    Park, K H; Bang, J H; Park, W B; Kim, H B; Kim, N J; Ahn, J K; Chang, K H; Oh, M D; Choe, K W

    2008-10-01

    We report on a 34-year-old male patient with AIDS who developed retrobulbar optic neuritis and meningoencephalitis following bilateral progressive outer retinal necrosis (PORN) caused by cytomegalovirus (CMV). This case documents the presumed association of PORN with retrobulbar optic neuritis, and CMV meningoencephalitis in an AIDS patient. PMID:18574556

  20. In the Early Stages of Diabetes, Rat Retinal Mitochondria Undergo Mild Uncoupling due to UCP2 Activity.

    PubMed

    Osorio-Paz, Ixchel; Uribe-Carvajal, Salvador; Salceda, Rocío

    2015-01-01

    In order to maintain high transmembrane ionic gradients, retinal tissues require a large amount of energy probably provided by a high rate of both, glycolysis and oxidative phosphorylation. However, little information exists on retinal mitochondrial efficiency. We analyzed the retinal mitochondrial activity in ex vivo retinas and in isolated mitochondria from normal rat retina and from short-term streptozotocin-diabetic rats. In normal ex vivo retinas, increasing glucose concentrations from 5.6 mM to 30 mM caused a four-fold increase in glucose accumulation and CO2 production. Retina from diabetic rats accumulated similar amounts of glucose. However, CO2 production was not as high. Isolated mitochondria from normal rat retina exhibited a resting rate of oxygen consumption of 14.6 ± 1.1 natgO (min.mg prot)(-1) and a respiratory control of 4.0. Mitochondria from 7, 20 and 45 days diabetic rats increased the resting rate of oxygen consumption and the activity of the electron transport complexes; under these conditions the mitochondrial transmembrane potential decreased. In spite of this, the ATP synthesis was not modified. GDP, an UCP2 inhibitor, increased mitochondrial membrane potential and superoxide production in controls and at 45 days of diabetes. The role of UCP2 is discussed. The results suggest that at the early stage of diabetes we studied, retinal mitochondria undergo adaptations leading to maintain energetic requirements and prevent oxidative stress. PMID:25951172

  1. Signaling Networks of Retinal Ganglion Cell Formation and the Potential Application of Stem Cell-Based Therapy in Retinal Degenerative Diseases.

    PubMed

    Wu, Nan; Wang, Yi; Yang, Lanbo; Cho, Kin-Sang

    2016-08-01

    Retinal degenerative diseases such as age-related macular degeneration, retinitis pigmentosa, and glaucoma result in permanent loss of retinal neurons and vision. Stem cell therapy could be a novel treatment strategy to restore visual function. In an ideal situation, a homogenous population of stem cell-derived retinal neurons with high purity is used for replacement therapy. Thus, it is crucial to elucidate the molecular mechanisms that regulate the development of retinal progenitor cells and subsequent generation of specific retinal neurons. Here, recent findings concerning the intrinsic and extrinsic factors that regulate retinal progenitor cell maintenance and differentiation are summarized, especially transcriptional factors and extrinsic signals. Understanding these mechanisms is indispensable because they have potential clinical applications, chiefly the generation of specific retinal cells such as retinal ganglion cells to treat glaucoma and other optic neuropathy diseases. PMID:27466076

  2. Estimating Time-to-Collision with Retinitis Pigmentosa

    ERIC Educational Resources Information Center

    Jones, Tim

    2006-01-01

    This article reports on the ability of observers who are sighted and those with low vision to make time-to-collision (TTC) estimations using video. The TTC estimations made by the observers with low vision were comparable to those made by the sighted observers, and both groups made underestimation errors that were similar to those that were…

  3. Hearing Loss Associated with Retinitis Pigmentosa. Short Reports.

    ERIC Educational Resources Information Center

    Karp, Adrienne

    1985-01-01

    The article describes a variation of Usher's Syndrome, a genetic condition characterized by visual and auditory impairments, in which moderate, postlingual, and sometimes progressive hearing impairments may go undetected. Identification guidelines are offered. (Author/CL)

  4. Genetics Home Reference: neuropathy, ataxia, and retinitis pigmentosa

    MedlinePlus

    ... ATP6 gene. This gene is contained in mitochondrial DNA , also known as mtDNA. Mitochondria are structures within ... a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria ...

  5. Improved content aware scene retargeting for retinitis pigmentosa patients

    PubMed Central

    2010-01-01

    Background In this paper we present a novel scene retargeting technique to reduce the visual scene while maintaining the size of the key features. The algorithm is scalable to implementation onto portable devices, and thus, has potential for augmented reality systems to provide visual support for those with tunnel vision. We therefore test the efficacy of our algorithm on shrinking the visual scene into the remaining field of view for those patients. Methods Simple spatial compression of visual scenes makes objects appear further away. We have therefore developed an algorithm which removes low importance information, maintaining the size of the significant features. Previous approaches in this field have included seam carving, which removes low importance seams from the scene, and shrinkability which dynamically shrinks the scene according to a generated importance map. The former method causes significant artifacts and the latter is inefficient. In this work we have developed a new algorithm, combining the best aspects of both these two previous methods. In particular, our approach is to generate a shrinkability importance map using as seam based approach. We then use it to dynamically shrink the scene in similar fashion to the shrinkability method. Importantly, we have implemented it so that it can be used in real time without prior knowledge of future frames. Results We have evaluated and compared our algorithm to the seam carving and image shrinkability approaches from a content preservation perspective and a compression quality perspective. Also our technique has been evaluated and tested on a trial included 20 participants with simulated tunnel vision. Results show the robustness of our method at reducing scenes up to 50% with minimal distortion. We also demonstrate efficacy in its use for those with simulated tunnel vision of 22 degrees of field of view or less. Conclusions Our approach allows us to perform content aware video resizing in real time using only information from previous frames to avoid jitter. Also our method has a great benefit over the ordinary resizing method and even over other image retargeting methods. We show that the benefit derived from this algorithm is significant to patients with fields of view 20° or less. PMID:20846440

  6. General pathophysiology in retinal degeneration.

    PubMed

    Wert, Katherine J; Lin, Jonathan H; Tsang, Stephen H

    2014-01-01

    Retinal degeneration, including that seen in age-related macular degeneration and retinitis pigmentosa (RP), is the most common form of neural degenerative disease in the world. There is great genetic and allelic heterogeneity of the various retinal dystrophies. Classifications of these diseases can be ambiguous, as there are similar clinical presentations in retinal degenerations arising from different genetic mechanisms. As would be expected, alterations in the activity of the phototransduction cascade, such as changes affecting the renewal and shedding of the photoreceptor OS, visual transduction, and/or retinol metabolism have a great impact on the health of the retina. Mutations within any of the molecules responsible for these visual processes cause several types of retinal and retinal pigment epithelium degenerative diseases. Apoptosis has been implicated in the rod cell loss seen in a mouse model of RP, but the precise mechanisms that connect the activation of these pathways to the loss of phosphodiesterase (PDE6β) function has yet to be defined. Additionally, the activation of apoptosis by CCAAT/-enhancer-binding protein homologous protein (CHOP), after activation of the unfolded protein response pathway, may be responsible for cell death, although the mechanism remains unknown. However, the mechanisms of cell death after loss of function of PDE6, which is a commonly studied mammalian model in research, may be generalizable to loss of function of different key proteins involved in the phototransduction cascade. PMID:24732759

  7. General Pathophysiology in Retinal Degeneration

    PubMed Central

    Wert, Katherine J.; Lin, Jonathan H.; Tsang, Stephen H.

    2015-01-01

    Retinal degeneration, including that seen in age-related macular degeneration and retinitis pigmentosa (RP), is the most common form of neural degenerative disease in the world. There is great genetic and allelic heterogeneity of the various retinal dystrophies. Classifications of these diseases can be ambiguous, as there are similar clinical presentations in retinal degenerations arising from different genetic mechanisms. As would be expected, alterations in the activity of the phototransduction cascade, such as changes affecting the renewal and shedding of the photoreceptor OS, visual transduction, and/ or retinol metabolism have a great impact on the health of the retina. Mutations within any of the molecules responsible for these visual processes cause several types of retinal and retinal pigment epithelium degenerative diseases. Apoptosis has been implicated in the rod cell loss seen in a mouse model of RP, but the precise mechanisms that connect the activation of these pathways to the loss of phosphodiesterase (PDE6β) function has yet to be defined. Additionally, the activation of apoptosis by CCAAT/-enhancer-binding protein homologous protein (CHOP), after activation of the unfolded protein response pathway, may be responsible for cell death, although the mechanism remains unknown. However, the mechanisms of cell death after loss of function of PDE6, which is a commonly studied mammalian model in research, may be generalizable to loss of function of different key proteins involved in the phototransduction cascade. PMID:24732759

  8. The Argus(®) II Retinal Prosthesis System.

    PubMed

    Luo, Yvonne Hsu-Lin; da Cruz, Lyndon

    2016-01-01

    The Argus(®) II Retinal Prosthesis System (Second Sight Medical Products) is the first prosthetic vision device to obtain regulatory approval in both Europe and the USA. As such it has entered the commercial market as a treatment for patients with profound vision loss from end-stage outer retinal disease, predominantly retinitis pigmentosa. To date, over 100 devices have been implanted worldwide, representing the largest group of patients currently treated with visual prostheses. The system works by direct stimulation of the relatively preserved inner retina via epiretinal microelectrodes, thereby replacing the function of the degenerated photoreceptors. Visual information from a glasses-mounted video camera is converted to a pixelated image by an external processor, before being transmitted to the microelectrode array at the macula. Elicited retinal responses are then relayed via the normal optic nerve to the cortex for interpretation. We reviewed the animal and human studies that led to the development of the Argus(®) II device. A sufficiently robust safety profile was demonstrated in the phase I/II clinical trial of 30 patients. Improvement of function in terms of orientation and mobility, target localisation, shape and object recognition, and reading of letters and short unrehearsed words have also been shown. There remains a wide variability in the functional outcomes amongst the patients and the factors contributing to these performance differences are still unclear. Future developments in terms of both software and hardware aimed at improving visual function have been proposed. Further experience in clinical outcomes is being acquired due to increasing implantation. PMID:26404104

  9. Microsystems Technology for Retinal Implants

    NASA Astrophysics Data System (ADS)

    Weiland, James

    2005-03-01

    The retinal prosthesis is targeted to treat age-related macular degeneration, retinitis pigmentosa, and other outer retinal degenerations. Simulations of artificial vision have predicted that 600-1000 individual pixels will be needed if a retinal prosthesis is to restore function such as reading large print and face recognition. An implantable device with this many electrode contacts will require microsystems technology as part of its design. An implantable retinal prosthesis will consist of several subsystems including an electrode array and hermetic packaging. Microsystems and microtechnology approaches are being investigated as possible solutions for these design problems. Flexible polydimethylsiloxane (PDMS) substrate electrode arrays and silicon micromachined electrode arrays are under development. Inactive PDMS electrodes have been implanted in 3 dogs to assess mechanical biocompatibility. 3 dogs were followed for 6 months. The implanted was securely fastened to the retina with a single retinal tack. No post-operative complications were evident. The array remained within 100 microns of the retinal surface. Histological evaluation showed a well preserved retina underneath the electrode array. A silicon device with electrodes suspended on micromachined springs has been implanted in 4 dogs (2 acute implants, 2 chronic implants). The device, though large, could be inserted into the eye and positioned on the retina. Histological analysis of the retina from the spring electrode implants showed that spring mounted posts penetrated the retina, thus the device will be redesigned to reduce the strength of the springs. These initial implants will provide information for the designers to make the next generation silicon device. We conclude that microsystems technology has the potential to make possible a retinal prosthesis with 1000 individual contacts in close proximity to the retina.

  10. Cytomegalovirus retinitis

    MedlinePlus

    ... to prevent its return. Alternative Names Cytomegalovirus retinitis Images Eye CMV retinitis CMV (cytomegalovirus) References Crumpacker CS. ... 5. Read More Antibody HIV/AIDS Immune response Retinal detachment Systemic WBC count Update Date 12/10/ ...

  11. Pars plana vitrectomy combined with internal limiting membrane peeling for recurrent macular edema due to branch retinal vein occlusion after antivascular endothelial growth factor treatments

    PubMed Central

    Shirakata, Yukari; Fukuda, Kouki; Fujita, Tomoyoshi; Nakano, Yuki; Nomoto, Hiroyuki; Yamaji, Hidetaka; Shiraga, Fumio; Tsujikawa, Akitaka

    2016-01-01

    Purpose To evaluate the anatomic and functional outcomes of pars plana vitrectomy combined with internal limiting membrane peeling for recurrent macular edema (ME) due to branch retinal vein occlusion (BRVO) after intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents. Methods Twenty-four eyes of 24 patients with treatment-naive ME from BRVO were treated with intravitreal injections of anti-VEGF agents. Recurred ME was treated with pars plana vitrectomy combined with internal limiting membrane peeling. Results After the surgery, ME was significantly reduced at 1 month (P=0.031) and the reduction increased with time (P=0.007 at the final visit). With the reduction in ME, treated eyes showed a slow improvement in visual acuity (VA). At the final visit, improvement in VA was statistically significant compared with baseline (P=0.048). The initial presence of cystoid spaces, serous retinal detachment, or subretinal hemorrhage under the fovea, as well as retinal perfusion status, showed no association with VA improvement. However, the presence of epiretinal membrane showed a significant association with the visual recovery. Although eyes without epiretinal membrane showed visual improvement (−0.10±0.32 in logarithm of the minimum angle of resolution [logMAR]), eyes with epiretinal membrane showed greater visual improvement (−0.38±0.12 in logMAR, P=0.012). Conclusion For recurrent ME due to BRVO after anti-VEGF treatment, particularly when accompanied by epiretinal membrane, pars plana vitrectomy combined with internal limiting membrane peeling might be a possible treatment option. PMID:26917950

  12. Vision Loss due to Central Retinal Artery Occlusion Following Embolization in a Case of a Giant Juvenile Nasopharyngeal Angiofibroma.

    PubMed

    Trivedi, Mihir; Desai, Roshani J; Potdar, Nayana A; Shinde, Chhaya A; Ukirde, Vivek; Bhuta, Maunil; Nair, Akshay Gopinathan

    2015-07-01

    Juvenile nasopharyngeal angiofibroma (JNA) is a benign, vascular, and locally aggressive tumor that arises in the nasal cavity, extending into the nasopharynx and often in to the orbit. It may rarely present to the ophthalmologist with proptosis and optic neuropathy. Preoperative embolization of JNA is done before surgical resection. In this communication, the authors report a rare occurrence of ipsilateral central retinal artery occlusion (CRAO) following embolization with polyvinyl alcohol in a 13-year-old boy with right-sided JNA. Retrospective review of the angiograms pointed out to a suspicious communication between the external carotid artery and the ophthalmic vessels. Pre-embolization detailed study of the angiograms is necessary to avoid such devastating complications. Although rare, vision loss is a possible complication arising from embolization of nasopharyngeal and intracranial tumors, and all patients undergoing these procedures should be informed of the risk of visual loss because it has a lasting impact on the quality of life. PMID:26167999

  13. Progesterone receptor signalling in retinal photoreceptor neuroprotection.

    PubMed

    Jackson, Alice C Wyse; Roche, Sarah L; Byrne, Ashleigh M; Ruiz-Lopez, Ana M; Cotter, Thomas G

    2016-01-01

    'Norgestrel', a synthetic form of the female hormone progesterone has been identified as potential drug candidate for the treatment of the degenerative eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of Norgestrel and begin to examine its potential mechanism of action in the retina. In this work, we identify and characterize the expression of progesterone receptors present in the C57 wild type and rd10 mouse model of retinitis pigmentosa. Classical progesterone receptors A and B (PR A/B), progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) and membrane progesterone receptors α, β and γ were found to be expressed. All receptors excluding PR A/B were also found in the 661W photoreceptor cell line. PGRMC1 is a key regulator of apoptosis and its expression is up-regulated in the degenerating rd10 mouse retina. Activated by Norgestrel through nuclear trafficking, siRNA knock down of PGRMC1 abrogated the protective properties of Norgestrel on damaged photoreceptors. Furthermore, specific inhibition of PGRMC1 by AG205 blocked Norgestrel-induced protection in stressed retinal explants. Therefore, we conclude that PGRMC1 is crucial to the neuroprotective effects of Norgestrel on stressed photoreceptors. The synthetic progestin 'Norgestrel' has been identified as a potential therapeutic for the treatment of Retinitis Pigmentosa, a degenerative eye disease. However, the mechanism behind this neuroprotection is currently unknown. In this work, we identify 'Progesterone Receptor Membrane Component 1' as the major progesterone receptor eliciting the protective effects of Norgestrel, both in vitro and ex vivo. This furthers our understanding of Norgestrel's molecular mechanism, which we hope will help bring Norgestrel one step closer to the clinic. PMID:26447367

  14. Dawn of ocular gene therapy: implications for molecular diagnosis in retinal disease

    PubMed Central

    Jacques, ZANEVELD; Feng, WANG; Xia, WANG; Rui, CHEN

    2013-01-01

    Personalized medicine aims to utilize genomic information about patients to tailor treatment. Gene replacement therapy for rare genetic disorders is perhaps the most extreme form of personalized medicine, in that the patients’ genome wholly determines their treatment regimen. Gene therapy for retinal disorders is poised to become a clinical reality. The eye is an optimal site for gene therapy due to the relative ease of precise vector delivery, immune system isolation, and availability for monitoring of any potential damage or side effects. Due to these advantages, clinical trials for gene therapy of retinal diseases are currently underway. A necessary precursor to such gene therapies is accurate molecular diagnosis of the mutation(s) underlying disease. In this review, we discuss the application of Next Generation Sequencing (NGS) to obtain such a diagnosis and identify disease causing genes, using retinal disorders as a case study. After reviewing ocular gene therapy, we discuss the application of NGS to the identification of novel Mendelian disease genes. We then compare current, array based mutation detection methods against next NGS-based methods in three retinal diseases: Leber’s Congenital Amaurosis, Retinitis Pigmentosa, and Stargardt’s disease. We conclude that next-generation sequencing based diagnosis offers several advantages over array based methods, including a higher rate of successful diagnosis and the ability to more deeply and efficiently assay a broad spectrum of mutations. However, the relative difficulty of interpreting sequence results and the development of standardized, reliable bioinformatic tools remain outstanding concerns. In this review, recent advances NGS based molecular diagnoses are discussed, as well as their implications for the development of personalized medicine. PMID:23393028

  15. VANISHING RETINAL DETACHMENT

    PubMed Central

    2015-01-01

    Purpose: The purpose of this report is to describe a case of rhegmatogenous retinal detachment in the setting of chronic kidney disease that exhibited complete retinal reattachment after serial hemodialysis. Methods: Retrospective case report. Results: A 58-year-old woman with acute vision loss was found to have a macula-involving rhegmatogenous retinal detachment. Due to chronic kidney disease, she continued with routinely scheduled hemodialysis for 1 week until surgical clearance was obtained. Preoperative examination revealed complete reattachment of the retina with a persistent retinal tear. Barrier laser was applied to the tear and the retina remained attached until the most recent follow-up 8 months later. The workup of alternate etiologies was unrevealing. Conclusion: This case describes a temporal association between hemodialysis and resolution of subretinal fluid due to rhegmatogenous retinal detachment. A potential causal linkage is suggested based on shifting fluid dynamics associated with hemodialysis. A shift in treatment paradigm is not advised. PMID:26352323

  16. Prospects for retinal gene replacement therapy.

    PubMed

    Smith, Alexander J; Bainbridge, James W; Ali, Robin R

    2009-04-01

    Inherited retinal degeneration, which includes conditions such as retinitis pigmentosa and Leber congenital amaurosis (LCA), affects approximately 1/3000 of the population in the Western world. It is characterized by loss of vision and results from mutations in any one of >100 different genes. There are currently no effective treatments, but many of the genes have now been identified and their functions elucidated, providing a major impetus to develop gene-based treatments. Preliminary results from three clinical trials indicate that the treatment of a form of LCA by gene therapy can be safe and effective. Here, we discuss the potential for treating other forms of retinal degeneration by gene therapy, focusing on the gene defects that are likely to be the most amenable to treatment. PMID:19303164

  17. Regenerative ophthalmology: Technologic and pharmacologic approaches to restoring sight via retinal prosthesis.

    PubMed

    Iezzi, R

    2016-01-01

    Retinal prosthesis technology can restore rudimentary form vision in patients with retinitis pigmentosa (RP) who have lost all eyesight. This continually advancing field within regenerative ophthalmology represents the merger of micro-electromechanical systems technology with neurosensory retina. This man-machine interface is reliant upon the long-term health of a neurosensory retina undergoing progressive pathophysiologic changes. Pharmacologic approaches that address the pathophysiologic consequences of RP will likely play an important role for all regenerative treatment strategies. PMID:26522735

  18. N -methyl- N -nitrosourea-induced retinal degeneration in mice.

    PubMed

    Chen, Yuan-Yuan; Liu, Shi-Liang; Hu, Dan-Ping; Xing, Yi-Qiao; Shen, Yin

    2014-04-01

    Mouse retinal degeneration models have been investigated for many years in the hope of understanding the mechanism of photoreceptor cell death. N -methyl- N -nitrosourea (MNU) has been previously shown to induce outer retinal degeneration in mice. After MNU was intraperitoneally injected in C57/BL mice, we observed a gradual decrease in the outer nuclear layer (ONL) thickness associated with photoreceptor outer segment loss, bipolar cell dendritic retraction and reactive gliosis. Reactive gliosis was confirmed by increased GFAP protein levels. More serious damage to the central retina as opposed to the peripheral retina was found in the MNU-induced retinal degeneration model. Retinal ganglion cells (RGC) appear to be spared for at least two months after MNU treatment. Following retinal vessel labelling, we observed vascular complexes in the distal vessels, indicating retinal vessel damage. In the remnant retinal photoreceptor of the MNU-treated mouse, concentrated colouring nuclei were detected by electron microscopy, together with the loss of mitochondria and displaced remnant synaptic ribbons in the photoreceptor. We also observed decreased mitochondrial protein levels and increased amounts of nitrosylation/nitration in the photoreceptors. The mechanism of MNU-induced apoptosis may result from oxidative stress or the loss of retinal blood supply. MNU-induced mouse retinal degeneration in the outer retina is a useful animal model for photoreceptor degeneration diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). PMID:24509257

  19. Predictors of short-term outcomes related to central subfield foveal thickness after intravitreal bevacizumab for macular edema due to central retinal vein occlusion

    PubMed Central

    Wang, Mei-Zi; Feng, Kang; Lu, Yao; Qian, Fang; Lu, Xin-Rong; Zang, Si-Wen; Zhao, Lin

    2016-01-01

    AIM To investigate the predictive factors for short-term effects of intravitreal bevacizumab injections on central subfield foveal thickness (CSFT) in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO). METHODS This was a retrospective study in 60 eyes treated with intravitreal bevacizumab injections for ME due to CRVO. Follow-up was three months. The Early Treatment Diabetic Retinopathy Study (ETDRS) score and CSFT measured by spectral-domain optical coherence tomography (SD-OCT) were used to observe the changes in best-corrected visual acuity (BCVA). Baseline BCVA, CSFT, age, CRVO duration and the presence of cystoid macular edema (CME) or subretinal fluid (SRF) were analyzed as potential predictive factors of the effects of intravitreal bevacizumab injections. RESULTS BCVA improved from 0.9 logMAR at baseline to 0.6 logMAR at 3mo, which was associated with a significant reduction in CSFT from 721 µm to 392 µm 3mo after injection. About 50% of CME cases and more than 90% of SRF cases responded to treatment with a complete resolution at 3mo. Age (P=0.036) and low baseline CSFT (P=0.037) were associated with a good 3-month prognosis. Patients >60 years old achieved better CME resolution (P=0.031) and lower CSFT at 3mo (305 µm vs 474 µm, P=0.003). CONCLUSION Intravitreal bevacizumab significantly improved visual acuity and CSFT in patients with CRVO after 3mo. Older age and lower baseline CSFT were good predictors of short-term CSFT outcomes. The retinal thickness response to bevacizumab might depend on the resolution of CME rather than SRF. PMID:26949616

  20. Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes

    PubMed Central

    Liu, Haitao; Tang, Jie; Du, Yunpeng; Saadane, Aicha; Tonade, Deoye; Samuels, Ivy; Veenstra, Alex; Palczewski, Krzysztof; Kern, Timothy S.

    2016-01-01

    Purpose Loss of photoreceptor cells is associated with retinal vascular degeneration in retinitis pigmentosa, whereas the presence of photoreceptor cells is implicated in vascular degeneration in diabetic retinopathy. To investigate how both the absence and presence of photoreceptors could damage the retinal vasculature, we compared two mouse models of photoreceptor degeneration (opsin−/− and RhoP23H/P23H ) and control C57Bl/5J mice, each with and without diabetes. Methods Retinal thickness, superoxide, expression of inflammatory proteins, ERG and optokinetic responses, leukocyte cytotoxicity, and capillary degeneration were evaluated at 1 to 10 months of age using published methods. Results Retinal photoreceptor cells degenerated completely in the opsin mutants by 2 to 4 months of age, and visual function subsided correspondingly. Retinal capillary degeneration was substantial while photoreceptors were still present, but slowed after the photoreceptors degenerated. Diabetes did not further exacerbate capillary degeneration in these models of photoreceptor degeneration, but did cause capillary degeneration in wild-type animals. Photoreceptor cells, however, did not degenerate in wild-type diabetic mice, presumably because the stress responses in these cells were less than in the opsin mutants. Retinal superoxide and leukocyte damage to retinal endothelium contributed to the degeneration of retinal capillaries in diabetes, and leukocyte-mediated damage was increased in both opsin mutants during photoreceptor cell degeneration. Conclusions Photoreceptor cells affect the integrity of the retinal microvasculature. Deterioration of retinal capillaries in opsin mutants was appreciable while photoreceptor cells were present and stressed, but was less after photoreceptors degenerated. This finding proves relevant to diabetes, where persistent stress in photoreceptors likewise contributes to capillary degeneration. PMID:27548901

  1. A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations.

    PubMed

    Downs, Louise M; Wallin-Håkansson, Berit; Boursnell, Mike; Marklund, Stefan; Hedhammar, Åke; Truvé, Katarina; Hübinette, Louise; Lindblad-Toh, Kerstin; Bergström, Tomas; Mellersh, Cathryn S

    2011-01-01

    Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (p(raw) = 1.94×10(-10), p(genome) = 1.0×10(-5)), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans. PMID:21738669

  2. Purinergic signaling in retinal degeneration and regeneration.

    PubMed

    Reichenbach, Andreas; Bringmann, Andreas

    2016-05-01

    Purinergic signaling is centrally involved in mediating the degeneration of the injured and diseased retina, the induction of retinal gliosis, and the protection of the retinal tissue from degeneration. Dysregulated calcium signaling triggered by overactivation of P2X7 receptors is a crucial step in the induction of neuronal and microvascular cell death under pathogenic conditions like ischemia-hypoxia, elevated intraocular pressure, and diabetes, respectively. Overactivation of P2X7 plays also a pathogenic role in inherited and age-related photoreceptor cell death and in the age-related dysfunction and degeneration of the retinal pigment epithelium. Gliosis of micro- and macroglial cells, which is induced and/or modulated by purinergic signaling and associated with an impaired homeostatic support to neurons, and the ATP-mediated propagation of retinal gliosis from a focal injury into the surrounding noninjured tissue are involved in inducing secondary cell death in the retina. On the other hand, alterations in the glial metabolism of extracellular nucleotides, resulting in a decreased level of ATP and an increased level of adenosine, may be neuroprotective in the diseased retina. Purinergic signals stimulate the proliferation of retinal glial cells which contributes to glial scarring which has protective effects on retinal degeneration and adverse effects on retinal regeneration. Pharmacological modulation of purinergic receptors, e.g., inhibition of P2X and activation of adenosine receptors, may have clinical importance for the prevention of photoreceptor, neuronal, and microvascular cell death in diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration, and glaucoma, respectively, for the clearance of retinal edema, and the inhibition of dysregulated cell proliferation in proliferative retinopathies. This article is part of a Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID:25998275

  3. A patient with branch retinal vein occlusion accompanied by superior ophthalmic vein thrombosis due to severe superior ophthalmic vein enlargement in a patient with graves ophthalmopathy.

    PubMed

    Park, Han Seok; Gye, Hyo Jeong; Kim, Joon Mo; Lee, Young Ji

    2014-07-01

    We report a patient with branch retinal vein occlusion (BRVO) accompanied by superior ophthalmic vein (SOV) thrombosis resulting from severe SOV enlargement in a patient with Graves ophthalmopathy (GO). A 78-year-old woman diagnosed with BRVO presented with reduced vision. She had a more than 20-year history of unilateral GO. Fluorescein angiography and spectralis optical coherence tomography revealed BRVO with cystoid macular edema. Approximately 5 months later, she complained of advanced left proptosis. A computed tomography scan at that time revealed dilated SOV with high internal attenuation due to SOV thrombosis of the left orbit. Because of the uncertain onset of SOV thrombosis and minimal signs of acute orbital congestion, we prescribed prophylactic daily aspirin to improve blood flow rather than a heparin-based treatment. In addition, she was treated with lubricants for exposure keratopathy and a dorzolamide/timolol eyedrops to prevent increases in intraocular pressure. This is the first clinical report of BRVO accompanied by SOV thrombosis due to SOV enlargement in chronic severe GO. It should be recognized that SOV thrombosis can lead to an increase in proptosis even in chronic GO. PMID:24978681

  4. Nutrition and retinal degenerations.

    PubMed

    Berson, E L

    2000-01-01

    Considerable progress has been made in the understanding and management of degenerative diseases of the retina involving photoreceptors. Nutritional approaches to treatment have proved successful in the case of the common forms of retinitis pigmentosa (supplementation with vitamin A), Bassen-Kornzweig disease (supplementation with vitamins A, E, and K), gyrate atrophy (low-protein, low-arginine diet and/or supplementation with vitamin B6), and Refsum disease (low-phytol, low-phytanic acid diet). The night blindness associated with Sorsby fundus dystrophy can be reversed over the short term with vitamin A. A significant trend for decreased risk for advanced or exudative ARMD has been reported among those whose diets contain a higher content of carotenoids, such as spinach and collard greens. A randomized trial is in progress to determine whether beta-carotene, vitamin C, and vitamin E as well as trace minerals, particularly zinc, will modify the course of ARMD. The difficulties that patients with retinal degenerations face as a result of their diminishing vision, sometimes over decades, cannot be underestimated. Nutritional therapy has proved effective in modifying the course of a number of these conditions; the therapeutic benefit of nutritional modification in diseases that have a genetic basis is of particular interest. Further research is warranted to determine the mechanisms by which these treatments provide their benefit as well as to identify other conditions that may yield to nutritional intervention. Risk-factor analyses of well-defined populations followed over time with food-frequency questionnaires in conjunction with careful assessments of visual function may reveal other dietary constituents that can modify the course of degenerative diseases of the retina. PMID:11064860

  5. Grid laser with modified pro re nata injection of bevacizumab and ranibizumab in macular edema due to branch retinal vein occlusion: MARVEL report no 2

    PubMed Central

    Narayanan, Raja; Panchal, Bhavik; Stewart, Michael W; Das, Taraprasad; Chhablani, Jay; Jalali, Subhadra; Hasnat Ali, Mohd

    2016-01-01

    Purpose The purpose of this study was to prospectively study the efficacy of grid laser combined with intravitreal bevacizumab or ranibizumab in eyes with macular edema due to branch retinal vein occlusion. Patients and methods Treatment-naïve eyes were enrolled to receive injections of ranibizumab or bevacizumab. During the first 6 months, patients were evaluated monthly and injected if the best-corrected visual acuity changed by five or more letters or fluid was noted on spectral domain optical coherence tomography (OCT); during the next 6 months, patients were evaluated bimonthly and injected only if the best-corrected visual acuity decreased by five or more letters with the associated fluid. Grid laser photocoagulation was performed if there was fluid on OCT and was repeated if patients were eligible after a minimum interval of 3 months. Results The mean numbers of ranibizumab and bevacizumab injections were, respectively, 3.2±1.5 and 3.0±1.4 in the first 6 months and 0.3±0.6 and 0.3±0.6 in the last 6 months. Moreover, 55/75 (73.33%) participants did not receive any injections in the last 6 months. The mean reductions in central retinal thickness at 12 months were 165.67 μm (P<0.001; 95% confidence interval −221.50 to −135.0) in the ranibizumab group and 184.78 μm (P<0.001; 95% confidence interval −246.49 to −140.0) in the bevacizumab group (P=0.079). More patients in the bevacizumab group compared to those in the ranibizumab group required rescue laser at 12 months (20 vs eleven; P=0.06). Conclusion Bimonthly evaluations after month 6 with very few pro re nata injections were effective in maintaining visual gains achieved during the first 6 months. Grid laser photocoagulation is effective in maintaining the vision even in the presence of fluid on OCT, although it’s required more often in patients treated with bevacizumab. PMID:27330272

  6. A method and technical equipment for an acute human trial to evaluate retinal implant technology

    NASA Astrophysics Data System (ADS)

    Hornig, Ralf; Laube, Thomas; Walter, Peter; Velikay-Parel, Michaela; Bornfeld, Norbert; Feucht, Matthias; Akguel, Harun; Rössler, Gernot; Alteheld, Nils; Lütke Notarp, Dietmar; Wyatt, John; Richard, Gisbert

    2005-03-01

    This paper reports on methods and technical equipment to investigate the epiretinal stimulation of the retina in blind human subjects in acute trials. Current is applied to the retina through a thin, flexible microcontact film (microelectrode array) with electrode diameters ranging from 50 to 360 µm. The film is mounted in a custom-designed surgical tool that is hand-held by the surgeon during stimulation. The eventual goal of the work is the development of a chronically implantable retinal prosthesis to restore a useful level of vision to patients who are blind with outer retinal degenerations, specifically retinitis pigmentosa and macular degeneration.

  7. A method and technical equipment for an acute human trial to evaluate retinal implant technology.

    PubMed

    Hornig, Ralf; Laube, Thomas; Walter, Peter; Velikay-Parel, Michaela; Bornfeld, Norbert; Feucht, Matthias; Akguel, Harun; Rössler, Gernot; Alteheld, Nils; Lütke Notarp, Dietmar; Wyatt, John; Richard, Gisbert

    2005-03-01

    This paper reports on methods and technical equipment to investigate the epiretinal stimulation of the retina in blind human subjects in acute trials. Current is applied to the retina through a thin, flexible microcontact film (microelectrode array) with electrode diameters ranging from 50 to 360 microm. The film is mounted in a custom-designed surgical tool that is hand-held by the surgeon during stimulation. The eventual goal of the work is the development of a chronically implantable retinal prosthesis to restore a useful level of vision to patients who are blind with outer retinal degenerations, specifically retinitis pigmentosa and macular degeneration. PMID:15876648

  8. Retinal Remodeling: Concerns, Emerging Remedies and Future Prospects

    PubMed Central

    Krishnamoorthy, Vidhyasankar; Cherukuri, Pitchaiah; Poria, Deepak; Goel, Manvi; Dagar, Sushma; Dhingra, Narender K.

    2016-01-01

    Deafferentation results not only in sensory loss, but also in a variety of alterations in the postsynaptic circuitry. These alterations may have detrimental impact on potential treatment strategies. Progressive loss of photoreceptors in retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, leads to several changes in the remnant retinal circuitry. Müller glial cells undergo hypertrophy and form a glial seal. The second- and third-order retinal neurons undergo morphological, biochemical and physiological alterations. A result of these alterations is that retinal ganglion cells (RGCs), the output neurons of the retina, become hyperactive and exhibit spontaneous, oscillatory bursts of spikes. This aberrant electrical activity degrades the signal-to-noise ratio in RGC responses, and thus the quality of information they transmit to the brain. These changes in the remnant retina, collectively termed “retinal remodeling”, pose challenges for genetic, cellular and bionic approaches to restore vision. It is therefore crucial to understand the nature of retinal remodeling, how it affects the ability of remnant retina to respond to novel therapeutic strategies, and how to ameliorate its effects. In this article, we discuss these topics, and suggest that the pathological state of the retinal output following photoreceptor loss is reversible, and therefore, amenable to restorative strategies. PMID:26924962

  9. Evaluation of patient suitability for a retinal prosthesis using structural and functional tests of inner retinal integrity

    NASA Astrophysics Data System (ADS)

    Huang, Qiuhen; Chowdhury, Vivek; Coroneo, Minas Theodore

    2009-06-01

    The purpose of this study was to assess inner retinal structure and function in patients with retinitis pigmentosa (RP) using optical coherence tomography (OCT) imaging of the retina, and electrical stimulation of the retina with a contact lens electrode. OCT images of 17 RP patients were acquired at the macula and at four quadrants of the peripheral retina in both eyes. Analysis was made of the residual inner retinal thickness and nerve fibre layer thickness in RP patients, and this was compared to normal controls. Eight of these patients further underwent contact lens electrical stimulation of one eye and thresholds for phosphene perception were obtained. OCT imaging showed a significant amount of inner retinal preservation in the peripheral retina and the macula of RP patients despite severe visual acuity and visual field loss. Phosphene thresholds were obtained across the range of pulse durations tested but were much higher than those obtained in normal controls. Phosphene thresholds in RP patients moderately correlated with inner retinal thicknesses as measured by OCT. Preservation of inner retinal structure in patients with RP and the responsiveness of these eyes to electrical stimulation suggest adequate inner retinal preservation for a retinal prosthesis to be successful.

  10. Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides:

    NASA Astrophysics Data System (ADS)

    Chen, Junping; Patil, Swanand; Seal, Sudipta; McGinnis, James F.

    2006-11-01

    Photoreceptor cells are incessantly bombarded with photons of light, which, along with the cells' high rate of oxygen metabolism, continuously exposes them to elevated levels of toxic reactive oxygen intermediates (ROIs). Vacancy-engineered mixed-valence-state cerium oxide nanoparticles (nanoceria particles) scavenge ROIs. Our data show that nanoceria particles prevent increases in the intracellular concentrations of ROIs in primary cell cultures of rat retina and, in vivo, prevent loss of vision due to light-induced degeneration of photoreceptor cells. These data indicate that the nanoceria particles may be effective in inhibiting the progression of ROI-induced cell death, which is thought to be involved in macular degeneration, retinitis pigmentosa and other blinding diseases, as well as the ROI-induced death of other cell types in diabetes, Alzheimer's disease, atherosclerosis, stroke and so on. The use of nanoceria particles as a direct therapy for multiple diseases represents a novel strategy and suggests that they may represent a unique platform technology.

  11. Toward high-resolution optoelectronic retinal prosthesis

    NASA Astrophysics Data System (ADS)

    Palanker, Daniel; Huie, Philip; Vankov, Alexander; Asher, Alon; Baccus, Steven

    2005-04-01

    It has been already demonstrated that electrical stimulation of retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. Current retinal implants provide very low resolution (just a few electrodes), while several thousand pixels are required for functional restoration of sight. We present a design of the optoelectronic retinal prosthetic system that can activate a retinal stimulating array with pixel density up to 2,500 pix/mm2 (geometrically corresponding to a visual acuity of 20/80), and allows for natural eye scanning rather than scanning with a head-mounted camera. The system operates similarly to "virtual reality" imaging devices used in military and medical applications. An image from a video camera is projected by a goggle-mounted infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. Such a system provides a broad field of vision by allowing for natural eye scanning. The goggles are transparent to visible light, thus allowing for simultaneous utilization of remaining natural vision along with prosthetic stimulation. Optical control of the implant allows for simple adjustment of image processing algorithms and for learning. A major prerequisite for high resolution stimulation is the proximity of neural cells to the stimulation sites. This can be achieved with sub-retinal implants constructed in a manner that directs migration of retinal cells to target areas. Two basic implant geometries are described: perforated membranes and protruding electrode arrays. Possibility of the tactile neural stimulation is also examined.

  12. A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration

    PubMed Central

    Carrigan, Matthew; Humphries, Pete; Palfi, Arpad; Kenna, Paul F; Farrar, G Jane

    2016-01-01

    Background The GNAT1 gene encodes the α subunit of the rod transducin protein, a key element in the rod phototransduction cascade. Variants in GNAT1 have been implicated in stationary night-blindness in the past, but unlike other proteins in the same pathway, it has not previously been implicated in retinitis pigmentosa. Methods A panel of 182 retinopathy-associated genes was sequenced to locate disease-causing mutations in patients with inherited retinopathies. Results Sequencing revealed a novel homozygous truncating mutation in the GNAT1 gene in a patient with significant pigmentary disturbance and constriction of visual fields, a presentation consistent with retinitis pigmentosa. This is the first report of a patient homozygous for a complete loss-of-function GNAT1 mutation. The clinical data from this patient provide definitive evidence of retinitis pigmentosa with late onset in addition to the lifelong night-blindness that would be expected from a lack of transducin function. Conclusion These data suggest that some truncating GNAT1 variants can indeed cause a recessive, mild, late-onset retinal degeneration in human beings rather than just stationary night-blindness as reported previously, with notable similarities to the phenotype of the Gnat1 knockout mouse. PMID:26472407

  13. [Vision engineering--photoelectric dye-based retinal prostheses: Okayama University model].

    PubMed

    Matsuo, Toshihiko

    2007-04-01

    Patients with retinitis pigmentosa lose photoreceptor cells by genetic abnormalities and hence become blind. Neurons such as bipolar cells and ganglion cells still remain alive even in the retina of these patients, and ganglion cells send axons to the brain as the optic nerve. The replacement of dead photoreceptor cells with something artificial is the basic concept of retinal prostheses. The remaining retinal neurons can be stimulated by either electric current or electric potential. Photodiode array and electrode array are two main ways to stimulate retinal neurons as retinal prostheses. These retinal prostheses have problems such as low sensitivity and requiring outer electric sources (batteries). To overcome the problems, we are developing photoelectric dye-based retinal prostheses which absorb light and convert photon energy to electric potentials. The prototype, photoelectric dye-coupled polyethylene film, could generate intracellular calcium elevation in photoreceptor-lacking retinal tissues and also in cultured retinal neurons. The photoelectric dye-based retinal prostheses are thin and soft, and therefore, a sheet of the film in a large size, corresponding to wide visual field, can be inserted into the vitreous and then to the subretinal space through a small opening by rolling up the film. After the production control and the quality control have been established, clinical trials of the photoelectric dye-based retinal prostheses would be planned in concordance with the Drugs and Medical Devices Law to prove the safety and the efficacy. PMID:17447519

  14. Screening retinal transplants with Fourier-domain OCT

    NASA Astrophysics Data System (ADS)

    Rao, Bin

    2009-02-01

    Transplant technologies have been studied for the recovery of vision loss from retinitis pigmentosa (RP) and age-related macular degeneration (AMD). In several rodent retinal degeneration models and in patients, retinal progenitor cells transplanted as layers to the subretinal space have been shown to restore or preserve vision. The methods for evaluation of transplants are expensive considering the large amount of animals. Alternatively, time-domain Stratus OCT was previously shown to be able to image the morphological structure of transplants to some extent, but could not clearly identify laminated transplants. The efficacy of screening retinal transplants with Fourier-domain OCT was studied on 37 S334ter line 3 rats with retinal degeneration 6-67 days after transplant surgery. The transplants were morphologically categorized as no transplant, detachment, rosettes, small laminated area and larger laminated area with both Fourier-domain OCT and histology. The efficacy of Fourier-domain OCT in screening retinal transplants was evaluated by comparing the categorization results with OCT and histology. Additionally, 4 rats were randomly selected for multiple OCT examinations (1, 5, 9, 14 and 21days post surgery) in order to determine the earliest image time of OCT examination since the transplanted tissue may need some time to show its tendency of growing. Finally, we demonstrated the efficacy of Fourier-domain OCT in screening retinal transplants in early stages and determined the earliest imaging time for OCT. Fourier-domain OCT makes itself valuable in saving resource spent on animals with unsuccessful transplants.

  15. Vitamin A Derivatives as Treatment Options for Retinal Degenerative Diseases

    PubMed Central

    Perusek, Lindsay; Maeda, Tadao

    2013-01-01

    The visual cycle is a sequential enzymatic reaction for vitamin A, all-trans-retinol, occurring in the outer layer of the human retina and is essential for the maintenance of vision. The central source of retinol is derived from dietary intake of both retinol and pro-vitamin A carotenoids. A series of enzymatic reactions, located in both the photoreceptor outer segment and the retinal pigment epithelium, transform retinol into the visual chromophore 11-cis-retinal, regenerating visual pigments. Retina specific proteins carry out the majority of the visual cycle, and any significant interruption in this sequence of reactions is capable of causing varying degrees of blindness. Among these important proteins are Lecithin:retinol acyltransferase (LRAT) and retinal pigment epithelium-specific 65-kDa protein (RPE65) known to be responsible for esterification of retinol to all-trans-retinyl esters and isomerization of these esters to 11-cis-retinal, respectively. Deleterious mutations in these genes are identified in human retinal diseases that cause blindness, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Herein, we discuss the pathology of 11-cis-retinal deficiency caused by these mutations in both animal disease models and human patients. We also review novel therapeutic strategies employing artificial visual chromophore 9-cis-retinoids which have been employed in clinical trials involving LCA patients. PMID:23857173

  16. Foveomacular retinitis.

    PubMed Central

    Kuming, B S

    1986-01-01

    A group of patients is described who developed the clinical features of foveomacular retinitis. No causative factors were isolated, and all patients strongly denied any type of sun gazing. It is possible that there is a group of patients who have the features of foveomacular retinitis but have not had any direct exposure to the sun. These patients would then constitute a primary type of foveomacular retinitis, as opposed to a secondary type which has a known cause and is synonymous with solar retinopathy. Images PMID:3790482

  17. Changes in ganglion cells during retinal degeneration.

    PubMed

    Saha, Susmita; Greferath, Ursula; Vessey, Kirstan A; Grayden, David B; Burkitt, Anthony N; Fletcher, Erica L

    2016-08-01

    Inherited retinal degeneration such as retinitis pigmentosa (RP) is associated with photoreceptor loss and concomitant morphological and functional changes in the inner retina. It is not known whether these changes are associated with changes in the density and distribution of synaptic inputs to retinal ganglion cells (RGCs). We quantified changes in ganglion cell density in rd1 and age-matched C57BL/6J-(wildtype, WT) mice using the immunocytochemical marker, RBPMS. Our data revealed that following complete loss of photoreceptors, (∼3months of age), there was a reduction in ganglion cell density in the peripheral retina. We next examined changes in synaptic inputs to A type ganglion cells by performing double labeling experiments in mice with the ganglion cell reporter lines, rd1-Thy1 and age-matched wildtype-Thy1. Ribbon synapses were identified by co-labelling with CtBP2 (RIBEYE) and conventional synapses with the clustering molecule, gephyrin. ON RGCs showed a significant reduction in RIBEYE-immunoreactive synapse density while OFF RGCs showed a significant reduction in the gephyrin-immmunoreactive synapse density. Distribution patterns of both synaptic markers across the dendritic trees of RGCs were unchanged. The change in synaptic inputs to RGCs was associated with a reduction in the number of immunolabeled rod bipolar and ON cone bipolar cells. These results suggest that functional changes reported in ganglion cells during retinal degeneration could be attributed to loss of synaptic inputs. PMID:27132232

  18. a Review of Retinal Prosthesis Approaches

    NASA Astrophysics Data System (ADS)

    Kien, Tran Trung; Maul, Tomas; Bargiela, Andrzej

    Age-related macular degeneration and retinitis pigmentosa are two of the most common diseases that cause degeneration in the outer retina, which can lead to several visual impairments up to blindness. Vision restoration is an important goal for which several different research approaches are currently being pursued. We are concerned with restoration via retinal prosthetic devices. Prostheses can be implemented intraocularly and extraocularly, which leads to different categories of devices. Cortical Prostheses and Optic Nerve Prostheses are examples of extraocular solutions while Epiretinal Prostheses and Subretinal Prostheses are examples of intraocular solutions. Some of the prostheses that are successfully implanted and tested in animals as well as humans can restore basic visual functions but still have limitations. This paper will give an overview of the current state of art of Retinal Prostheses and compare the advantages and limitations of each type. The purpose of this review is thus to summarize the current technologies and approaches used in developing Retinal Prostheses and therefore to lay a foundation for future designs and research directions.

  19. The Rate of Vitamin A Dimerization in Lipofuscinogenesis, Fundus Autofluorescence, Retinal Senescence and Degeneration.

    PubMed

    Washington, Ilyas; Saad, Leonide

    2016-01-01

    One of the earliest events preceding several forms of retinal degeneration is the formation and accumulation of vitamin A dimers in the retinal pigment epithelium (RPE) and underlying Bruch's membrane (BM). Such degenerations include Stargardt disease, Best disease, forms of retinitis pigmentosa, and age-related macular degeneration (AMD). Since their discovery in the 1990's, dimers of vitamin A, have been postulated as chemical triggers driving retinal senescence and degeneration. There is evidence to suggest that the rate at which vitamin A dimerizes and the eye's response to the dimerization products may dictate the retina's lifespan. Here, we present outstanding questions, finding the answers to which may help to elucidate the role of vitamin A dimerization in retinal degeneration. PMID:26427431

  20. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery.

    PubMed

    Weber, Michel; Rabinowitz, Joseph; Provost, Nathalie; Conrath, Hervé; Folliot, Sébastien; Briot, Delphine; Chérel, Yan; Chenuaud, Pierre; Samulski, Jude; Moullier, Philippe; Rolling, Fabienne

    2003-06-01

    We previously described chimeric recombinant adeno-associated virus (rAAV) vectors 2/4 and 2/5 as the most efficient vectors in rat retina. We now characterize these two vectors carrying the CMV.gfp genome following subretinal injection in the Wistar rat, beagle dog, and cynomolgus macaque. Both serotypes displayed stable GFP expression for the duration of the experiment (6 months) in all three animal models. Similar to the AAV-2 serotype, AAV-2/5 transduced both RPE and photoreceptor cells, with higher level of transduction in photoreceptors, whereas rAAV-2/4 transduction was unambiguously restricted to RPE cells. This unique specificity found conserved among all three species makes AAV-2/4-derived vectors attractive for retinal diseases originating in RPE such as Leber congenital amaurosis (RPE65) or retinitis pigmentosa due to a mutated mertk gene. To provide further important preclinical data, vector shedding was monitored by PCR in various biological fluids for 2 months post-rAAV administration. Following rAAV-2/4 and -5 subretinal delivery in dogs (n = 6) and in nonhuman primates (n = 2), vector genome was found in lacrymal and nasal fluids for up to 3-4 days and in the serum for up to 15-20 days. Overall, these findings will have a practical impact on the development of future gene therapy trials of retinal diseases. PMID:12788651

  1. Retinal Disorders

    MedlinePlus

    ... be serious enough to cause blindness. Examples are Macular degeneration - a disease that destroys your sharp, central vision Diabetic eye disease Retinal detachment - a medical emergency, when the retina is ... children. Macular pucker - scar tissue on the macula Macular hole - ...

  2. Retinal Detachment

    MedlinePlus

    ... immediately. Treatment How is retinal detachment treated? Small holes and tears are treated with laser surgery or ... laser surgery tiny burns are made around the hole to “weld” the retina back into place. Cryopexy ...

  3. Resolution of Persistent Cystoid Macular Edema due to Central Retinal Vein Occlusion in a Vitrectomized Eye following Intravitreal Implant of Dexamethasone 0.7 mg

    PubMed Central

    Reibaldi, Michele; Russo, Andrea; Zagari, Marco; Toro, Mario; Grande De, Vittorio; Cifalinò, Valentina; Rametta, Stefania; Faro, Salvatore; Longo, Antonio

    2012-01-01

    We report the case of a 62-year-old woman with a history of vitreoretinal surgery for vitreous hemorrhage secondary to central retinal vein occlusion (CRVO). Because of the persistence of macular edema (ME), she received 2 intravitreal injections of bevacizumab 0.5 mg (Avastin®, Genentech/Roche) three months after vitrectomy, without functional or anatomical improvement. Six months after vitrectomy, she therefore received an intravitreal implant of dexamethasone 0.7 mg (Ozurdex®). An improvement in her best-corrected visual acuity and central macular thickness, as measured by optical coherence tomography, was detected 7 days after the injection, and complete resolution of the ME and retinal hemorrhages was observed 6 months after the injection. Dexamethasone intravitreal implant might be an effective treatment option in ME secondary to CRVO, also in vitrectomized eyes. PMID:22615698

  4. Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies?

    PubMed

    Saad, Leonide; Washington, Ilyas

    2016-01-01

    We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non-disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway. PMID:26427432

  5. Probabilistic retinal vessel segmentation

    NASA Astrophysics Data System (ADS)

    Wu, Chang-Hua; Agam, Gady

    2007-03-01

    Optic fundus assessment is widely used for diagnosing vascular and non-vascular pathology. Inspection of the retinal vasculature may reveal hypertension, diabetes, arteriosclerosis, cardiovascular disease and stroke. Due to various imaging conditions retinal images may be degraded. Consequently, the enhancement of such images and vessels in them is an important task with direct clinical applications. We propose a novel technique for vessel enhancement in retinal images that is capable of enhancing vessel junctions in addition to linear vessel segments. This is an extension of vessel filters we have previously developed for vessel enhancement in thoracic CT scans. The proposed approach is based on probabilistic models which can discern vessels and junctions. Evaluation shows the proposed filter is better than several known techniques and is comparable to the state of the art when evaluated on a standard dataset. A ridge-based vessel tracking process is applied on the enhanced image to demonstrate the effectiveness of the enhancement filter.

  6. Identification of Helicobacter pylori in skin biopsy of prurigo pigmentosa.

    PubMed

    Missall, Tricia A; Pruden, Samuel; Nelson, Christine; Fohn, Laurel; Vidal, Claudia I; Hurley, M Yadira

    2012-06-01

    A 23-year-old Chinese man presented with a 3-year history of a pruritic eruption. On examination, pink urticarial papules associated with hyperpigmented reticulated patches were noted on his neck, back, and upper chest. Histopathology revealed vacuolar interface dermatitis and numerous gram-negative rods within a dilated hair follicle. The organisms were reactive with anti-Helicobacter pylori immunohistochemisty. The histologic findings and clinical presentation support the diagnosis of prurigo pigmentosa. Additional testing demonstrated a positive urease breath test and serum H. pylori IgG antibodies. The patient was referred to gastroenterology and treated with appropriate antibiotics. After treatment, esophagogastroduodenoscopy revealed chronic gastritis without evidence of H. pylori infection and his skin showed reticulated hyperpigmented patches without evidence of active inflammatory papules. Although previous reports have associated prurigo pigmentosa to H. Pylori gastritis, this is the first report of H. pylori organisms identified in a skin biopsy of prurigo pigmentosa. PMID:22197863

  7. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells in retinal disease.

    PubMed

    Feigl, Beatrix; Zele, Andrew J

    2014-08-01

    Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are a class of photoreceptors with established roles in non-image-forming processes. Their contributions to image-forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. Intrinsically photosensitive retinal ganglion cells can be divided into five ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioral marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma, and hereditary optic neuropathy. We briefly review the anatomical distributions, projections, and basic physiological mechanisms of ipRGCs and their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the PLR can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction. PMID:24879087

  8. Inner retinal change in a novel rd1-FTL mouse model of retinal degeneration

    PubMed Central

    Greferath, Ursula; Anderson, Emily E.; Jobling, Andrew I.; Vessey, Kirstan A.; Martinez, Gemma; de Iongh, Robb U.; Kalloniatis, Michael; Fletcher, Erica L.

    2015-01-01

    While photoreceptor loss is the most devastating result of inherited retinal degenerations such as retinitis pigmentosa, inner retinal neurons also undergo significant alteration. Detailing these changes has become important as many vision restorative therapies target the remaining neurons. In this study, the rd1-Fos-Tau-LacZ (rd1-FTL) mouse model was used to explore inner retinal change at a late stage of retinal degeneration, after the loss of photoreceptor nuclei. The rd1-FTL model carries a mutation in the phosphodiesterase gene, Pde6b, and an axonally targeted transgenic beta galactosidase reporter system under the control of the c-fos promoter. Retinae of transgenic rd1-FTL mice and control FTL animals aged 2–12 months were processed for indirect fluorescence immunocytochemistry. At 2 months of age, a time when the majority of photoreceptor nuclei are lost, there was negligible c-fos reporter (FTL) expression, however, from 4 months, reporter expression was observed to increase within subpopulations of amacrine and ganglion cells within the central retina. These areas of inner retinal FTL expression coincided with regions that contained aberrant Müller cells. Specifically, these cells exhibited reduced glutamine synthetase and Kir4.1 immunolabelling, whilst showing evidence of proliferative gliosis (increased cyclinD1 and glial fibrillary acidic protein expression). These changes were limited to distinct regions where cone photoreceptor terminals were absent. Overall, these results highlight that distinct areas of the rd1-FTL central retina undergo significant glial alterations after cone photoreceptor loss. These areas coincide with up-regulation of the c-fos reporter in the inner retina, which may represent a change in neuronal function/plasticity. The rd1-FTL mouse is a useful model system to probe changes that occur in the inner retina at later stages of retinal degeneration. PMID:26283925

  9. Undersized Dendritic Arborizations in Retinal Ganglion Cells of the Rd1 Mutant Mouse: A Paradigm of Early Onset Photoreceptor Degeneration*

    PubMed Central

    Damiani, Devid; Novelli, Elena; Mazzoni, Francesca; Strettoi, Enrica

    2014-01-01

    Retinitis pigmentosa (RP) is a family of inherited diseases causing progressive photoreceptor death. Retinal ganglion cells (RGCs) form the biological substrate for various therapeutic approaches designed to restore vision in RP individuals. Assessment of survival and preservation of RGCs in animal paradigms mimicking the human disease is of key importance for appropriate implementation of vision repair strategies. Here we studied the survival of RGCs in the rd1 mutant mouse, a known model of early onset, autosomic recessive RP, at various stages of photoreceptor degeneration. Furthermore, we analyzed the morphology of various types of RGCs using the newly generated transgenic mouse rd1/Thy1-GFP, in which the rd1 mutation is associated with green fluorescent protein (GFP) expression in a small population of different RGCs. We found excellent survival of cells at up to 1 year of age, a time at which the inner retina is known to have severely reorganized and partially degenerated. However, 50% of the cells analyzed within all RGC types exhibit an undersized dendritic tree, spanning about half of the normal area. Undersized cells are found both in adult and in very young (1-month-old) mice. This suggests that their aberrant phenotype is due to incomplete dendritic development, possibly as a consequence of altered visual input at the time of dendritic arbor refinement. These data show the importance of the timing of photoreceptor death in RGC dendritic development. PMID:22102216

  10. Design of a high-resolution optoelectronic retinal prosthesis

    NASA Astrophysics Data System (ADS)

    Palanker, Daniel; Vankov, Alexander; Huie, Phil; Baccus, Stephen

    2005-03-01

    It has been demonstrated that electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. However, current retinal implants provide very low resolution (just a few electrodes), whereas at least several thousand pixels would be required for functional restoration of sight. This paper presents the design of an optoelectronic retinal prosthetic system with a stimulating pixel density of up to 2500 pix mm-2 (corresponding geometrically to a maximum visual acuity of 20/80). Requirements on proximity of neural cells to the stimulation electrodes are described as a function of the desired resolution. Two basic geometries of sub-retinal implants providing required proximity are presented: perforated membranes and protruding electrode arrays. To provide for natural eye scanning of the scene, rather than scanning with a head-mounted camera, the system operates similar to 'virtual reality' devices. An image from a video camera is projected by a goggle-mounted collimated infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. The goggles are transparent to visible light, thus allowing for the simultaneous use of remaining natural vision along with prosthetic stimulation. Optical delivery of visual information to the implant allows for real-time image processing adjustable to retinal architecture, as well as flexible control of image processing algorithms and stimulation parameters.

  11. Combined Mastocytoma-hemangioma in a Patient with Urticaria Pigmentosa

    PubMed Central

    Seung, Na Reu; Kang, Min Hee; Park, Eun Joo; Kim, Chul Woo; Cho, Hee Jin; Kim, Kwang Ho

    2008-01-01

    A patient with long-standing urticaria pigmentosa presented with a pea-sized reddish to purplish papule on the posterior part of the right ear. Histopathologic examination revealed numerous dilated vascular structures in the upper dermis and mast cell infiltrations throughout the whole dermis, consistent with combined mastocytoma-hemangioma. The mast cells were strongly positive with Giemsa stain.

  12. [Urticaria pigmentosa: clinical and therapeutic aspects for the paediatrician].

    PubMed

    Moll-Manzur, Catherina; Araos-Baeriswyl, Esteban; Downey, Camila; Dossi, María T

    2016-08-01

    Urticaria pigmentosa, also known as maculopapular mastocytosis, is the most common type of paediatric mastocytosis. It presents with yellow to brown macules or papules, usually located on trunk and extremities. Regarding its diagnostic and therapeutic implications, the objective of this article is to serve as an update for the paediatrician on the most relevant aspects of this pathology. PMID:27399017

  13. Changes in aquaporin-4 and Kir4.1 expression in rats with inherited retinal dystrophy.

    PubMed

    Lassiale, S; Valamanesh, F; Klein, C; Hicks, D; Abitbol, M; Versaux-Botteri, C

    2016-07-01

    Muller glial cells (MGC) are essential for normal functioning of retina. They are especially involved in potassium (K+) and water homeostasis, via inwardly rectifying K+ (Kir 4.1) and aquaporin-4 (AQP4) channels respectively. Because MGC appear morphologically and functionally altered in most retinal pathologies, we studied the expression of AQP 4 and Kir 4.1 during the time course of progressive retinal degeneration in Royal College of Surgeons (RCS) rats, an animal model for the hereditary human retinal degenerative disease Retinitis pigmentosa. Simultaneous detection of AQP4 and Kir 4.1 was performed by quantitative real-time polymerase chain reaction (QRT-PCR), Western blot and immunohistochemistry at birth and during progression of the pathology. Although small quantities of AQP4 and Kir 4.1 mRNA were detected at birth (postnatal day (PNd) 0) in both control and dystrophic rat retinas, proteins could not be detected at this age. Detectable proteins appeared in the second week of postnatal life. From PNd15 onwards, the time course in the expression of both AQP4 and Kir 4.1 mRNAs and protein was similar in dystrophic and control rats, with a progressive increase peaking at PNd60 and a subsequent decrease by one year. AQP4 protein and mRNA content were significantly lowered in dystrophic compared to control rats. Kir 4.1 protein levels were also lower in dystrophic retinas, while mRNA concentrations were unchanged and/or slightly higher in dystrophic rats. The discrepancies between Kir4.1 mRNA and protein suggest perturbation in protein translation due to the pathology. AQP4 and Kir 4.1/vimentin co-immunolabeling showed that: 1) apical radial processes of some MGC invaded the subretinal zone, and 2) MGC morphology was distorted in advanced pathology. MGC became hypertrophic both during the pathology and also with age in control rats. In conclusion, our results confirm that this inherited photoreceptor degeneration also leads to progressive alterations in

  14. Tickling the retina: integration of subthreshold electrical pulses can activate retinal neurons

    NASA Astrophysics Data System (ADS)

    Sekhar, S.; Jalligampala, A.; Zrenner, E.; Rathbun, D. L.

    2016-08-01

    Objective. The field of retinal prosthetics has made major progress over the last decade, restoring visual percepts to people suffering from retinitis pigmentosa. The stimulation pulses used by present implants are suprathreshold, meaning individual pulses are designed to activate the retina. In this paper we explore subthreshold pulse sequences as an alternate stimulation paradigm. Subthreshold pulses have the potential to address important open problems such as fading of visual percepts when patients are stimulated at moderate pulse repetition rates and the difficulty in preferentially stimulating different retinal pathways. Approach. As a first step in addressing these issues we used Gaussian white noise electrical stimulation combined with spike-triggered averaging to interrogate whether a subthreshold sequence of pulses can be used to activate the mouse retina. Main results. We demonstrate that the retinal network can integrate multiple subthreshold electrical stimuli under an experimental paradigm immediately relevant to retinal prostheses. Furthermore, these characteristic stimulus sequences varied in their shape and integration window length across the population of retinal ganglion cells. Significance. Because the subthreshold sequences activate the retina at stimulation rates that would typically induce strong fading (25 Hz), such retinal ‘tickling’ has the potential to minimize the fading problem. Furthermore, the diversity found across the cell population in characteristic pulse sequences suggests that these sequences could be used to selectively address the different retinal pathways (e.g. ON versus OFF). Both of these outcomes may significantly improve visual perception in retinal implant patients.

  15. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases.

    PubMed

    Cuenca, Nicolás; Fernández-Sánchez, Laura; Campello, Laura; Maneu, Victoria; De la Villa, Pedro; Lax, Pedro; Pinilla, Isabel

    2014-11-01

    Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies. PMID:25038518

  16. Activation of Bone Marrow-Derived Microglia Promotes Photoreceptor Survival in Inherited Retinal Degeneration

    PubMed Central

    Sasahara, Manabu; Otani, Atsushi; Oishi, Akio; Kojima, Hiroshi; Yodoi, Yuko; Kameda, Takanori; Nakamura, Hajime; Yoshimura, Nagahisa

    2008-01-01

    The role of microglia in neurodegeneration is controversial, although microglial activation in the retina has been shown to provide an early response against infection, injury, ischemia, and degeneration. Here we show that endogenous bone marrow (BM)-derived microglia play a protective role in vascular and neural degeneration in the retinitis pigmentosa model of inherited retinal degeneration. BM-derived cells were recruited to the degenerating retina where they differentiated into microglia and subsequently localized to the degenerating vessels and neurons. Inhibition of stromal-derived factor-1 in the retina reduced the number of BM-derived microglia and accelerated the rate of neurovascular degeneration. Systemic depletion of myeloid progenitors also accelerated the degenerative process. Conversely, activation of BM-derived myeloid progenitors by systemic administration of both granulocyte colony-stimulating factor and erythropoietin resulted in the deceleration of retinal degeneration and the promotion of cone cell survival. These data indicate that BM-derived microglia may play a protective role in retinitis pigmentosa. Functional activation of BM-derived myeloid progenitors by cytokine therapy may provide a novel strategy for the treatment of inherited retinal degeneration and other neurodegenerative diseases, regardless of the underlying genetic defect. PMID:18483210

  17. Retinal detachment

    MedlinePlus

    ... of the first symptoms of new flashes of light and floaters. ... diabetes. See your eye care specialist once a year. You may need more frequent visits if you have risk factors for retinal detachment. Be alert to symptoms of new flashes of light and floaters.

  18. PARP1 Gene Knock-Out Increases Resistance to Retinal Degeneration without Affecting Retinal Function

    PubMed Central

    Sahaboglu, Ayse; Tanimoto, Naoyuki; Kaur, Jasvir; Sancho-Pelluz, Javier; Huber, Gesine; Fahl, Edda; Arango-Gonzalez, Blanca; Zrenner, Eberhart; Ekström, Per; Löwenheim, Hubert; Seeliger, Mathias; Paquet-Durand, François

    2010-01-01

    Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP. PMID:21124852

  19. Ablation of retinal ciliopathy protein RPGR results in altered photoreceptor ciliary composition

    PubMed Central

    Rao, Kollu N.; Li, Linjing; Anand, Manisha; Khanna, Hemant

    2015-01-01

    Cilia regulate several developmental and homeostatic pathways that are critical to survival. Sensory cilia of photoreceptors regulate phototransduction cascade for visual processing. Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are a prominent cause of severe blindness disorders due to degeneration of mature photoreceptors. However, precise function of RPGR is still unclear. Here we studied the involvement of RPGR in ciliary trafficking by analyzing the composition of photoreceptor sensory cilia (PSC) in Rpgrko retina. Using tandem mass spectrometry analysis followed by immunoblotting, we detected few alterations in levels of proteins involved in proteasomal function and vesicular trafficking in Rpgrko PSC, prior to onset of degeneration. We also found alterations in the levels of high molecular weight soluble proteins in Rpgrko PSC. Our data indicate RPGR regulates entry or retention of soluble proteins in photoreceptor cilia but spares the trafficking of key structural and phototransduction-associated proteins. Given a frequent occurrence of RPGR mutations in severe photoreceptor degeneration due to ciliary disorders, our results provide insights into pathways resulting in altered mature cilia function in ciliopathies. PMID:26068394

  20. Protective Effects of Human iPS-Derived Retinal Pigmented Epithelial Cells in Comparison with Human Mesenchymal Stromal Cells and Human Neural Stem Cells on the Degenerating Retina in rd1 mice.

    PubMed

    Sun, Jianan; Mandai, Michiko; Kamao, Hiroyuki; Hashiguchi, Tomoyo; Shikamura, Masayuki; Kawamata, Shin; Sugita, Sunao; Takahashi, Masayo

    2015-05-01

    Retinitis pigmentosa (RP) is a group of visual impairments characterized by progressive rod photoreceptor cell loss due to a genetic background. Pigment epithelium-derived factor (PEDF) predominantly secreted by the retinal pigmented epithelium (RPE) has been reported to protect photoreceptors in retinal degeneration models, including rd1. In addition, clinical trials are currently underway outside Japan using human mesenchymal stromal cells and human neural stem cells to protect photoreceptors in RP and dry age-related macular degeneration, respectively. Thus, this study aimed to investigate the rescue effects of induced pluripotent stem (iPS)-RPE cells in comparison with those types of cells used in clinical trials on photoreceptor degeneration in rd1 mice. Cells were injected into the subretinal space of immune-suppressed 2-week-old rd1 mice. The results demonstrated that human iPS-RPE cells significantly attenuated photoreceptor degeneration on postoperative days (PODs) 14 and 21 and survived longer up to at least 12 weeks after operation than the other two types of graft cells with less immune responses and apoptosis. The mean PEDF concentration in the intraocular fluid in RPE-transplanted eyes was more than 1 µg/ml at PODs 14 and 21, and this may have contributed to the protective effect of RPE transplantation. Our findings suggest that iPS-RPE cells serve as a competent source to delay photoreceptor degeneration through stable survival in degenerating ocular environment and by releasing neuroprotective factors such as PEDF. PMID:25728228

  1. Cell replacement and visual restoration by retinal sheet transplants.

    PubMed

    Seiler, Magdalene J; Aramant, Robert B

    2012-11-01

    Retinal diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) affect millions of people. Replacing lost cells with new cells that connect with the still functional part of the host retina might repair a degenerating retina and restore eyesight to an unknown extent. A unique model, subretinal transplantation of freshly dissected sheets of fetal-derived retinal progenitor cells, combined with its retinal pigment epithelium (RPE), has demonstrated successful results in both animals and humans. Most other approaches are restricted to rescue endogenous retinal cells of the recipient in earlier disease stages by a 'nursing' role of the implanted cells and are not aimed at neural retinal cell replacement. Sheet transplants restore lost visual responses in several retinal degeneration models in the superior colliculus (SC) corresponding to the location of the transplant in the retina. They do not simply preserve visual performance - they increase visual responsiveness to light. Restoration of visual responses in the SC can be directly traced to neural cells in the transplant, demonstrating that synaptic connections between transplant and host contribute to the visual improvement. Transplant processes invade the inner plexiform layer of the host retina and form synapses with presumable host cells. In a Phase II trial of RP and ARMD patients, transplants of retina together with its RPE improved visual acuity. In summary, retinal progenitor sheet transplantation provides an excellent model to answer questions about how to repair and restore function of a degenerating retina. Supply of fetal donor tissue will always be limited but the model can set a standard and provide an informative base for optimal cell replacement therapies such as embryonic stem cell (ESC)-derived therapy. PMID:22771454

  2. Cell replacement and visual restoration by retinal sheet transplants

    PubMed Central

    Seiler, Magdalene J.; Aramant, Robert B.

    2012-01-01

    Retinal diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) affect millions of people. Replacing lost cells with new cells that connect with the still functional part of the host retina might repair a degenerating retina and restore eyesight to an unknown extent. A unique model, subretinal transplantation of freshly dissected sheets of fetal-derived retinal progenitor cells, combined with its retinal pigment epithelium (RPE), has demonstrated successful results in both animals and humans. Most other approaches are restricted to rescue endogenous retinal cells of the recipient in earlier disease stages by a ‘nursing’ role of the implanted cells and are not aimed at neural retinal cell replacement. Sheet transplants restore lost visual responses in several retinal degeneration models in the superior colliculus (SC) corresponding to the location of the transplant in the retina. They do not simply preserve visual performance – they increase visual responsiveness to light. Restoration of visual responses in the SC can be directly traced to neural cells in the transplant, demonstrating that synaptic connections between transplant and host contribute to the visual improvement. Transplant processes invade the inner plexiform layer of the host retina and form synapses with presumable host cells. In a Phase II trial of RP and ARMD patients, transplants of retina together with its RPE improved visual acuity. In summary, retinal progenitor sheet transplantation provides an excellent model to answer questions about how to repair and restore function of a degenerating retina. Supply of fetal donor tissue will always be limited but the model can set a standard and provide an informative base for optimal cell replacement therapies such as embryonic stem cell (ESC)-derived therapy. PMID:22771454

  3. A CMOS active pixel sensor for retinal stimulation

    NASA Astrophysics Data System (ADS)

    Prydderch, Mark L.; French, Marcus J.; Mathieson, Keith; Adams, Christopher; Gunning, Deborah; Laudanski, Jonathan; Morrison, James D.; Moodie, Alan R.; Sinclair, James

    2006-02-01

    Degenerative photoreceptor diseases, such as age-related macular degeneration and retinitis pigmentosa, are the most common causes of blindness in the western world. A potential cure is to use a microelectronic retinal prosthesis to provide electrical stimulation to the remaining healthy retinal cells. We describe a prototype CMOS Active Pixel Sensor capable of detecting a visual scene and translating it into a train of electrical pulses for stimulation of the retina. The sensor consists of a 10 x 10 array of 100 micron square pixels fabricated on a 0.35 micron CMOS process. Light incident upon each pixel is converted into output current pulse trains with a frequency related to the light intensity. These outputs are connected to a biocompatible microelectrode array for contact to the retinal cells. The flexible design allows experimentation with signal amplitudes and frequencies in order to determine the most appropriate stimulus for the retina. Neural processing in the retina can be studied by using the sensor in conjunction with a Field Programmable Gate Array (FPGA) programmed to behave as a neural network. The sensor has been integrated into a test system designed for studying retinal response. We present the most recent results obtained from this sensor.

  4. Retinal Detachment Vision Simulator

    MedlinePlus

    ... Retina Treatment Retinal Detachment Vision Simulator Retinal Detachment Vision Simulator Mar. 01, 2016 How does a detached or torn retina affect your vision? If a retinal tear is occurring, you may ...

  5. Hsp90 as a Potential Therapeutic Target in Retinal Disease.

    PubMed

    Aguilà, Mònica; Cheetham, Michael E

    2016-01-01

    The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration. Hsp90 is also a potential target in uveal melanoma. Mechanistically, Hsp90 inhibition can evoke a dual response in the retina; stimulating a stress response with molecular chaperone expression. Thereby leading to an improvement in visual function and photoreceptor survival; however, prolonged inhibition can also stimulate the degradation of Hsp90 client proteins potentially deleteriously affect vision. Here, we review the multiple roles of Hsp90 in the retina and the therapeutic potential of Hsp90 as a target. PMID:26427407

  6. Comparative sequence analyses of rhodopsin and RPE65 reveal patterns of selective constraint across hereditary retinal disease mutations.

    PubMed

    Hauser, Frances E; Schott, Ryan K; Castiglione, Gianni M; Van Nynatten, Alexander; Kosyakov, Alexander; Tang, Portia L; Gow, Daniel A; Chang, Belinda S W

    2016-01-01

    Retinitis pigmentosa (RP) comprises several heritable diseases that involve photoreceptor, and ultimately retinal, degeneration. Currently, mutations in over 50 genes have known links to RP. Despite advances in clinical characterization, molecular characterization of RP remains challenging due to the heterogeneous nature of causal genes, mutations, and clinical phenotypes. In this study, we compiled large datasets of two important visual genes associated with RP: rhodopsin, which initiates the phototransduction cascade, and the retinoid isomerase RPE65, which regenerates the visual cycle. We used a comparative evolutionary approach to investigate the relationship between interspecific sequence variation and pathogenic mutations that lead to degenerative retinal disease. Using codon-based likelihood methods, we estimated evolutionary rates (d N/d S) across both genes in a phylogenetic context to investigate differences between pathogenic and nonpathogenic amino acid sites. In both genes, disease-associated sites showed significantly lower evolutionary rates compared to nondisease sites, and were more likely to occur in functionally critical areas of the proteins. The nature of the dataset (e.g., vertebrate or mammalian sequences), as well as selection of pathogenic sites, affected the differences observed between pathogenic and nonpathogenic sites. Our results illustrate that these methods can serve as an intermediate step in understanding protein structure and function in a clinical context, particularly in predicting the relative pathogenicity (i.e., functional impact) of point mutations and their downstream phenotypic effects. Extensions of this approach may also contribute to current methods for predicting the deleterious effects of candidate mutations and to the identification of protein regions under strong constraint where we expect pathogenic mutations to occur. PMID:26750628

  7. Current perspectives of herpesviral retinitis and choroiditis.

    PubMed

    Madhavan, H N; Priya, K; Biswas, J

    2004-10-01

    Vision-threatening viral retinitis are primarily caused by members of the herpesvirus family. The biology and molecular characterization of herpesviruses, clinical presentations of retinopathies, pathology and pathogenesis including the host responses, epidemiology and the laboratory methods of aetiological diagnosis of these diseases are described. Clinical syndromes are acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), cytomegalovirus (CMV) retinitis, multifocal choroiditis and serpiginous choroiditis besides other viral retinopathies. Herpes simplex virus (HSV) retinitis is more common in immunocompetent persons while varicella zoster virus (VZV) affects both immunocompetent and immunosuppressed patients equally. CMV retinitis is most common among patients with AIDS. The currently employed laboratory methods of antigen detection, virus isolation and antibody detection by enzyme linked immuno-sorbent assay (ELISA) have low sensitivity. Polymerase chain reaction (PCR) has increased the value of diagnosis due to its high clinical sensitivity and absolute specificity in detection of herpesviruses in intraocular specimens. PMID:16295367

  8. Prospectives for Gene Therapy of Retinal Degenerations

    PubMed Central

    Thumann, Gabriele

    2012-01-01

    Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness. Retinal degenerations can be divided into two groups, a group in which the defect has been linked to a specific gene and a second group that has a complex etiology that includes environmental and genetic influences. The first group encompasses a number of relatively rare diseases with the most prevalent being Retinitis pigmentosa that affects approximately 1 million individuals worldwide. Attempts have been made to correct the defective gene by transfecting the appropriate cells with the wild-type gene and while these attempts have been successful in animal models, human gene therapy for these inherited retinal degenerations has only begun recently and the results are promising. To the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). These retinal degenerations have a genetic component since they occur more often in families with affected probands but they are also linked to environmental factors, specifically elevated intraocular pressure, age and high blood sugar levels respectively. The economic and medical impact of these three diseases can be assessed by the number of individuals affected; AMD affects over 30 million, DR over 40 million and glaucoma over 65 million individuals worldwide. The basic defect in these diseases appears to be the relative lack of a neurogenic environment; the neovascularization that often accompanies these diseases has suggested that a decrease in pigment epithelium-derived factor (PEDF), at least in part, may be responsible for the neurodegeneration since PEDF is not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularization. In the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell

  9. Rapid regression of exudative maculopathy in idiopathic retinitis, vasculitis, aneurysms and neuroretinitis syndrome after intravitreal ranibizumab.

    PubMed

    Marín-Lambíes, Cristina; Gallego-Pinazo, Roberto; Salom, David; Navarrete, Javier; Díaz-Llopis, Manuel

    2012-05-01

    The idiopathic retinitis, vasculitis, aneurysms and neuroretinitis syndrome is a rare retinal vascular disorder characterized by multiple leaking aneurysmal dilations, retinal vasculitis, neuroretinitis and peripheral vascular ischemia. Visual loss mainly occurs due to the development of retinal neovascularization and/or exudative maculopathy. Although the treatment of choice has not yet been established, retinal photocoagulation seems to be the best option to control the disease and to prevent its progression. Herein, we report a case of idiopathic retinitis, vasculitis, aneurysms and neuroretinitis syndrome with both retinal neovascularization and macular exudation successfully managed with intravitreal ranibizumab (Lucentis(®)) as adjunctive therapy to retinal photocoagulation. PMID:22949913

  10. Intra-familial Similarity of Wide-Field Fundus Autofluorescence in Inherited Retinal Dystrophy.

    PubMed

    Furutani, Yuka; Ogino, Ken; Oishi, Akio; Gotoh, Norimoto; Makiyama, Yukiko; Oishi, Maho; Kurimoto, Masafumi; Yoshimura, Nagahisa

    2016-01-01

    To examine the similarity of wide-field fundus autofluorescence (FAF) imaging in inherited retinal dystrophy between siblings and between parents and their children. The subjects included 17 siblings (12 with retinitis pigmentosa and 5 with cone rod dystrophy) and 10 parent-child pairs (8 with retinitis pigmentosa and 2 with cone rod dystrophy). We quantified the similarity of wide-field FAF using image processing techniques of cropping, binarization, superimposition, and subtraction. The estimated similarity of the siblings was compared with that of the parent-child pairs and that of the age-matched unrelated patients. The similarity between siblings was significantly higher that of parent-child pairs or that of age-matched unrelated patients (P = 0.004 and P = 0.049, respectively). Wide-field FAF images were similar between siblings with inherited retinal dystrophy but different between parent-child pairs. This suggests that aging is a confounding factor in genotype-phenotype correlation studies. PMID:26427425

  11. Taurine provides neuroprotection against retinal ganglion cell degeneration.

    PubMed

    Froger, Nicolas; Cadetti, Lucia; Lorach, Henri; Martins, Joao; Bemelmans, Alexis-Pierre; Dubus, Elisabeth; Degardin, Julie; Pain, Dorothée; Forster, Valérie; Chicaud, Laurent; Ivkovic, Ivana; Simonutti, Manuel; Fouquet, Stéphane; Jammoul, Firas; Léveillard, Thierry; Benosman, Ryad; Sahel, José-Alain; Picaud, Serge

    2012-01-01

    Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases. PMID:23115615

  12. Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration

    PubMed Central

    Froger, Nicolas; Cadetti, Lucia; Lorach, Henri; Martins, Joao; Bemelmans, Alexis-Pierre; Dubus, Elisabeth; Degardin, Julie; Pain, Dorothée; Forster, Valérie; Chicaud, Laurent; Ivkovic, Ivana; Simonutti, Manuel; Fouquet, Stéphane; Jammoul, Firas; Léveillard, Thierry; Benosman, Ryad; Sahel, José-Alain; Picaud, Serge

    2012-01-01

    Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases. PMID:23115615

  13. Effect of Stimulus Waveform of Biphasic Current Pulse on Retinal Ganglion Cell Responses in Retinal Degeneration (rd1) mice

    PubMed Central

    Ahn, Kun No; Ahn, Jeong Yeol; Kim, Jae-hyung; Cho, Kyoungrok; Koo, Kyo-in; Senok, Solomon S.

    2015-01-01

    A retinal prosthesis is being developed for the restoration of vision in patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Determining optimal electrical stimulation parameters for the prosthesis is one of the most important elements for the development of a viable retinal prosthesis. Here, we investigated the effects of different charge-balanced biphasic pulses with regard to their effectiveness in evoking retinal ganglion cell (RGC) responses. Retinal degeneration (rd1) mice were used (n=17). From the ex-vivo retinal preparation, retinal patches were placed ganglion cell layer down onto an 8×8 multielectrode array (MEA) and RGC responses were recorded while applying electrical stimuli. For asymmetric pulses, 1st phase of the pulse is the same with symmetric pulse but the amplitude of 2nd phase of the pulse is less than 10 µA and charge balanced condition is satisfied by lengthening the duration of the pulse. For intensities (or duration) modulation, duration (or amplitude) of the pulse was fixed to 500 µs (30 µA), changing the intensities (or duration) from 2 to 60 µA (60 to 1000 µs). RGCs were classified as response-positive when PSTH showed multiple (3~4) peaks within 400 ms post stimulus and the number of spikes was at least 30% more than that for the immediate pre-stimulus 400 ms period. RGC responses were well modulated both with anodic and cathodic phase-1st biphasic pulses. Cathodic phase-1st pulses produced significantly better modulation of RGC activity than anodic phase-1st pulses regardless of symmetry of the pulse. PMID:25729279

  14. XLPRA: A canine retinal degeneration inherited as an X-linked trait

    SciTech Connect

    Acland, G.M.; Blanton, S.H.; Hershfield, B.; Aguirre, G.D.

    1994-08-01

    Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene. 58 refs., 1 fig., 3 tabs.

  15. High Resolution MALDI Imaging Mass Spectrometry of Retinal Tissue Lipids

    NASA Astrophysics Data System (ADS)

    Anderson, David M. G.; Ablonczy, Zsolt; Koutalos, Yiannis; Spraggins, Jeffrey; Crouch, Rosalie K.; Caprioli, Richard M.; Schey, Kevin L.

    2014-08-01

    Matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) has the ability to provide an enormous amount of information on the abundances and spatial distributions of molecules within biological tissues. The rapid progress in the development of this technology significantly improves our ability to analyze smaller and smaller areas and features within tissues. The mammalian eye has evolved over millions of years to become an essential asset for survival, providing important sensory input of an organism's surroundings. The highly complex sensory retina of the eye is comprised of numerous cell types organized into specific layers with varying dimensions, the thinnest of which is the 10 μm retinal pigment epithelium (RPE). This single cell layer and the photoreceptor layer contain the complex biochemical machinery required to convert photons of light into electrical signals that are transported to the brain by axons of retinal ganglion cells. Diseases of the retina, including age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy, occur when the functions of these cells are interrupted by molecular processes that are not fully understood. In this report, we demonstrate the use of high spatial resolution MALDI IMS and FT-ICR tandem mass spectrometry in the Abca4 -/- knockout mouse model of Stargardt disease, a juvenile onset form of macular degeneration. The spatial distributions and identity of lipid and retinoid metabolites are shown to be unique to specific retinal cell layers.

  16. Preventing retinal apoptosis--is there a common therapeutic theme?

    PubMed

    Doonan, Francesca; Groeger, Gillian; Cotter, Thomas G

    2012-07-01

    There is an urgent need for therapies for retinal diseases; retinitis pigmentosa sufferers have no treatment options available and those targeted at other retinopathies have shown limited effectiveness. The process of programmed cell death or apoptosis although complex, remains a possible target for the treatment of retinal diseases. Having identified apoptosis in the vertebrate retina in populations of immature neurons as an essential part of development it was proposed that re-activation of these developmental cell death pathways might provide insight into the death mechanisms operating in retinal diseases. However, the discovery that numerous factors initiate and mediate the apoptotic cascade in mature photoreceptors has resulted in a relatively untargeted approach to examining and arresting apoptosis in the retina. In the last 5 years, mouse models have been treated with a diverse range of drugs or factors including anti-oxidants, growth factors, steroid hormones, calcium/calpain inhibitors and tetracycline antibiotics. Therefore to draw a unifying theme from these broad research areas is challenging. However, this review focusses on two targets which are currently under investigation, reactive oxygen species and mammalian target of rapamycin, drawing together the common themes of these research areas. PMID:22366479

  17. First-in-Human Trial of a Novel Suprachoroidal Retinal Prosthesis

    PubMed Central

    Ayton, Lauren N.; Blamey, Peter J.; Guymer, Robyn H.; Luu, Chi D.; Nayagam, David A. X.; Sinclair, Nicholas C.; Shivdasani, Mohit N.; Yeoh, Jonathan; McCombe, Mark F.; Briggs, Robert J.; Opie, Nicholas L.; Villalobos, Joel; Dimitrov, Peter N.; Varsamidis, Mary; Petoe, Matthew A.; McCarthy, Chris D.; Walker, Janine G.; Barnes, Nick; Burkitt, Anthony N.; Williams, Chris E.; Shepherd, Robert K.; Allen, Penelope J.

    2014-01-01

    Retinal visual prostheses (“bionic eyes”) have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in-human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration. Trial Registration Clinicaltrials.gov NCT01603576 PMID:25521292

  18. Photoreceptor counting and montaging of en-face retinal images from an adaptive optics fundus camera

    NASA Astrophysics Data System (ADS)

    Xue, Bai; Choi, Stacey S.; Doble, Nathan; Werner, John S.

    2007-05-01

    A fast and efficient method for quantifying photoreceptor density in images obtained with an en-face flood-illuminated adaptive optics (AO) imaging system is described. To improve accuracy of cone counting, en-face images are analyzed over extended areas. This is achieved with two separate semiautomated algorithms: (1) a montaging algorithm that joins retinal images with overlapping common features without edge effects and (2) a cone density measurement algorithm that counts the individual cones in the montaged image. The accuracy of the cone density measurement algorithm is high, with >97% agreement for a simulated retinal image (of known density, with low contrast) and for AO images from normal eyes when compared with previously reported histological data. Our algorithms do not require spatial regularity in cone packing and are, therefore, useful for counting cones in diseased retinas, as demonstrated for eyes with Stargardt's macular dystrophy and retinitis pigmentosa.

  19. Branch retinal vein occlusion.

    PubMed

    Hamid, Sadaf; Mirza, Sajid Ali; Shokh, Ishrat

    2008-01-01

    Retinal vein occlusions (RVO) are the second commonest sight threatening vascular disorder. Branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) are the two basic types of vein occlusion. Branch retinal vein occlusion is three times more common than central retinal vein occlusion and- second only to diabetic retinopathy as the most common retinal vascular cause of visual loss. The origin of branch retinal vein occlusion undoubtedly includes both systemic factors such as hypertension and local anatomic factors such as arteriovenous crossings. Branch retinal vein occlusion causes a painless decrease in vision, resulting in misty or distorted vision. Current treatment options don't address the underlying aetiology of branch retinal vein occlusion. Instead they focus on treating sequelae of the occluded venous branch, such as macular oedema, vitreous haemorrhage and traction retinal detachment from neovascularization. Evidences suggest that the pathogenesis of various types of retinal vein occlusion, like many other ocular vascular occlusive disorders, is a multifactorial process and there is no single magic bullet that causes retinal vein occlusion. A comprehensive management of patients with retinal vascular occlusions is necessary to correct associated diseases or predisposing abnormalities that could lead to local recurrences or systemic event. Along with a review of the literature, a practical approach for the management of retinal vascular occlusions is required, which requires collaboration between the ophthalmologist and other physicians: general practitioner, cardiologist, internist etc. as appropriate according to each case. PMID:19385476

  20. Erythrosis Pigmentosa Peribuccalis in an Adolescent: Dermoscopic Description and Management.

    PubMed

    Luna, Paula Carolina; Abad, María Eugenia; González, Virginia M; Vigovich, Felix; Casas, José Gabriel; Larralde, Margarita

    2016-01-01

    Erythrosis pigmentosa peribuccalis is an infrequent condition, with fewer than 35 cases reported in the literature, that affects mainly women. It presents as small papules that form a hyperpigmented plaque around the mouth and nose. Little is known about the etiology of this condition, its dermoscopic characteristics have not been described, and no effective treatment has been reported. We report a 15-year-old girl with this rare dermatosis who was successfully managed with daily calcipotriol, weekly topical ivermectin, and strict photoprotection. We also describe for the first time the dermoscopic findings of this entity. PMID:26823296

  1. Neuroglobin Protection in Retinal Ischemia

    PubMed Central

    Chan, Anita S.Y.; Saraswathy, Sindhu; Rehak, Matus; Ueki, Mari

    2012-01-01

    Purpose. Neuroglobin (Ngb) is a vertebrate globin that is predominantly expressed in the retina and brain. To explore the role of Ngb in retinal neuroprotection during ischemia reperfusion (IR), the authors examined the effect of Ngb overexpression in the retina in vivo by using Ngb-transgenic (Ngb-Tg) mice. Methods. Retinal IR was induced in Ngb overexpressing Ngb-Tg mice and wild type (WT) mice by cannulating the anterior chamber and transiently elevating the IOP for 60 minutes. After Day 7 of reperfusion, the authors evaluated Ngb mRNA and protein expression in nonischemic control as well as ischemic mice and its effect on retinal histology, mitochondrial oxidative stress, and apoptosis, using morphometry and immunohistochemistry, quantitative PCR analysis and Western blot techniques. Results. Ngb-Tg mice without ischemia overexpress Ngb mRNA 11.3-fold (SE ± 0.457, P < 0.05) higher than WT control mice, and this overexpression of Ngb protein was localized to the mitochondria of the ganglion cells, outer and inner plexiform layers, and photoreceptor inner segments. This overexpression of Ngb is associated with decreased mitochondrial DNA damage in Ngb-Tg mice with IR in comparison with WT. Ngb-Tg mice with IR also revealed significant preservation of retinal thickness, significantly less activated caspase 3 protein expression, and apoptosis in comparison with WT mice. Conclusions. Neuroglobin overexpression plays a neuroprotective role against retinal ischemia reperfusion injury due to decreasing of mitochondrial oxidative stress-mediated apoptosis. PMID:22167093

  2. Clinical Trials in Retinal Dystrophies

    PubMed Central

    Grob, Seanna R.; Finn, Avni; Papakostas, Thanos D.; Eliott, Dean

    2016-01-01

    Research development is burgeoning for genetic and cellular therapy for retinal dystrophies. These dystrophies are the focus of many research efforts due to the unique biology and accessibility of the eye, the transformative advances in ocular imaging technology that allows for in vivo monitoring, and the potential benefit people would gain from success in the field – the gift of renewed sight. Progress in the field has revealed the immense complexity of retinal dystrophies and the challenges faced by researchers in the development of this technology. This study reviews the current trials and advancements in genetic and cellular therapy in the treatment of retinal dystrophies and also discusses the current and potential future challenges. PMID:26957839

  3. Retinal spot size with wavelength

    NASA Astrophysics Data System (ADS)

    Rockwell, Benjamin A.; Hammer, Daniel X.; Kennedy, Paul K.; Amnotte, Rodney E.; Eilert, Brent; Druessel, Jeffrey J.; Payne, Dale J.; Phillips, Shana L.; Stolarski, David J.; Noojin, Gary D.; Thomas, Robert J.; Cain, Clarence P.

    1997-06-01

    We have made an indirect in-vivo determination of spot size focusing in the rhesus monkey model. Measurement of the laser induced breakdown threshold both in-vitro and in-vivo allow correlation and assignment of a spot size after focusing through the living eye. We discuss and analyze the results and show how trends in minimum visible lesion data should be assessed in light of chromatic aberration. National laser safety standards are based on minimal visual lesion (MVL) threshold studies in different animal models. The energy required for a retinal lesion depends upon may parameters including wavelength and retinal spot size. We attempt to explain trends in reported MVL threshold studies using a model of the eye which allows calculation of changes in retinal spot size due to chromatic aberration.

  4. Adenosine triphosphate-induced photoreceptor death and retinal remodeling in rats

    PubMed Central

    Vessey, Kirstan A; Greferath, Ursula; Aplin, Felix P; Jobling, Andrew I; Phipps, Joanna A; Ho, Tracy; De Iongh, Robbert U; Fletcher, Erica L

    2014-01-01

    Many common causes of blindness involve the death of retinal photoreceptors, followed by progressive inner retinal cell remodeling. For an inducible model of retinal degeneration to be useful, it must recapitulate these changes. Intravitreal administration of adenosine triphosphate (ATP) has recently been found to induce acute photoreceptor death. The aim of this study was to characterize the chronic effects of ATP on retinal integrity. Five-week-old, dark agouti rats were administered 50 mM ATP into the vitreous of one eye and saline into the other. Vision was assessed using the electroretinogram and optokinetic response and retinal morphology investigated via histology. ATP caused significant loss of visual function within 1 day and loss of 50% of the photoreceptors within 1 week. At 3 months, 80% of photoreceptor nuclei were lost, and total photoreceptor loss occurred by 6 months. The degeneration and remodeling were similar to those found in heritable retinal dystrophies and age-related macular degeneration and included inner retinal neuronal loss, migration, and formation of new synapses; Müller cell gliosis, migration, and scarring; blood vessel loss; and retinal pigment epithelium migration. In addition, extreme degeneration and remodeling events, such as neuronal and glial migration outside the neural retina and proliferative changes in glial cells, were observed. These extreme changes were also observed in the 2-year-old P23H rhodopsin transgenic rat model of retinitis pigmentosa. This ATP-induced model of retinal degeneration may provide a valuable tool for developing pharmaceutical therapies or for testing electronic implants aimed at restoring vision. J. Comp. Neurol. 522:2928–2950, 2014. © 2014 Wiley Periodicals, Inc. PMID:24639102

  5. Retinal Image Quality During Accommodation

    PubMed Central

    López-Gil, N.; Martin, J.; Liu, T.; Bradley, A.; Díaz-Muñoz, D.; Thibos, L.

    2013-01-01

    Purpose We asked if retinal image quality is maximum during accommodation, or sub-optimal due to accommodative error, when subjects perform an acuity task. Methods Subjects viewed a monochromatic (552nm), high-contrast letter target placed at various viewing distances. Wavefront aberrations of the accommodating eye were measured near the endpoint of an acuity staircase paradigm. Refractive state, defined as the optimum target vergence for maximising retinal image quality, was computed by through-focus wavefront analysis to find the power of the virtual correcting lens that maximizes visual Strehl ratio. Results Despite changes in ocular aberrations and pupil size during binocular viewing, retinal image quality and visual acuity typically remain high for all target vergences. When accommodative errors lead to sub-optimal retinal image quality, acuity and measured image quality both decline. However, the effect of accommodation errors of on visual acuity are mitigated by pupillary constriction associated with accommodation and binocular convergence and also to binocular summation of dissimilar retinal image blur. Under monocular viewing conditions some subjects displayed significant accommodative lag that reduced visual performance, an effect that was exacerbated by pharmacological dilation of the pupil. Conclusions Spurious measurement of accommodative error can be avoided when the image quality metric used to determine refractive state is compatible with the focusing criteria used by the visual system to control accommodation. Real focusing errors of the accommodating eye do not necessarily produce a reliably measurable loss of image quality or clinically significant loss of visual performance, probably because of increased depth-of-focus due to pupil constriction. When retinal image quality is close to maximum achievable (given the eye’s higher-order aberrations), acuity is also near maximum. A combination of accommodative lag, reduced image quality, and reduced

  6. Vitritis in Pediatric Genetic Retinal Disorders

    PubMed Central

    Stunkel, Maria; Bhattarai, Sajag; Kemerley, Andrew; Stone, Edwin M.; Wang, Kai; Mullins, Robert F.; Drack, Arlene V.

    2014-01-01

    Structured Abstract Purpose To determine which types of pediatric retinal degeneration are associated with inflammatory cells in the anterior vitreous (AV). Design Retrospective, observational study in humans. Methods Retrospective chart review was performed for pediatric patients with suspected retinal degeneration presenting to a single examiner from 2008–2013. Age, visual acuity (VA), slit lamp examination of AV (SLAV), clinical and molecular genetic diagnoses were documented. Anterior vitreous cells were graded clinically with SLAV from rare cells (1–4) to 1+ (5–9), 2+ (10–30), or 3+ (more than 30). Cells were also counted in magnified slit beam photographs masked to molecular diagnosis when obtainable. Main outcome measures Cell counts in SLAV, best corrected VA, molecular and clinical diagnoses. Results One hundred and five charts were evaluated, 68 of which (64.8%) included SLAV data. Numerous (1+ or greater) cells were present in 22/68 (32.4%) patients, whereas 4/68 (5.9%) had rare cells and 42/68 (61.8%) had no cells. The average age between patients with cells, no-cells, and rare cells did not differ significantly (p=0.25). VA averaged 20/124 in patients with cells, 20/143 in patients with no-cells, and 20/68 in patients with rare cells (p= 0.70). The most frequent diagnoses with cells included Bardet Biedl syndrome, Leber congenital amaurosis (LCA), and retinitis pigmentosa. The most frequent diagnoses without cells included congenital stationary night blindness, LCA, Stargardt disease, and blue cone monochromacy. Discussion A non-random subset of pediatric retinal degenerations exhibit vitritis. Cells were present in 5/5 BBS patients (a progressive degeneration) whereas cells were not detected in any of the 12 patients with CSNB (a stable dysfunction). Conclusion Studying vitritis in pediatric retinal degenerations may reveal whether inflammation accompanies progressive vision loss in certain sub-types. Potentially, inflammation could be treated

  7. Intraocular and extraocular cameras for retinal prostheses: Effects of foveation by means of visual prosthesis simulation

    NASA Astrophysics Data System (ADS)

    McIntosh, Benjamin Patrick

    Blindness due to Age-Related Macular Degeneration and Retinitis Pigmentosa is unfortunately both widespread and largely incurable. Advances in visual prostheses that can restore functional vision in those afflicted by these diseases have evolved rapidly from new areas of research in ophthalmology and biomedical engineering. This thesis is focused on further advancing the state-of-the-art of both visual prostheses and implantable biomedical devices. A novel real-time system with a high performance head-mounted display is described that enables enhanced realistic simulation of intraocular retinal prostheses. A set of visual psychophysics experiments is presented using the visual prosthesis simulator that quantify, in several ways, the benefit of foveation afforded by an eye-pointed camera (such as an eye-tracked extraocular camera or an implantable intraocular camera) as compared with a head-pointed camera. A visual search experiment demonstrates a significant improvement in the time to locate a target on a screen when using an eye-pointed camera. A reach and grasp experiment demonstrates a 20% to 70% improvement in time to grasp an object when using an eye-pointed camera, with the improvement maximized when the percept is blurred. A navigation and mobility experiment shows a 10% faster walking speed and a 50% better ability to avoid obstacles when using an eye-pointed camera. Improvements to implantable biomedical devices are also described, including the design and testing of VLSI-integrable positive mobile ion contamination sensors and humidity sensors that can validate the hermeticity of biomedical device packages encapsulated by hermetic coatings, and can provide early warning of leaks or contamination that may jeopardize the implant. The positive mobile ion contamination sensors are shown to be sensitive to externally applied contamination. A model is proposed to describe sensitivity as a function of device geometry, and verified experimentally. Guidelines are

  8. Panel-Based Population Next-Generation Sequencing for Inherited Retinal Degenerations.

    PubMed

    Carrigan, Matthew; Duignan, Emma; Malone, Conor P G; Stephenson, Kirk; Saad, Tahira; McDermott, Ciara; Green, Andrew; Keegan, David; Humphries, Peter; Kenna, Paul F; Farrar, G Jane

    2016-01-01

    Inherited retinopathies affect approximately two and a half million people globally, yet the majority of affected patients lack clear genetic diagnoses given the diverse range of genes and mutations implicated in these conditions. We present results from a next-generation sequencing study of a large inherited retinal disease patient population, with the goal of providing clear and actionable genetic diagnoses. Targeted sequencing was performed on 539 individuals from 309 inherited retinal disease pedigrees. Causative mutations were identified in the majority (57%, 176/309) of pedigrees. We report the association of many previously unreported variants with retinal disease, as well as new disease phenotypes associated with known genes, including the first association of the SLC24A1 gene with retinitis pigmentosa. Population statistics reporting the genes most commonly implicated in retinal disease in the cohort are presented, as are some diagnostic conundrums that can arise during such studies. Inherited retinal diseases represent an exemplar group of disorders for the application of panel-based next-generation sequencing as an effective tool for detection of causative mutations. PMID:27624628

  9. Changes in ganglion cell physiology during retinal degeneration influence excitability by prosthetic electrodes

    NASA Astrophysics Data System (ADS)

    Cho, Alice; Ratliff, Charles; Sampath, Alapakkam; Weiland, James

    2016-04-01

    Objective. Here we investigate ganglion cell physiology in healthy and degenerating retina to test its influence on threshold to electrical stimulation. Approach. Age-related Macular Degeneration and Retinitis Pigmentosa cause blindness via outer retinal degeneration. Inner retinal pathways that transmit visual information to the central brain remain intact, so direct electrical stimulation from prosthetic devices offers the possibility for visual restoration. Since inner retinal physiology changes during degeneration, we characterize physiological properties and responses to electrical stimulation in retinal ganglion cells (RGCs) of both wild type mice and the rd10 mouse model of retinal degeneration. Main results. Our aggregate results support previous observations that elevated thresholds characterize diseased retinas. However, a physiology-driven classification scheme reveals distinct sub-populations of ganglion cells with thresholds either normal or strongly elevated compared to wild-type. When these populations are combined, only a weakly elevated threshold with large variance is observed. The cells with normal threshold are more depolarized at rest and exhibit periodic oscillations. Significance. During degeneration, physiological changes in RGCs affect the threshold stimulation currents required to evoke action potentials.

  10. Saffron reduces ATP-induced retinal cytotoxicity by targeting P2X7 receptors.

    PubMed

    Corso, Lucia; Cavallero, Anna; Baroni, Debora; Garbati, Patrizia; Prestipino, Gianfranco; Bisti, Silvia; Nobile, Mario; Picco, Cristiana

    2016-03-01

    P2X7-type purinergic receptors are distributed throughout the nervous system where they contribute to physiological and pathological functions. In the retina, this receptor is found in both inner and outer cells including microglia modulating signaling and health of retinal cells. It is involved in retinal neurodegenerative disorders such as retinitis pigmentosa and age-related macular degeneration (AMD). Experimental studies demonstrated that saffron protects photoreceptors from light-induced damage preserving both retinal morphology and visual function and improves retinal flicker sensitivity in AMD patients. To evaluate a possible interaction between saffron and P2X7 receptors (P2X7Rs), different cellular models and experimental approaches were used. We found that saffron positively influences the viability of mouse primary retinal cells and photoreceptor-derived 661W cells exposed to ATP, and reduced the ATP-induced intracellular calcium increase in 661W cells. Similar results were obtained on HEK cells transfected with recombinant rat P2X7R but not on cells transfected with rat P2X2R. Finally, patch-clamp experiments showed that saffron inhibited cationic currents in HEK-P2X7R cells. These results point out a novel mechanism through which saffron may exert its protective role in neurodegeneration and support the idea that P2X7-mediated calcium signaling may be a crucial therapeutic target in the treatment of neurodegenerative diseases. PMID:26739703

  11. The Role of X-Chromosome Inactivation in Retinal Development and Disease

    PubMed Central

    Fahim, Abigail T.; Daiger, Stephen P.

    2016-01-01

    The expression of X-linked genes is equalized between males and females in mammalian species through X-Chromosome inactivation (XCI). Every cell in a female mammalian embryo randomly chooses one X Chromosome for epigenetic silencing at the 8–16 cell stage, resulting in a Gaussian distribution of XCI ratios with a peak at 50:50. At the tail extremes of this distribution, X-linked recessive mutations can manifest in disease in female carriers if the mutant allele is disproportionately active. The role of XCI skewing, if any, in X-linked retinal disease is still unknown, although many have speculated that such skewing accounts for phenotypic variation in female carriers of X-linked retinitis pigmentosa (XlRP). Some investigators have used clinical findings such as tapetal-like reflex, pigmentary changes, and multifocal ERG parameters to approximate XCI patches in the retina. These studies are limited by small cohorts and the relative inaccessibility of retinal tissue for genetic and epigenetic analysis. Although blood has been used as a proxy for other tissues in determining XCI ratios, blood XCI skews with age out of proportion to other tissues and may not accurately reflect retinal XCI ratios. Future investigations in determining retinal XCI ratios and the contribution of XCI to phenotype could potentially impact prognosis for female carriers of X-linked retinal disease. PMID:26427428

  12. Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

    PubMed Central

    Grimm, Christian; Wenzel, Andreas; Stanescu, Dinu; Samardzija, Marijana; Hotop, Svenja; Groszer, Mathias; Naash, Muna; Gassmann, Max; Remé, Charlotte

    2010-01-01

    Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinant human Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa (RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments. PMID:15215287

  13. Retinal Optical Coherence Tomography Imaging

    NASA Astrophysics Data System (ADS)

    Drexler, Wolfgang; Fujimoto, James G.

    The eye is essentially transparent, transmitting light with only minimal optical attenuation and scattering providing easy optical access to the anterior segment as well as the retina. For this reason, ophthalmic and especially retinal imaging has been not only the first but also most successful clinical application for optical coherence tomography (OCT). This chapter focuses on the development of OCT technology for retinal imaging. OCT has significantly improved the potential for early diagnosis, understanding of retinal disease pathogenesis, as well as monitoring disease progression and response to therapy. Development of ultrabroad bandwidth light sources and high-speed detection techniques has enabled significant improvements in ophthalmic OCT imaging performance, demonstrating the potential of three-dimensional, ultrahigh-resolution OCT (UHR OCT) to perform noninvasive optical biopsy of the living human retina, i.e., the in vivo visualization of microstructural, intraretinal morphology in situ approaching the resolution of conventional histopathology. Significant improvements in axial resolution and speed not only enable three-dimensional rendering of retinal volumes but also high-definition, two-dimensional tomograms, topographic thickness maps of all major intraretinal layers, as well as volumetric quantification of pathologic intraretinal changes. These advances in OCT technology have also been successfully applied in several animal models of retinal pathologies. The development of light sources emitting at alternative wavelengths, e.g., around #1,060 nm, not only enabled three-dimensional OCT imaging with enhanced choroidal visualization but also improved OCT performance in cataract patients due to reduced scattering losses in this wavelength region. Adaptive optics using deformable mirror technology, with unique high stroke to correct higher-order ocular aberrations, with specially designed optics to compensate chromatic aberration of the human eye, in

  14. FPGA design for dual-spectrum Visual Scene Preparation in retinal prosthesis.

    PubMed

    Al Yaman, Musa; Al-Atabany, Walid; Bystrov, Alex; Degenaar, Patrick

    2014-01-01

    A method of Visual Scene Preparation for the patients suffering Retinitis Pigmentosa is implemented in hardware for the first time. The scene is captured with two cameras, one visible spectrum and one infra-red, in order to distinguish between the live and non-live objects. The live objects are subsequently emphasized in the output image, thus helping a patient to see the most significant detail with the healthy part of the retina. The implementation uses Verilog language and FPGA platform. A system prototype is analyzed and compared to MATLAB results. PMID:25571039

  15. Investigation of SLA4A3 as a candidate gene for human retinal disease.

    PubMed

    Downs, Louise M; Webster, Andrew R; Moore, Anthony T; Michaelides, Michel; Ali, Robin R; Hardcastle, Alison J; Mellersh, Cathryn S

    2016-01-01

    SLC4A3 has been shown to cause retinal degeneration in a genetically engineered knockout mouse, and in a naturally occurring form of canine progressive retinal atrophy considered to be the equivalent of retinitis pigmentosa in humans (RP). This study was undertaken to investigate if SLC4A3 coding variants were implicated in human retinal degeneration. SLC4A3 exons were amplified and sequenced in 200 patients with autosomal recessive retinal degeneration who had no known molecular diagnosis for their condition, which included 197 unrelated individuals with suspected RP and three individuals with other forms of retinal disease. Three rare variants were identified that were predicted to be potentially pathogenic, however each variant was heterozygous in a single patient and therefore not considered disease-causing in isolation. Of these three variants, SNP-3 was the rarest, with an allele frequency of 7.06 x 10(-5) (>46,000 exomes from the ExAC database). In conclusion, no compound heterozygous or homozygous potentially pathogenic variants were identified that would account for recessive RP or retinal degeneration in this cohort, however the possibility remains that the rare variants identified could be acting with as yet undiscovered mutations in introns or regulatory regions. SLC4A3 remains an excellent candidate gene for human retinal degeneration, and with the advent of whole exome and whole genome sequencing of cohorts of molecularly unsolved patients with syndromic and non-syndromic forms of retinal degeneration, SLC4A3 may yet be implicated in human disease. PMID:27211793

  16. Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations.

    PubMed

    Sun, Xun; Park, James H; Gumerson, Jessica; Wu, Zhijian; Swaroop, Anand; Qian, Haohua; Roll-Mecak, Antonina; Li, Tiansen

    2016-05-24

    Mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of retinitis pigmentosa, a blinding retinal disease resulting from photoreceptor degeneration. A photoreceptor specific ORF15 variant of RPGR (RPGR(ORF15)), carrying multiple Glu-Gly tandem repeats and a C-terminal basic domain of unknown function, localizes to the connecting cilium where it is thought to regulate cargo trafficking. Here we show that tubulin tyrosine ligase like-5 (TTLL5) glutamylates RPGR(ORF15) in its Glu-Gly-rich repetitive region containing motifs homologous to the α-tubulin C-terminal tail. The RPGR(ORF15) C-terminal basic domain binds to the noncatalytic cofactor interaction domain unique to TTLL5 among TTLL family glutamylases and targets TTLL5 to glutamylate RPGR. Only TTLL5 and not other TTLL family glutamylases interacts with RPGR(ORF15) when expressed transiently in cells. Consistent with this, a Ttll5 mutant mouse displays a complete loss of RPGR glutamylation without marked changes in tubulin glutamylation levels. The Ttll5 mutant mouse develops slow photoreceptor degeneration with early mislocalization of cone opsins, features resembling those of Rpgr-null mice. Moreover TTLL5 disease mutants that cause human retinal dystrophy show impaired glutamylation of RPGR(ORF15) Thus, RPGR(ORF15) is a novel glutamylation substrate, and this posttranslational modification is critical for its function in photoreceptors. Our study uncovers the pathogenic mechanism whereby absence of RPGR(ORF15) glutamylation leads to retinal pathology in patients with TTLL5 gene mutations and connects these two genes into a common disease pathway. PMID:27162334

  17. Genetic pediatric retinal diseases

    PubMed Central

    Say, Emil Anthony T.

    2014-01-01

    Hereditary pediatric retinal diseases are a diverse group of disorders with pathologies affecting different cellular structures or retinal development. Many can mimic typical pediatric retinal disease such as retinopathy of prematurity, vitreous hemorrhage, retinal detachment and cystoid macular edema. Multisystem involvement is frequently seen in hereditary pediatric retinal disease. A thorough history coupled with a good physical examination can oftentimes lead the ophthalmologist or pediatrician to the correct genetic test and correct diagnosis. In some instances, evaluation of parents or siblings may be required to determine familial involvement when the history is inconclusive or insufficient and clinical suspicion is high.

  18. Genetics Home Reference: Naegeli-Franceschetti-Jadassohn syndrome/dermatopathia pigmentosa reticularis

    MedlinePlus

    ... hard, and callused, a condition known as palmoplantar keratoderma. Some affected individuals also have blistering on their ... for Ichthyosis and Related Skin Types (FIRST): Palmoplantar Keratodermas Genetic Testing Registry: Dermatopathia pigmentosa reticularis Genetic Testing ...

  19. Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

    PubMed Central

    Matsui, Rodrigo; Cideciyan, Artur V.; Schwartz, Sharon B.; Sumaroka, Alexander; Roman, Alejandro J.; Swider, Malgorzata; Huang, Wei Chieh; Sheplock, Rebecca; Jacobson, Samuel G.

    2015-01-01

    Purpose To characterize in detail the phenotype and genotype of patients with pericentral retinal degeneration (PRD). Methods Patients were screened for an annular ring scotoma ranging from 3° to 40° (n = 28, ages 24–71) with kinetic perimetry. All patients had pigmentary retinopathy in the region of the dysfunction. Further studies included cross-sectional and en face imaging, static chromatic perimetry, and electroretinography. Molecular screening was performed. Results Genotypes of 14 of 28 PRD patients were identified: There were mutations in eight different genes previously associated with autosomal dominant or autosomal recessive RDs. Kinetic fields monitored in some patients over years to more than a decade could be stable or show increased extent of the scotoma. Electroretinograms were recordable but with different severities of dysfunction. Patterns of photoreceptor outer nuclear layer (ONL) loss corresponded to the distribution of visual dysfunction. Outer nuclear layer thickness topography and en face imaging indicated that the greatest disease expression was in the area of known highest rod photoreceptor density. Conclusions Molecular heterogeneity was a feature of the PRD phenotype. Many of the molecular causes were also associated with other phenotypes, such as maculopathies, typical retinitis pigmentosa (RP) and cone–rod dystrophy. The pericentral pattern of retinal degeneration is thus confirmed to be an uncommon phenotype of many different genotypes rather than a distinct disease entity. PMID:26393467

  20. Retinal dystrophies, genomic applications in diagnosis and prospects for therapy.

    PubMed

    Nash, Benjamin M; Wright, Dale C; Grigg, John R; Bennetts, Bruce; Jamieson, Robyn V

    2015-04-01

    Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs. PMID:26835369

  1. Therapeutic Approaches to Histone Reprogramming in Retinal Degeneration

    PubMed Central

    Kleinman, Mark E.

    2016-01-01

    Recent data have revealed epigenetic derangements and subsequent chromatin remodeling as a potent biologic switch for chronic inflammation and cell survival which are important therapeutic targets in the pathogenesis of several retinal degenerations. Histone deacetylases (HDACs) are a major component of this system and serve as a unique control of the chromatin remodeling process. With a multitude of targeted HDAC inhibitors now available, their use in both basic science and clinical studies has widened substantially. In the field of ocular biology, there are data to suggest that HDAC inhibition may suppress neovascularization and may be a possible treatment for retinitis pigmentosa and dry age-related macular degeneration (AMD). However, the effects of these inhibitors on cell survival and chemokine expression in the chorioretinal tissues remain very unclear. Here, we review the multifaceted biology of HDAC activity and pharmacologic inhibition while offering further insight into the importance of this epigenetic pathway in retinal degenerations. Our laboratory investigations aim to open translational avenues to advance dry AMD therapeutics while exploring the role of acetylation on inflammatory gene expression in the aging and degenerating retina. PMID:26427391

  2. Clinical characteristics and current therapies for inherited retinal degenerations.

    PubMed

    Sahel, José-Alain; Marazova, Katia; Audo, Isabelle

    2015-02-01

    Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances. PMID:25324231

  3. Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration*

    PubMed Central

    Ramon, Eva; Cordomí, Arnau; Aguilà, Mònica; Srinivasan, Sundaramoorthy; Dong, Xiaoyun; Moore, Anthony T.; Webster, Andrew R.; Cheetham, Michael E.; Garriga, Pere

    2014-01-01

    Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited degenerative retinopathies caused by abnormalities of photoreceptors or retinal pigment epithelium in the retina leading to progressive sight loss. Rhodopsin is the prototypical G-protein-coupled receptor located in the vertebrate retina and is responsible for dim light vision. Here, novel M39R and N55K variants were identified as causing an intriguing sector phenotype of RP in affected patients, with selective degeneration in the inferior retina. To gain insights into the molecular aspects associated with this sector RP phenotype, whose molecular mechanism remains elusive, the mutations were constructed by site-directed mutagenesis, expressed in heterologous systems, and studied by biochemical, spectroscopic, and functional assays. M39R and N55K opsins had variable degrees of chromophore regeneration when compared with WT opsin but showed no gross structural misfolding or altered trafficking. M39R showed a faster rate for transducin activation than WT rhodopsin with a faster metarhodopsinII decay, whereas N55K presented a reduced activation rate and an altered photobleaching pattern. N55K also showed an altered retinal release from the opsin binding pocket upon light exposure, affecting its optimal functional response. Our data suggest that these sector RP mutations cause different protein phenotypes that may be related to their different clinical progression. Overall, these findings illuminate the molecular mechanisms of sector RP associated with rhodopsin mutations. PMID:25359768

  4. Transplanting Retinal Cells using Bucky Paper for Support

    NASA Technical Reports Server (NTRS)

    Loftus, David J.; Cinke, Martin; Meyyappan, Meyya; Fishman, Harvey; Leng, Ted; Huie, Philip; Bilbao, Kalayaan

    2004-01-01

    A novel treatment for retinal degenerative disorders involving transplantation of cells into the eye is currently under development at NASA Ames Research Center and Stanford University School of Medicine. The technique uses bucky paper as a support material for retinal pigment epithelial (RPE) cells, iris pigment epithelial (IPE) cells, and/or stem cells. This technology is envisioned as a treatment for age-related macular degeneration, which is the leading cause of blindness in persons over age 65 in Western nations. Additionally, patients with other retinal degenerative disorders, such as retinitis pigmentosa, may be treated by this strategy. Bucky paper is a mesh of carbon nanotubes (CNTs), as shown in Figure 1, that can be made from any of the commercial sources of CNTs. Bucky paper is biocompatible and capable of supporting the growth of biological cells. Because bucky paper is highly porous, nutrients, oxygen, carbon dioxide, and waste can readily diffuse through it. The thickness, density, and porosity of bucky paper can be tailored in manufacturing. For transplantation of cells into the retina, bucky paper serves simultaneously as a substrate for cell growth and as a barrier for new blood vessel formation, which can be a problem in the exudative type of macular degeneration. Bucky paper is easily handled during surgical implantation into the eye. Through appropriate choice of manufacturing processes, bucky paper can be made relatively rigid yet able to conform to the retina when the bucky paper is implanted. Bucky paper offers a distinct advantage over other materials that have been investigated for retinal cell transplantation - lens capsule and Descemet's membrane - which are difficult to handle during surgery because they are flimsy and do not stay flat.

  5. Retinal Remodeling and Metabolic Alterations in Human AMD

    PubMed Central

    Jones, Bryan W.; Pfeiffer, Rebecca L.; Ferrell, William D.; Watt, Carl B.; Tucker, James; Marc, Robert E.

    2016-01-01

    Age-related macular degeneration (AMD) is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression. The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this article is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE), for remodeling of the the neural retina. Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP), a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming) in progressive retinal degenerations such as retinitis pigmentosa (RP). We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease. PMID:27199657

  6. Delivery of neurotrophic factors and therapeutic proteins for retinal diseases.

    PubMed

    Thanos, Chris; Emerich, Dwaine

    2005-11-01

    Neurotrophic factors have the ability to protect and initiate growth of neurons. In the central nervous system, neurotrophic factors are neuroprotective in a wide range of disease states. Similarly, disease pathologies of the neurosensory retina respond favourably in animal models of retinitis pigmentosa, macular degeneration, glaucoma and others. With advances in drug delivery and cell therapy, an almost universal increase in efficacy is being realised. Now, repeated injections of neurotrophic factors are being replaced by controlled delivery of cell-mediated factor secretion, reducing the number of potential acute side effects. Tissue engineering strategies in conjunction with gene-modulated protein therapy or gene transfer are creating a unique treatment niche and are quickly gaining acclaim in the clinic. This review surveys the founding and current work on neurotrophic factors such as CNTF, BDNF, GDNF, LEDGF, PEDF and others. Ongoing clinical trials and successful preclinical studies are summarised as well. PMID:16255648

  7. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea.

    PubMed

    Kim, Jae Kyung; Chung, Woon Kyong; Chang, Sung Eun; Ko, Joo Yeon; Lee, Jong Hee; Won, Chong Hyun; Lee, Mi Woo; Choi, Jee Ho; Moon, Kee Chan

    2012-11-01

    Prurigo pigmentosa is a recurrent dermatosis with severe pruritus and several peculiar clinical features. Its exact etiology and pathogenesis are unclear. The aim of this study was to investigate the clinical features and chronological changes in the histopathology of prurigo pigmentosa in Korean patients and to assess the etiology of this condition. We reviewed the medical records, clinical photographs and biopsy specimens from 50 patients diagnosed with prurigo pigmentosa. Mean age at diagnosis was 23.7 years (range, 15-61 years). Prurigo pigmentosa started as urticarial papules or plaques, changing first to papulovesicles and then to reticulated brownish macules. The most frequent sites were the back and chest, especially depressed areas such as the central back and inter-mammary area. Dietary change was suspected as a cause of prurigo pigmentosa in 17 patients. Histopathologically, early-stage lesions had dermatitis herpetiformis-like features; fully-developed lesions displayed impetigo-like or acute, generalized, exanthematous, pustulosis-like features; and late lesions presented with post-inflammatory hyperpigmentation-like features. Oral minocycline, with or without dapsone, was effective in inhibiting the appearance of new lesions, but did not prevent recurrence. Prurigo pigmentosa is not rare in Korea, is apparently associated with dietary modification and preferentially involves the depressed regions of the trunk. PMID:22901017

  8. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells

    PubMed Central

    Tochitsky, Ivan; Polosukhina, Aleksandra; Degtyar, Vadim E.; Gallerani, Nicholas; Smith, Caleb M.; Friedman, Aaron; Van Gelder, Russell N.; Trauner, Dirk; Kaufer, Daniela; Kramer, Richard H.

    2014-01-01

    Summary Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, non-functional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD. PMID:24559673

  9. Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells.

    PubMed

    Tochitsky, Ivan; Polosukhina, Aleksandra; Degtyar, Vadim E; Gallerani, Nicholas; Smith, Caleb M; Friedman, Aaron; Van Gelder, Russell N; Trauner, Dirk; Kaufer, Daniela; Kramer, Richard H

    2014-02-19

    Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here, we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD. PMID:24559673

  10. Isolated case of mental retardation and ataxia due to a de novo mitochondrial T8993G mutation

    SciTech Connect

    De Coo, I.F.M.; Smeets, H.J.M.; Oost, B.A. van

    1996-03-01

    Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) and subacute necrotizing encephalomyelopathy (Leigh disease) are both associated with an alteration of nt 8993 in the mitochondrial ATPase 6 gene. In NARP, the T-to-G transversion at that position changes leucine into arginine. In Leigh syndrome, the same mutation can be found, as can a T-to-C transition, which changes this leucine into proline. Clinical manifestations occur for NARP when {approximately}60%-90% mutated mtDNA is present. In case of Leigh, these percentages usually exceed 95%. It is known that this mutation can segregate very rapidly within pedigrees. Here we report on a sporadic case with mental retardation and ataxia without retinitis pigmentosa in which the T8993G mutation was found. 13 refs., 1 fig.

  11. Building retinal connectomes.

    PubMed

    Marc, Robert E; Jones, Bryan W; Lauritzen, J Scott; Watt, Carl B; Anderson, James R

    2012-08-01

    Understanding vertebrate vision depends on knowing, in part, the complete network graph of at least one representative retina. Acquiring such graphs is the business of synaptic connectomics, emerging as a practical technology due to improvements in electron imaging platform control, management software for large-scale datasets, and availability of data storage. The optimal strategy for building complete connectomes uses transmission electron imaging with 2 nm or better resolution, molecular tags for cell identification, open-access data volumes for navigation, and annotation with open-source tools to build 3D cell libraries, complete network diagrams and connectivity databases. The first forays into retinal connectomics have shown that even nominally well-studied cells have much richer connection graphs than expected. PMID:22498714

  12. Quantitative genetic analysis of retinal degeneration in the blind cavefish Astyanax mexicanus.

    PubMed

    O'Quin, Kelly E; Yoshizawa, Masato; Doshi, Pooja; Jeffery, William R

    2013-01-01

    The retina is the light-sensitive tissue of the eye that facilitates vision. Mutations within genes affecting eye development and retinal function cause a host of degenerative visual diseases, including retinitis pigmentosa and anophthalmia/microphthalmia. The characin fish Astyanax mexicanus includes both eyed (surface fish) and eyeless (cavefish) morphs that initially develop eyes with normal retina; however, early in development, the eyes of cavefish degenerate. Since both surface and cave morphs are members of the same species, they serve as excellent evolutionary mutant models with which to identify genes causing retinal degeneration. In this study, we crossed the eyed and eyeless forms of A. mexicanus and quantified the thickness of individual retinal layers among 115 F(2) hybrid progeny. We used next generation sequencing (RAD-seq) and microsatellite mapping to construct a dense genetic map of the Astyanax genome, scan for quantitative trait loci (QTL) affecting retinal thickness, and identify candidate genes within these QTL regions. The map we constructed for Astyanax includes nearly 700 markers assembled into 25 linkage groups. Based on our scans with this map, we identified four QTL, one each associated with the thickness of the ganglion, inner nuclear, outer plexiform, and outer nuclear layers of the retina. For all but one QTL, cavefish alleles resulted in a clear reduction in the thickness of the affected layer. Comparative mapping of genetic markers within each QTL revealed that each QTL corresponds to an approximately 35 Mb region of the zebrafish genome. Within each region, we identified several candidate genes associated with the function of each affected retinal layer. Our study is the first to examine Astyanax retinal degeneration in the context of QTL mapping. The regions we identify serve as a starting point for future studies on the genetics of retinal degeneration and eye disease using the evolutionary mutant model Astyanax. PMID:23437360

  13. A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium.

    PubMed

    Meunier, Isabelle; Lenaers, Guy; Bocquet, Béatrice; Baudoin, Corinne; Piro-Megy, Camille; Cubizolle, Aurélie; Quilès, Mélanie; Jean-Charles, Albert; Cohen, Salomon Yves; Merle, Harold; Gaudric, Alain; Labesse, Gilles; Manes, Gaël; Péquignot, Marie; Cazevieille, Chantal; Dhaenens, Claire-Marie; Fichard, Agnès; Ronkina, Natalia; Arthur, Simon J; Gaestel, Matthias; Hamel, Christian P

    2016-03-01

    Inherited retinal dystrophies are clinically and genetically heterogeneous with significant number of cases remaining genetically unresolved. We studied a large family from the West Indies islands with a peculiar retinal disease, the Martinique crinkled retinal pigment epitheliopathy that begins around the age of 30 with retinal pigment epithelium (RPE) and Bruch's membrane changes resembling a dry desert land and ends with a retinitis pigmentosa. Whole-exome sequencing identified a heterozygous c.518T>C (p.Leu173Pro) mutation in MAPKAPK3 that segregates with the disease in 14 affected and 28 unaffected siblings from three generations. This unknown variant is predicted to be damaging by bioinformatic predictive tools and the mutated protein to be non-functional by crystal structure analysis. MAPKAPK3 is a serine/threonine protein kinase of the p38 signaling pathway that is activated by a variety of stress stimuli and is implicated in cellular responses and gene regulation. In contrast to other tissues, MAPKAPK3 is highly expressed in the RPE, suggesting a crucial role for retinal physiology. Expression of the mutated allele in HEK cells revealed a mislocalization of the protein in the cytoplasm, leading to cytoskeleton alteration and cytodieresis inhibition. In Mapkapk3-/- mice, Bruch's membrane is irregular with both abnormal thickened and thinned portions. In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration. PMID:26744326

  14. Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration.

    PubMed

    Noailles, Agustina; Maneu, Victoria; Campello, Laura; Gómez-Vicente, Violeta; Lax, Pedro; Cuenca, Nicolás

    2016-01-01

    Microglia act as the resident immune cells of the central nervous system, including the retina. In response to damaging stimuli microglia adopt an activated state, which can progress into a phagocytic phenotype and play a potentially harmful role by eliciting the expression and release of pro-inflammatory cytokines. The aim of the present study was to assess longitudinal changes in microglia during retinal degeneration in the homozygous P23H rat, a model of dominant retinitis pigmentosa. Microglial phenotypes, morphology and density were analyzed by immunohistochemistry, flow cytometry, and cytokine antibody array. In addition, we performed electroretinograms to evaluate the retinal response. In the P23H retina, sclera, choroid and ciliary body, inflammatory cells increased in number compared with the control at all ages analyzed. As the rats became older, a higher number of amoeboid MHC-II(+) cells were observed in the P23H retina, which correlated with an increase in the expression of pro-inflammatory cytokines. These findings suggest that, in the P23H model, retinal neuroinflammation persists throughout the rat's life span even after photoreceptor depletion. Therefore, the inclusion of anti-inflammatory drugs at advanced stages of the neurodegenerative process may provide better retinal fitness so the remaining cells could still be used as targets of cellular or gene therapies. PMID:27624537

  15. Mutations in human IFT140 cause non-syndromic retinal degeneration.

    PubMed

    Xu, Mingchu; Yang, Lizhu; Wang, Feng; Li, Huajin; Wang, Xia; Wang, Weichen; Ge, Zhongqi; Wang, Keqing; Zhao, Li; Li, Hui; Li, Yumei; Sui, Ruifang; Chen, Rui

    2015-10-01

    Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are two genetically heterogeneous retinal degenerative disorders. Despite the identification of a number of genes involved in LCA and RP, the genetic etiology remains unknown in many patients. In this study, we aimed to identify novel disease-causing genes of LCA and RP. Retinal capture sequencing was initially performed to screen mutations in known disease-causing genes in different cohorts of LCA and RP patients. For patients with negative results, we performed whole exome sequencing and applied a series of variant filtering strategies. Sanger sequencing was done to validate candidate causative IFT140 variants. Exome sequencing data analysis led to the identification of IFT140 variants in multiple unrelated non-syndromic LCA and RP cases. All the variants are extremely rare and predicted to be damaging. All the variants passed Sanger validation and segregation tests provided that the family members' DNA was available. The results expand the phenotype spectrum of IFT140 mutations to non-syndromic retinal degeneration, thus extending our understanding of intraflagellar transport and primary cilia biology in the retina. This work also improves the molecular diagnosis of retinal degenerative disease. PMID:26216056

  16. Photobiomodulation reduces photoreceptor death and regulates cytoprotection in early states of P23H retinal dystrophy

    NASA Astrophysics Data System (ADS)

    Kirk, Diana K.; Gopalakrishnan, Sandeep; Schmitt, Heather; Abroe, Betsy; Stoehr, Michele; Dubis, Adam; Carroll, Joseph; Stone, Jonathan; Valter, Krisztina; Eells, Janis

    2013-03-01

    Irradiation by light in the far-red to near-infrared (NIR) region of the spectrum (photobiomodulation, PBM) has been demonstrated to attenuate the severity of neurodegenerative disease in experimental and clinical studies. The purpose of this study was to test the hypothesis that 670 nm PBM would protect against the loss of retinal function and improve photoreceptor survival in a rodent model of retinitis pigmentosa, the P23H transgenic rat. P23H rat pups were treated once per day with a 670 nm LED array (180 sec treatments at 50 mW/cm2; fluence 9 joules/cm2) (Quantum Devices Inc., Barneveld WI) from postnatal day (p) 16-20 or from p10-20. Sham-treated rats were restrained, but not exposed to NIR light. The status of the retina was determined at p22 by assessment of mitochondrial function, oxidative stress and cell death. In a second series of studies, retinal status was assessed at p30 by measuring photoreceptor function by ERG and retinal morphology by Spectral Domain Optical Coherence Tomography (SD-OCT). 670 nm PBM increased retinal mitochondrial cytochrome oxidase activity and upregulated the retina's production of the key mitochondrial antioxidant enzyme, MnSOD. PBM also attenuated photoreceptor cell loss and improved photoreceptor function. PBM protects photoreceptors in the developing P23H retina, by augmenting mitochondrial function and stimulating antioxidant protective pathways. Photobiomodulation may have therapeutic potential, where mitochondrial damage is a step in the death of photoreceptors.

  17. Inherited retinal disorders in South Africa and the clinical impact of evolving technologies.

    PubMed

    Roberts, L; Goliath, R; Rebello, G; Bardien, S; September, A V; Bartmann, L; Loubser, F; Greenberg, L J; Ramesar, R S

    2016-01-01

    Retinal degenerative disorders (RDDs) encompass a group of inherited diseases characterised by vision loss. The genetic and clinical complexity poses a challenge in unravelling the molecular genetic aetiology of this group of disorders. Furthermore, the population diversity in South Africa (SA) presents researchers with a particularly complicated task. Rapid advances in the development of cutting-edge technological platforms over the past two decades, however, have assisted in overcoming some of the challenges. The RDD research team has utilised these escalating technologies, which has facilitated a corresponding increase in molecular diagnoses. A biorepository has been established and comprises ~3 200 patient DNA samples archived with many forms of RDD (including retinitis pigmentosa, macular dystrophies, Stargardt disease, Leber congenital amaurosis, Usher syndrome and Bardet Biedl syndrome). A comprehensive review is presented of the SA journey spanning 25 years, into elucidating the molecular genetic basis of various forms of RDD in SA. PMID:27245521

  18. Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets.

    PubMed

    Arsenijevic, Yvan

    2016-01-01

    During different forms of neurodegenerative diseases, including the retinal degeneration, several cell cycle proteins are expressed in the dying neurons from Drosophila to human revealing that these proteins are a hallmark of neuronal degeneration. This is true for animal models of Alzheimer's, and Parkinson's diseases, Amyotrophic Lateral Sclerosis and for Retinitis Pigmentosa as well as for acute injuries such as stroke and light damage. Longitudinal investigation and loss-of-function studies attest that cell cycle proteins participate to the process of cell death although with different impacts, depending on the disease. In the retina, inhibition of cell cycle protein action can result to massive protection. Nonetheless, the dissection of the molecular mechanisms of neuronal cell death is necessary to develop adapted therapeutic tools to efficiently protect photoreceptors as well as other neuron types. PMID:26427434

  19. Plasma amino-acids in hereditary retinal disease. Ornithine, lysine, and taurine.

    PubMed Central

    Berson, E. L.; Schmidt, S. Y.; Rabin, A. R.

    1976-01-01

    Plasma free amino-acids were measured in 41 patients with hereditary chorio-retinal degenerations including 26 with retinitis pigmentosa and five with gyrate atrophy of the choroid, six relatives of patients with gyrate atrophy, and 13 normal subjects. Patients with gyrate atrophy had very increased levels of ornithine and slightly decreased mean lysine values. Most relatives had slightly increased ornithine. Taurine, known to be deficient in the plasma of casein-fed cats with photoreceptor degeneration, was normal in all patients. Amino-acid precursors and metabolites of ornithine and taurine were also normal in the plasma. Although the association of high ornithine and gyrate atrophy appears constant, high levels of ornithine alone do not necessarily lead to this degeneration; one patient with known hyperammonaemia, homocitrullinuria and a tenfold increase in plasma ornithine was found to have a normal fundus appearance and normal electroretinogram. PMID:1268174

  20. Clinical Features of Newly Diagnosed Cytomegalovirus Retinitis in Northern Thailand

    PubMed Central

    Ausayakhun, Somsanguan; Keenan, Jeremy D; Ausayakhun, Sakarin; Jirawison, Choeng; Khouri, Claire M; Skalet, Alison H; Heiden, David; Holland, Gary N; Margolis, Todd P

    2011-01-01

    Purpose To characterize the clinical manifestations of cytomegalovirus (CMV) retinitis in northern Thailand. Design Prospective, observational cross-sectional study. Methods We recorded characteristics of 52 consecutive patients newly diagnosed with CMV retinitis at a tertiary university-based medical center in northern Thailand. Indirect ophthalmoscopy by experienced ophthalmologists was supplemented with fundus photography to determine the proportion of eyes with various clinical features of CMV retinitis. Results Of the 52 patients with CMV retinitis, 55.8% were female. All were HIV-positive. The vast majority (90.4%) had started antiretroviral therapy. CMV retinitis was bilateral in 46.2% of patients. Bilateral visual acuity worse than 20/60 was observed in 23.1% of patients. Of 76 eyes with CMV retinitis, 61.8% had zone I disease and 21.6% had lesions involving the fovea. Lesions larger than 25% of the retinal area were observed in 57.5% of affected eyes. CMV retinitis lesions commonly had marked or severe border opacity (47.4% of eyes). Vitreous haze was often present (46.1% of eyes). Visual impairment was more common in eyes with larger retinitis lesions. Retinitis lesion size, used as a proxy for duration of disease, was associated with fulminant appearance (OR 1.24 [1.01 – 1.51]), and marked or severe border opacity (OR 1.36 [1.11 – 1.67]). Based on lesion size, retinitis preceded antiretroviral treatment in each patient. Conclusions Patients presenting to a tertiary medical center in northern Thailand have advanced CMV retinitis, possibly due to delayed diagnosis. Earlier screening and treatment of CMV retinitis may limit progression of disease and prevent visual impairment in this population. PMID:22265148

  1. Design of a High-resolution Optoelectronic Retinal Prosthesis

    NASA Astrophysics Data System (ADS)

    Palanker, Daniel

    2005-03-01

    It has been demonstrated that electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. So far retinal implants have had just a few electrodes, whereas at least several thousand pixels would be required for any functional restoration of sight. We will discuss physical limitations on the number of stimulating electrodes and on delivery of information and power to the retinal implant. Using a model of extracellular stimulation we derive the threshold values of current and voltage as a function of electrode size and distance to the target cell. Electrolysis, tissue heating, and cross-talk between neighboring electrodes depend critically on separation between electrodes and cells, thus strongly limiting the pixels size and spacing. Minimal pixel density required for 20/80 visual acuity (2500 pixels/mm2, pixel size 20 um) cannot be achieved unless the target neurons are within 7 um of the electrodes. At a separation of 50 um, the density drops to 44 pixels/mm2, and at 100 um it is further reduced to 10 pixels/mm2. We will present designs of subretinal implants that provide close proximity of electrodes to cells using migration of retinal cells to target areas. Two basic implant geometries will be described: perforated membranes and protruding electrode arrays. In addition, we will discuss delivery of information to the implant that allows for natural eye scanning of the scene, rather than scanning with a head-mounted camera. It operates similarly to ``virtual reality'' imaging devices where an image from a video camera is projected by a goggle-mounted collimated infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. Optical delivery of visual information to the implant allows for flexible control of the image processing algorithms and stimulation parameters. In summary, we will describe solutions to some of the major problems

  2. Electrophysiology Alterations in Primary Visual Cortex Neurons of Retinal Degeneration (S334ter-line-3) Rats

    PubMed Central

    Chen, Ke; Wang, Yi; Liang, Xiaohua; Zhang, Yihuai; Ng, Tsz Kin; Chan, Leanne Lai Hang

    2016-01-01

    The dynamic nature of the brain is critical for the success of treatments aimed at restoring vision at the retinal level. The success of these treatments relies highly on the functionality of the surviving neurons along the entire visual pathway. Electrophysiological properties at the retina level have been investigated during the progression of retinal degeneration; however, little is known about the changes in electrophysiological properties that occur in the primary visual cortex (V1) during the course of retinal degeneration. By conducting extracellular recording, we examined the electrophysiological properties of V1 in S334ter-line-3 rats (a transgenic model of retinal degeneration developed to express a rhodopsin mutation similar to that found in human retinitis pigmentosa patients). We measured the orientation tuning, spatial and temporal frequency tunings and the receptive field (RF) size for 127 V1 neurons from 11 S334ter-3 rats and 10 Long-Evans (LE) rats. V1 neurons in the S334ter-3 rats showed weaker orientation selectivity, lower optimal spatial and temporal frequency values and a smaller receptive field size compared to the LE rats. These results suggest that the visual cognitive ability significantly changes during retinal degeneration. PMID:27225415

  3. Electrophysiology Alterations in Primary Visual Cortex Neurons of Retinal Degeneration (S334ter-line-3) Rats.

    PubMed

    Chen, Ke; Wang, Yi; Liang, Xiaohua; Zhang, Yihuai; Ng, Tsz Kin; Chan, Leanne Lai Hang

    2016-01-01

    The dynamic nature of the brain is critical for the success of treatments aimed at restoring vision at the retinal level. The success of these treatments relies highly on the functionality of the surviving neurons along the entire visual pathway. Electrophysiological properties at the retina level have been investigated during the progression of retinal degeneration; however, little is known about the changes in electrophysiological properties that occur in the primary visual cortex (V1) during the course of retinal degeneration. By conducting extracellular recording, we examined the electrophysiological properties of V1 in S334ter-line-3 rats (a transgenic model of retinal degeneration developed to express a rhodopsin mutation similar to that found in human retinitis pigmentosa patients). We measured the orientation tuning, spatial and temporal frequency tunings and the receptive field (RF) size for 127 V1 neurons from 11 S334ter-3 rats and 10 Long-Evans (LE) rats. V1 neurons in the S334ter-3 rats showed weaker orientation selectivity, lower optimal spatial and temporal frequency values and a smaller receptive field size compared to the LE rats. These results suggest that the visual cognitive ability significantly changes during retinal degeneration. PMID:27225415

  4. Enhanced differentiation and delivery of mouse retinal progenitor cells using a micropatterned biodegradable thin-film polycaprolactone scaffold.

    PubMed

    Yao, Jing; Ko, Chi Wan; Baranov, Petr Y; Regatieri, Caio V; Redenti, Stephen; Tucker, Budd A; Mighty, Jason; Tao, Sarah L; Young, Michael J

    2015-04-01

    The deterioration of retinal tissue in advanced stages of retinitis pigmentosa and age-related macular degeneration and the lack of signaling cues for laminar regeneration are significant challenges highlighting the need for a tissue engineering approach to retinal repair. In this study, we fabricated a biodegradable thin-film polycaprolactone (PCL) scaffold with varying surface topographies using microfabrication techniques. Mouse retinal progenitor cells (mRPCs) cultured on PCL scaffolds exhibited enhanced potential to differentiate toward a photoreceptor fate in comparison to mRPCs cultured on control substrates, suggesting that PCL scaffolds are promising as substrates to guide differentiation of mRPCs toward a photoreceptor fate in vitro before transplantation. When cocultured with the retinal explants of rhodopsin null mice, mRPC/PCL constructs showed increased mRPC integration rates compared to directly applied dissociated mRPCs. Moreover, these mRPC/PCL constructs could be delivered into the subretinal space of rhodopsin null mice with minimal disturbance of the host retina. Whether cocultured with retinal explants or transplanted into the subretinal space, newly integrated mRPCs localized to the outer nuclear layer and expressed appropriate markers of photoreceptor fate. Thus, the PCL scaffold provides a platform to guide differentiation and organized delivery of mRPCs as a practical strategy to repair damaged retina. PMID:25517296

  5. Enhanced Differentiation and Delivery of Mouse Retinal Progenitor Cells Using a Micropatterned Biodegradable Thin-Film Polycaprolactone Scaffold

    PubMed Central

    Yao, Jing; Ko, Chi Wan; Baranov, Petr Y.; Regatieri, Caio V.; Redenti, Stephen; Tucker, Budd A.; Mighty, Jason; Tao, Sarah L.

    2015-01-01

    The deterioration of retinal tissue in advanced stages of retinitis pigmentosa and age-related macular degeneration and the lack of signaling cues for laminar regeneration are significant challenges highlighting the need for a tissue engineering approach to retinal repair. In this study, we fabricated a biodegradable thin-film polycaprolactone (PCL) scaffold with varying surface topographies using microfabrication techniques. Mouse retinal progenitor cells (mRPCs) cultured on PCL scaffolds exhibited enhanced potential to differentiate toward a photoreceptor fate in comparison to mRPCs cultured on control substrates, suggesting that PCL scaffolds are promising as substrates to guide differentiation of mRPCs toward a photoreceptor fate in vitro before transplantation. When cocultured with the retinal explants of rhodopsin null mice, mRPC/PCL constructs showed increased mRPC integration rates compared to directly applied dissociated mRPCs. Moreover, these mRPC/PCL constructs could be delivered into the subretinal space of rhodopsin null mice with minimal disturbance of the host retina. Whether cocultured with retinal explants or transplanted into the subretinal space, newly integrated mRPCs localized to the outer nuclear layer and expressed appropriate markers of photoreceptor fate. Thus, the PCL scaffold provides a platform to guide differentiation and organized delivery of mRPCs as a practical strategy to repair damaged retina. PMID:25517296

  6. Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystrophy and mutations in the human RDS/peripherin gene.

    PubMed Central

    Apfelstedt-Sylla, E; Theischen, M; Rüther, K; Wedemann, H; Gal, A; Zrenner, E

    1995-01-01

    Clinical phenotypes of patients with mutations in the human RDS/peripherin gene are described. A 67-year-old woman, who carried a 1 base pair deletion in codon 307, presented with typical late onset autosomal dominant retinitis pigmentosa (RP). In another autosomal dominant pedigree, a nonsense mutation at codon 46 caused 'inverse' retinitis pigmentosa-like fundus changes associated with progressive cone-rod degeneration in a 58-year-old man, whereas his 40-year-old son presented with yellow deposits in the retinal pigment epithelial layer resembling a pattern dystrophy, and with moderately reduced rod and cone function, as determined by two colour dark adapted threshold perimetry and electroretinography. It is suggested that both clinical pictures within this latter family may represent manifestations of fundus flavimaculatus. The clinical data of the three patients provide further evidence for the remarkable variety of disease expression within and between families with mutations in the RDS/peripherin gene. Currently, the most comprehensive statement could be that RDS/peripherin mutations are associated either with typical RP or with various forms of flecked retinal disease. Images PMID:7880786

  7. A Novel Form of Progressive Retinal Atrophy in Swedish Vallhund Dogs

    PubMed Central

    Cooper, Ann E.; Ahonen, Saija; Rowlan, Jessica S.; Duncan, Alison; Seppälä, Eija H.; Vanhapelto, Päivi; Lohi, Hannes; Komáromy, András M.

    2014-01-01

    Inherited retinal degenerations, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), represent leading causes of incurable blindness in humans. This is also true in dogs, where the term progressive retinal atrophy (PRA) is used to describe inherited photoreceptor degeneration resulting in progressive vision loss. Because of the similarities in ocular anatomy, including the presence of a cone photoreceptor-rich central retinal region, and the close genotype-phenotype correlation, canine models contribute significantly to the understanding of retinal disease mechanisms and the development of new therapies. The screening of the pure-bred dog population for new forms of PRA represents an important strategy to establish new large animal models. By examining 324 dogs of the Swedish vallhund breed in seven countries and across three continents, we were able to describe a new and unique form of PRA characterized by the multifocal appearance of red and brown discoloration of the tapetal fundus followed over time by thinning of the retina. We propose three stages of the disease based on the appearance of the ocular fundus and associated visual deficits. Electroretinography revealed a gradual loss of both rod and cone photoreceptor-mediated function in Stages 2 and 3 of the disease. In the few dogs that suffered from pronounced vision loss, night-blindness occurred first in late Stage 2, followed by decreased day-vision in Stage 3. Histologic examinations confirmed the loss of photoreceptor cells at Stage 3, which was associated with the accumulation of autofluorescent material in the adjacent retinal pigment epithelium. Pedigree analysis was suggestive of an autosomal-recessive mode of inheritance. Mutations in six known canine retinal degeneration genes as well as hypovitaminosis E were excluded as causes of the disease. The observed variability in the age of disease onset and rate of progression suggest the presence of genetic and/or environmental

  8. Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

    PubMed Central

    Beltran, William A.; Cideciyan, Artur V.; Iwabe, Simone; Swider, Malgorzata; Kosyk, Mychajlo S.; McDaid, Kendra; Martynyuk, Inna; Ying, Gui-Shuang; Shaffer, James; Deng, Wen-Tao; Boye, Sanford L.; Lewin, Alfred S.; Hauswirth, William W.; Jacobson, Samuel G.; Aguirre, Gustavo D.

    2015-01-01

    Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP. PMID:26460017

  9. Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease.

    PubMed

    Beltran, William A; Cideciyan, Artur V; Iwabe, Simone; Swider, Malgorzata; Kosyk, Mychajlo S; McDaid, Kendra; Martynyuk, Inna; Ying, Gui-Shuang; Shaffer, James; Deng, Wen-Tao; Boye, Sanford L; Lewin, Alfred S; Hauswirth, William W; Jacobson, Samuel G; Aguirre, Gustavo D

    2015-10-27

    Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP. PMID:26460017

  10. Retinal structure and function preservation by polysaccharides of wolfberry in a mouse model of retinal degeneration

    PubMed Central

    Wang, Ke; Xiao, Jia; Peng, Bo; Xing, Feiyue; So, Kwok-Fai; Tipoe, George L.; Lin, Bin

    2014-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited disorders caused by mutations in a variety of genes that are mostly expressed by rod cells, which results in initial death of rod photoreceptors followed by gradual death of cone photoreceptors. RP is currently untreatable and usually leads to partial or complete blindness. Here, we explored the potential neuroprotective effects of polysaccharides of wolfberry, which are long known to possess primary beneficial properties in the eyes, on photoreceptor apoptosis in the rd10 mouse model of RP. We found that these polysaccharides provided long-term morphological and functional preservation of photoreceptors and improved visual behaviors in rd10 mice. Moreover, we demonstrated that polysaccharides exerted neuroprotective effects through antioxidant, anti-inflammatory and anti-apoptotic mechanisms. Furthermore, we identified that polysaccharides modulated inflammation and apoptosis partly through inhibition of NF-κB and HIF-1α expressions, respectively. Overall, we demonstrated the synergistic protective effects of polysaccharides in preserving photoreceptors against degeneration in rd10 mice. Our study provides rationale and scientific support on using polysaccharides of wolfberry as one supplementary treatment of RP patients in the future. PMID:25535040

  11. Progressive Retinal Atrophy in the Border Collie: A new XLPRA

    PubMed Central

    Vilboux, Thierry; Chaudieu, Gilles; Jeannin, Patricia; Delattre, Delphine; Hedan, Benoit; Bourgain, Catherine; Queney, Guillaume; Galibert, Francis; Thomas, Anne; André, Catherine

    2008-01-01

    Background Several forms of progressive retinal atrophy (PRA) segregate in more than 100 breeds of dog with each PRA segregating in one or a few breeds. This breed specificity may be accounted for by founder effects and genetic drift, which have reduced the genetic heterogeneity of each breed, thereby facilitating the identification of causal mutations. We report here a new form of PRA segregating in the Border Collie breed. The clinical signs, including the loss of night vision and a progressive loss of day vision, resulting in complete blindness, occur at the age of three to four years and may be detected earlier through systematic ocular fundus examination and electroretinography (ERG). Results Ophthalmic examinations performed on 487 dogs showed that affected dogs present a classical form of PRA. Of those, 274 have been sampled for DNA extraction and 87 could be connected through a large pedigree. Segregation analysis suggested an X-linked mode of transmission; therefore both XLPRA1 and XLPRA2 mutations were excluded through the genetic tests. Conclusion Having excluded these mutations, we suggest that this PRA segregating in Border Collie is a new XLPRA (XLPRA3) and propose it as a potential model for the homologous human disease, X-Linked Retinitis Pigmentosa. PMID:18315866

  12. Near-Infrared Photobiomodulation in Retinal Injury and Disease.

    PubMed

    Eells, Janis T; Gopalakrishnan, Sandeep; Valter, Krisztina

    2016-01-01

    Evidence is growing that exposure of tissue to low energy photon irradiation in the far-red (FR) to near-infrared (NIR) range of the spectrum, collectively termed "photobiomodulation" (PBM) can restore the function of damaged mitochondria, upregulate the production of cytoprotective factors and prevent apoptotic cell death. PBM has been applied clinically in the treatment of soft tissue injuries and acceleration of wound healing for more than 40 years. Recent studies have demonstrated that FR/NIR photons penetrate diseased tissues including the retina. The therapeutic effects of PBM have been hypothesized to result from intracellular signaling pathways triggered when FR/NIR photons are absorbed by the mitochondrial photoacceptor molecule, cytochrome c oxidase, culminating in improved mitochondrial energy metabolism, increased cytoprotective factor production and cell survival. Investigations in rodent models of methanol-induced ocular toxicity, light damage, retinitis pigmentosa and age-related macular degeneration have demonstrated the PBM attenuates photoreceptor cell death, protects retinal function and exerts anti-inflammatory actions. PMID:26427443

  13. Retinal pathways influence temporal niche

    PubMed Central

    Doyle, Susan E.; Yoshikawa, Tomoko; Hillson, Holly; Menaker, Michael

    2008-01-01

    In mammals, light input from the retina entrains central circadian oscillators located in the suprachiasmatic nuclei (SCN). The phase of circadian activity rhythms with respect to the external light:dark cycle is reversed in diurnal and nocturnal species, although the phase of SCN rhythms relative to the light cycle remains unchanged. Neural mechanisms downstream from the SCN are therefore believed to determine diurnality or nocturnality. Here, we report a switch from nocturnal to diurnal entrainment of circadian activity rhythms in double-knockout mice lacking the inner-retinal photopigment melanopsin (OPN4) and RPE65, a key protein used in retinal chromophore recycling. These mice retained only a small amount of rod function. The change in entrainment phase of Rpe65−/−;Opn4−/− mice was accompanied by a reversal of the rhythm of clock gene expression in the SCN and a reversal in acute masking effects of both light and darkness on activity, suggesting that the nocturnal to diurnal switch is due to a change in the neural response to light upstream from the SCN. A switch from nocturnal to diurnal activity rhythms was also found in wild-type mice transferred from standard intensity light:dark cycles to light:dark cycles in which the intensity of the light phase was reduced to scotopic levels. These results reveal a novel mechanism by which changes in retinal input can mediate acute temporal-niche switching. PMID:18695249

  14. Differential Diagnosis of Retinal Vasculitis

    PubMed Central

    Abu El-Asrar, Ahmed M.; Herbort, Carl P.; Tabbara, Khalid F.

    2009-01-01

    Retinal vaculitis is a sight-threatening inflammatory eye condition that involves the retinal vessels. Detection of retinal vasculitis is made clinically, and confirmed with the help of fundus fluorescein angiography. Active vascular disease is characterized by exudates around retinal vessels resulting in white sheathing or cuffing of the affected vessels. In this review, a practical approach to the diagnosis of retinal vasculitis is discussed based on ophthalmoscopic and fundus fluorescein angiographic findings. PMID:20404987

  15. Retinal vascular regeneration.

    PubMed

    Otani, Atsushi; Friedlander, Martin

    2005-01-01

    We discuss the potential use of stem cells for therapeutic angiogenesis in the treatment of retinal diseases. We demonstrate that the clinical utility of these EPC may be not limited in the treatment of ischemic retinal diseases but may also have application for the treatment of retinal degenerative disorders and for a form of cell-based gene therapy. One of the greatest potential benefits of bone marrow derived EPC therapy is the possible use of autologous grafts. Nonetheless, potential toxicities and unregulated cell growth will need to be carefully evaluated before this approach is brought to the clinics. PMID:15804843

  16. Modeling the response of ON and OFF retinal bipolar cells during electric stimulation

    PubMed Central

    Werginz, P.; Benav, H.; Zrenner, E.; Rattay, F.

    2015-01-01

    Retinal implants allowing blind people suffering from diseases like retinitis pigmentosa and macular degeneration to regain rudimentary vision are struggling with several obstacles. One of the main problems during external electric stimulation is the co-activation of the ON and OFF pathways which results in mutual impairment. In this study the response of ON and OFF cone retinal bipolar cells during extracellular electric stimulation from the subretinal space was examined. To gain deeper insight into the behavior of these cells sustained L-type and transient T-type calcium channels were integrated in the synaptic terminals of reconstructed 3D morphologies of ON and OFF cone bipolar cells. Intracellular calcium concentration in the synaptic regions of the model neurons was investigated as well since calcium influx is a crucial parameter for cell-to-cell activity between bipolar cells and retinal ganglion cells. It was shown that monophasic stimulation results in significant different calcium concentrations in the synaptic terminals of ON and OFF bipolar cells. Intracellular calcium increased to values up to fourfold higher in the OFF bipolar model neuron in comparison to the ON bipolar cell. Furthermore, geometric properties strongly influence the activation of bipolar cells. Monophasic, biphasic, single and repetitive pulses with similar lengths, amplitudes and polarities were applied to the two model neurons. PMID:25499837

  17. Natural Compounds from Saffron and Bear Bile Prevent Vision Loss and Retinal Degeneration.

    PubMed

    Fernández-Sánchez, Laura; Lax, Pedro; Noailles, Agustina; Angulo, Antonia; Maneu, Victoria; Cuenca, Nicolás

    2015-01-01

    All retinal disorders, regardless of their aetiology, involve the activation of oxidative stress and apoptosis pathways. The administration of neuroprotective factors is crucial in all phases of the pathology, even when vision has been completely lost. The retina is one of the most susceptible tissues to reactive oxygen species damage. On the other hand, proper development and functioning of the retina requires a precise balance between the processes of proliferation, differentiation and programmed cell death. The life-or-death decision seems to be the result of a complex balance between pro- and anti-apoptotic signals. It has been recently shown the efficacy of natural products to slow retinal degenerative process through different pathways. In this review, we assess the neuroprotective effect of two compounds used in the ancient pharmacopoeia. On one hand, it has been demonstrated that administration of the saffron constituent safranal to P23H rats, an animal model of retinitis pigmentosa, preserves photoreceptor morphology and number, the capillary network and the visual response. On the other hand, it has been shown that systemic administration of tauroursodeoxycholic acid (TUDCA), the major component of bear bile, to P23H rats preserves cone and rod structure and function, together w