Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants.

PubMed

Ungar, Rachel A; Giri, Neelam; Pao, Maryland; Khincha, Payal P; Zhou, Weiyin; Alter, Blanche P; Savage, Sharon A

2018-06-01

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease. © 2018 Wiley Periodicals, Inc.

Pneumococcal vaccine failure: can it be a primary immunodeficiency?

PubMed

Moinho, Rita; Brett, Ana; Ferreira, Gisela; Lemos, Sónia

2014-06-12

Vaccine failure is a rare condition and the need to investigate a primary immunodeficiency is controversial. We present the case of a 4-year-old boy, with complete antipneumococcal vaccination, who had necrotising pneumonia with pleural effusion and severe pancytopaenia with need for transfusion. A vaccine-serotype Streptococcus pneumoniae was isolated in the blood culture. On follow-up, detailed medical history, laboratory and genetic investigation led to the diagnosis of X linked dyskeratosis congenita. Dyskeratosis congenita is an inherited disorder that causes shortening or dysfunction of telomeres, affecting mainly rapidly dividing cells (particularly in the skin and haematopoietic system). It leads to bone marrow failure, combined immunodeficiency and predisposition to cancer. The confirmation of this diagnosis allows genetic counselling and medical monitoring of these patients, in order to detect early complications such as bone marrow aplasia or malignancies. 2014 BMJ Publishing Group Ltd.

A case report of heterozygous TINF2 gene mutation associated with pulmonary fibrosis in a patient with dyskeratosis congenita.

PubMed

Du, Hongchun; Guo, Yubiao; Ma, Di; Tang, Kejing; Cai, Decheng; Luo, Yifeng; Xie, Canmao

2018-05-01

Dyskeratosis congenita (DC) is a rare inherited disease characterized by the classical mucocutaneous triad. Pulmonary fibrosis, bone marrow failure, and solid tumors are the main causes of mortality in DC. Pathogenic variants in TERT, TERC, and DKC1 have been identified in individuals with familial pulmonary fibrosis. Mutations in TINF2 gene have been reported to be associated with bone marrow failure in most cases. However, the relationship between TINF2 mutation and pulmonary fibrosis is not yet clear. Here, we report the case of a 32-year-old woman presented with irritating cough for 2 years and progressive breathlessness for 6 months. The patient was diagnosed with DC based on the following clinical evidences. Along with some family members, she had the typical mucocutaneous triad and pulmonary fibrosis. A heterozygous mutation (c.844C>T), located in exon 6 of TINF2 gene, that changed arginine to cysteine (Arg282Cys) was identified in this proband by whole exome sequencing. The patient received corticosteroid therapy but refused to receive lung transplantation. The proband died of respiratory failure 4 months after the diagnosis. The missense mutation was located in the conserved region of TINF2 gene and predicted to be deleterious by altering the protein structure. Lung transplantation should be considered for improved survival of patients with DC, and pulmonary fibrosis. Whole exome and whole genome sequencing should be widely used in the identification of such rare genetic variants for clinical diagnosis. The study of DC with pulmonary fibrosis can provide a more appropriate means of clinical research and therapy to the unfortunate patients who suffer from this rare disorder.

Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre-RNP

PubMed Central

Trahan, Christian; Dragon, François

2009-01-01

Dyskeratosis congenita (DC) is an inherited disorder that implicates defects in the biology of telomeres, which are maintained by telomerase, a ribonucleoprotein with reverse transcriptase activity. Like all H/ACA RNAs, the H/ACA domain of nascent human telomerase RNA (hTR) forms a pre-RNP with H/ACA proteins NAF1, dyskerin, NOP10, and NHP2 in vivo. To assess the pre-RNP assembly of hTR mutants that poorly accumulate in vivo, we developed an in vitro system that uses components of human origin. Pre-RNPs were reconstituted with synthetic 32P-labeled RNAs and 35S-labeled proteins produced in rabbit reticulocyte lysate, and immunoprecipitations were carried out to analyze RNP formation. We show that human NAF1 cannot bind directly to the H/ACA domain of hTR, and requires the core trimer dyskerin-NOP10-NHP2 to be efficiently incorporated into the pre-RNP. This order of assembly seems common to H/ACA RNAs since it was observed with snoRNA ACA36 and scaRNA U92, which are predicted to guide pseudouridylation of 18S rRNA and U2 snRNA, respectively. However, the processing H/ACA snoRNA U17 did not conform to this rule, as NAF1 alone was able to bind it. We also provide the first evidence that DC-related mutations of hTR C408G and Δ378-451 severely impair pre-RNP assembly. Integrity of boxes H and ACA of hTR are also crucial for pre-RNP assembly, while the CAB box is dispensable. Our results offer new insights into the defects caused by some mutations located in the H/ACA domain of hTR. PMID:19095616

Dyskeratosis congenita--two siblings with a new missense mutation in the DKC1 gene.

PubMed

Coelho, Joana Dias; Lestre, Sara; Kay, Teresa; Lopes, Maria João Paiva; Fiadeiro, Teresa; Apetato, Margarida

2011-01-01

Dyskeratosis congenital is reported in two siblings. They presented with the classic triad of mucocutaneous features: leukoplakia of the tongue, dystrophic nails, and a widespread reticulate pigmentation on the neck and upper chest. A genetic analysis was performed and a new missense mutation S356P, hemizygous, was identified in the DKC1 gene in both patients. Acitretin was started at a low-dose in both patients, resulting in clinical improvement and important, positive psychosocial effects. © 2011 Wiley Periodicals, Inc.

The C-Terminal Extension Unique to the Long Isoform of the Shelterin Component TIN2 Enhances Its Interaction with TRF2 in a Phosphorylation- and Dyskeratosis Congenita Cluster-Dependent Fashion.

PubMed

Nelson, Nya D; Dodson, Lois M; Escudero, Laura; Sukumar, Ann T; Williams, Christopher L; Mihalek, Ivana; Baldan, Alessandro; Baird, Duncan M; Bertuch, Alison A

2018-06-15

TIN2 is central to the shelterin complex, linking the telomeric proteins TRF1 and TRF2 with TPP1/POT1. Mutations in TINF2 , which encodes TIN2, that are found in dyskeratosis congenita (DC) result in very short telomeres and cluster in a region shared by the two TIN2 isoforms, TIN2S (short) and TIN2L (long). Here we show that TIN2L, but not TIN2S, is phosphorylated. TRF2 interacts more with TIN2L than TIN2S, and both the DC cluster and phosphorylation promote this enhanced interaction. The binding of TIN2L, but not TIN2S, is affected by TRF2-F120, which is also required for TRF2's interaction with end processing factors such as Apollo. Conversely, TRF1 interacts more with TIN2S than with TIN2L. A DC-associated mutation further reduces TIN2L-TRF1, but not TIN2S-TRF1, interaction. Cells overexpressing TIN2L or phosphomimetic TIN2L are permissive to telomere elongation, whereas cells overexpressing TIN2S or phosphodead TIN2L are not. Telomere lengths are unchanged in cell lines in which TIN2L expression has been eliminated by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-mediated mutation. These results indicate that TIN2 isoforms are biochemically and functionally distinguishable and that shelterin composition could be fundamentally altered in patients with TINF2 mutations. Copyright © 2018 Nelson et al.

[Recurrent pulmonary infection and oral mucosal ulcer].

PubMed

Kuang, Fei-Mei; Tang, Lan-Lan; Zhang, Hui; Xie, Min; Yang, Ming-Hua; Yang, Liang-Chun; Yu, Yan; Cao, Li-Zhi

2017-04-01

An 8-year-old girl who had experienced intermittent cough and fever over a 3 year period, was admitted after experiencing a recurrence for one month. One year ago the patient experienced a recurrent oral mucosal ulcer. Physical examination showed vitiligo in the skin of the upper right back. Routine blood tests and immune function tests performed in other hospitals had shown normal results. Multiple lung CT scans showed pulmonary infection. The patient had recurrent fever and cough and persistent presence of some lesions after anti-infective therapy. The antitubercular therapy was ineffective. Routine blood tests after admission showed agranulocytosis. Gene detection was performed and she was diagnosed with dyskeratosis congenita caused by homozygous mutation in RTEL1. Patients with dyskeratosis congenita with RTEL1 gene mutation tend to develop pulmonary complications. Since RTEL1 gene sequence is highly variable with many mutation sites and patterns and can be inherited via autosomal dominant or recessive inheritance, this disease often has various clinical manifestations, which may lead to missed diagnosis or misdiagnosis. For children with unexplained recurrent pulmonary infection, examinations of the oral cavity, skin, and nails and toes should be taken and routine blood tests should be performed to exclude dyskeratosis congenita. There are no specific therapies for dyskeratosis congenita at present, and when bone marrow failure and pulmonary failure occur, hematopoietic stem cell transplantation and lung transplantation are the only therapies. Androgen and its derivatives are effective in some patients. Drugs targeting the telomere may be promising for patients with dyskeratosis congenita.

Genetics Home Reference: pachyonychia congenita

MedlinePlus

... CD, Eliason MJ, Smith FJ. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011 ... ME, McLean WH, Sprecher E, Smith FJ. The molecular genetic analysis of the expanding pachyonychia congenita case collection. ...

Investigation of the Genetics of Hematologic Diseases

ClinicalTrials.gov

2017-10-17

Bone Marrow Failure Syndromes; Erythrocyte Disorder; Leukocyte Disorder; Hemostasis; Blood Coagulation Disorder; Sickle Cell Disease; Dyskeratosis Congenita; Diamond-Blackfan Anemia; Congenital Thrombocytopenia; Severe Congenital Neutropenia; Fanconi Anemia

Incidental finding of cutaneous meningeal heterotopia in aplasia cutis congenita.

PubMed

Kenyon, Katharine; Zedek, Daniel; Sayed, Christopher

2016-07-01

Aplasia cutis congenita and cutaneous meningeal heterotopia are both rare congenital conditions that most commonly occur on the scalp and may appear clinically and histologically similar. A subtype of aplasia cutis congenita, membranous aplasia cutis congenita, and cutaneous meningeal heterotopia are both proposed to result from neural tube closure errors. However, neither non-membranous nor membranous aplasia cutis congenita are known to occur together with cutaneous meningeal heterotopia in the same lesion. We report the incidental finding of cutaneous meningeal heterotopia within a lesion of aplasia cutis congenita. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Exome Sequencing Links Mutations in PARN and RTEL1 with Familial Pulmonary Fibrosis and Telomere Shortening

PubMed Central

Stuart, Bridget D.; Choi, Jungmin; Zaidi, Samir; Xing, Chao; Holohan, Brody; Chen, Rui; Choi, Mihwa; Dharwadkar, Pooja; Torres, Fernando; Girod, Carlos E.; Weissler, Jonathan; Fitzgerald, John; Kershaw, Corey; Klesney-Tait, Julia; Mageto, Yolanda; Shay, Jerry W.; Ji, Weizhen; Bilguvar, Kaya; Mane, Shrikant; Lifton, Richard P.; Garcia, Christine Kim

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial pulmonary fibrosis kindreds. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no prior connection to telomere biology or disease, with five novel heterozygous damaging mutations in unrelated cases and none in controls (P-value = 1.3 × 10−8); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more novel damaging and missense variants at conserved residues in cases than controls (P = 1.6 × 10−6). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths and epigenetic inheritance of short telomeres was seen in family members. Together these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction. PMID:25848748

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.

PubMed

Stuart, Bridget D; Choi, Jungmin; Zaidi, Samir; Xing, Chao; Holohan, Brody; Chen, Rui; Choi, Mihwa; Dharwadkar, Pooja; Torres, Fernando; Girod, Carlos E; Weissler, Jonathan; Fitzgerald, John; Kershaw, Corey; Klesney-Tait, Julia; Mageto, Yolanda; Shay, Jerry W; Ji, Weizhen; Bilguvar, Kaya; Mane, Shrikant; Lifton, Richard P; Garcia, Christine Kim

2015-05-01

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis

PubMed Central

Soler, Vincent José; Tran-Viet, Khanh-Nhat; Galiacy, Stéphane D; Limviphuvadh, Vachiranee; Klemm, Thomas Patrick; St Germain, Elizabeth; Fournié, Pierre R; Guillaud, Céline; Maurer-Stroh, Sebastian; Hawthorne, Felicia; Suarez, Cyrielle; Kantelip, Bernadette; Afshari, Natalie A; Creveaux, Isabelle; Luo, Xiaoyan; Meng, Weihua; Calvas, Patrick; Cassagne, Myriam; Arné, Jean-Louis; Rozen, Steven G; Malecaze, François; Young, Terri L

2014-01-01

Background Corneal intraepithelial dyskeratosis is an extremely rare condition. The classical form, affecting Native American Haliwa-Saponi tribe members, is called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present a new form of corneal intraepithelial dyskeratosis for which we identified the causative gene by using deep sequencing technology. Methods and results A seven member Caucasian French family with two corneal intraepithelial dyskeratosis affected individuals (6-year-old proband and his mother) was ascertained. The proband presented with bilateral complete corneal opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal dyskeratosis were associated with the phenotype. Histopathology studies of cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative PCR ruled out 4q35 duplication, classically described in HBID cases. Next generation sequencing with mean coverage of 50× using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variants and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with available databases were performed. A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This was a de novo mutation in the proband’s mother, following segregation in the family, and not found in 738 control DNA samples. NLRP1 expression was determined in adult corneal epithelium. The amino acid change was found to destabilise significantly the protein structure. Conclusions We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene. The NLRP1 gene product is implicated in inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 polymorphisms are associated with various diseases. PMID:23349227

Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

ClinicalTrials.gov

2017-07-24

Thalassemia; Sickle Cell Disease; Glanzmann Thrombasthenia; Wiskott-Aldrich Syndrome; Chronic-granulomatous Disease; Severe Congenital Neutropenia; Leukocyte Adhesion Deficiency; Schwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Fanconi Anemia; Dyskeratosis-congenita; Chediak-Higashi Syndrome; Severe Aplastic Anemia

BMT Abatacept for Non-Malignant Diseases

ClinicalTrials.gov

2018-05-16

Hurler Syndrome; Fanconi Anemia; Glanzmann Thrombasthenia; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; Severe Congenital Neutropenia; Leukocyte Adhesion Deficiency; Shwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Dyskeratosis-congenita; Chediak-Higashi Syndrome; Severe Aplastic Anemia; Thalassemia Major; Hemophagocytic Lymphohistiocytosis; Sickle Cell Disease

Atrichia congenita

PubMed Central

Chouhan, Chandraprakash; Khullar, Rajeev; Rao, Pankaj; Raidas, Ramesh

2015-01-01

Atrichia congenita is a rare genodermatoses is characterized by a mutation of the human hairless (HR) gene on chromosome 8p22. There is loss of scalp hair between one to six months of age, after which no growth occurs. Eyebrow, eyelash, and body hair may also be sparse or absent; patients may have a few pubic and axillary hairs. The condition may present in isolation or along with other defects. PMID:26500870

p53 downregulates the Fanconi anaemia DNA repair pathway.

PubMed

Jaber, Sara; Toufektchan, Eléonore; Lejour, Vincent; Bardot, Boris; Toledo, Franck

2016-04-01

Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53(Δ31), a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53(Δ31/Δ31) fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53(Δ31/Δ31) fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop.

Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs.

PubMed

Machado-Pinilla, Rosario; Liger, Dominique; Leulliot, Nicolas; Meier, U Thomas

2012-10-01

The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes.

Mechanism of the AAA+ ATPases pontin and reptin in the biogenesis of H/ACA RNPs

PubMed Central

Machado-Pinilla, Rosario; Liger, Dominique; Leulliot, Nicolas; Meier, U. Thomas

2012-01-01

The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes. PMID:22923768

The H/ACA RNP assembly factor SHQ1 functions as an RNA mimic.

PubMed

Walbott, Hélène; Machado-Pinilla, Rosario; Liger, Dominique; Blaud, Magali; Réty, Stéphane; Grozdanov, Petar N; Godin, Kate; van Tilbeurgh, Herman; Varani, Gabriele; Meier, U Thomas; Leulliot, Nicolas

2011-11-15

SHQ1 is an essential assembly factor for H/ACA ribonucleoproteins (RNPs) required for ribosome biogenesis, pre-mRNA splicing, and telomere maintenance. SHQ1 binds dyskerin/NAP57, the catalytic subunit of human H/ACA RNPs, and this interaction is modulated by mutations causing X-linked dyskeratosis congenita. We report the crystal structure of the C-terminal domain of yeast SHQ1, Shq1p, and its complex with yeast dyskerin/NAP57, Cbf5p, lacking its catalytic domain. The C-terminal domain of Shq1p interacts with the RNA-binding domain of Cbf5p and, through structural mimicry, uses the RNA-protein-binding sites to achieve a specific protein-protein interface. We propose that Shq1p operates as a Cbf5p chaperone during RNP assembly by acting as an RNA placeholder, thereby preventing Cbf5p from nonspecific RNA binding before association with an H/ACA RNA and the other core RNP proteins.

The H/ACA RNP assembly factor SHQ1 functions as an RNA mimic

PubMed Central

Walbott, Hélène; Machado-Pinilla, Rosario; Liger, Dominique; Blaud, Magali; Réty, Stéphane; Grozdanov, Petar N.; Godin, Kate; van Tilbeurgh, Herman; Varani, Gabriele; Meier, U. Thomas; Leulliot, Nicolas

2011-01-01

SHQ1 is an essential assembly factor for H/ACA ribonucleoproteins (RNPs) required for ribosome biogenesis, pre-mRNA splicing, and telomere maintenance. SHQ1 binds dyskerin/NAP57, the catalytic subunit of human H/ACA RNPs, and this interaction is modulated by mutations causing X-linked dyskeratosis congenita. We report the crystal structure of the C-terminal domain of yeast SHQ1, Shq1p, and its complex with yeast dyskerin/NAP57, Cbf5p, lacking its catalytic domain. The C-terminal domain of Shq1p interacts with the RNA-binding domain of Cbf5p and, through structural mimicry, uses the RNA–protein-binding sites to achieve a specific protein–protein interface. We propose that Shq1p operates as a Cbf5p chaperone during RNP assembly by acting as an RNA placeholder, thereby preventing Cbf5p from nonspecific RNA binding before association with an H/ACA RNA and the other core RNP proteins. PMID:22085966

p53 downregulates the Fanconi anaemia DNA repair pathway

PubMed Central

Jaber, Sara; Toufektchan, Eléonore; Lejour, Vincent; Bardot, Boris; Toledo, Franck

2016-01-01

Germline mutations affecting telomere maintenance or DNA repair may, respectively, cause dyskeratosis congenita or Fanconi anaemia, two clinically related bone marrow failure syndromes. Mice expressing p53Δ31, a mutant p53 lacking the C terminus, model dyskeratosis congenita. Accordingly, the increased p53 activity in p53Δ31/Δ31 fibroblasts correlated with a decreased expression of 4 genes implicated in telomere syndromes. Here we show that these cells exhibit decreased mRNA levels for additional genes contributing to telomere metabolism, but also, surprisingly, for 12 genes mutated in Fanconi anaemia. Furthermore, p53Δ31/Δ31 fibroblasts exhibit a reduced capacity to repair DNA interstrand crosslinks, a typical feature of Fanconi anaemia cells. Importantly, the p53-dependent downregulation of Fanc genes is largely conserved in human cells. Defective DNA repair is known to activate p53, but our results indicate that, conversely, an increased p53 activity may attenuate the Fanconi anaemia DNA repair pathway, defining a positive regulatory feedback loop. PMID:27033104

Papular acantholytic dyskeratosis of the vulva associated with familial Hailey-Hailey disease.

PubMed

Yu, W Y; Ng, E; Hale, C; Hu, S; Pomeranz, M K

2016-08-01

Papular acantholytic dyskeratosis (PAD) of the vulva is a rare, chronic disorder first described in 1984. It presents in young women as white to skin-coloured smooth papules over the vulva, which are persistent but asymptomatic. Histologically, there is hyperkeratosis and focal parakeratosis with acantholytic and dyskeratotic cells forming corps ronds and grains, placing PAD within Ackerman's spectrum of focal acantholytic dyskeratoses with Hailey-Hailey disease (HHD) and Darier disease. There have been 17 previous reports of PAD of the vulva, to our knowledge. Only one demonstrated a familial pattern, and none of the cases was associated with a family history of HHD. This is the first report of PAD and HHD in a single family, suggesting that PAD and HHD lie on a spectrum of disease and are genetically linked. © 2016 British Association of Dermatologists.

Reduced Telomere Length in older Men with Premutation Alleles of the Fragile X Mental Retardation 1 Gene

PubMed Central

Jenkins, Edmund C.; Tassone, Flora; Ye, Lingling; Gu, Hong; Xi, Man; Velinov, Milen; Brown, W. Ted; Hagerman, Randi J.; Hagerman, Paul J.

2009-01-01

Reduced telomere length has recently been reported in T lymphocytes of individuals with trisomy 21 Down syndrome (DS) and dementia. Shorter telomeres also have been documented in dyskeratosis congenita, cell senescence, Alzheimer disease, and neoplastic transformation. These observations suggest that similar shortening may occur in people with fragile X-associated tremor/ataxia syndrome (FXTAS), which frequently is accompanied by dementia. To test this hypothesis, telomere length has been quantified in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5/5 individuals with FXTAS and dementia, in 2/2 individuals with FXTAS without dementia, and in 3/3 individuals with the fragile X premutation only (p values ranged from <.001 to <.05; Student’s t test), indicating that telomere shortening is associated with the premutation expansion of the FMR1 gene. The current study design allowed simultaneous comparisons among control, premutation, FXTAS, and FXTAS with dementia samples, and showed nearly equal degrees of shortening relative to controls among the three premutation sample groups. Thus, telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS. PMID:18478592

A case report of recessive myotonia congenita and early onset cognitive impairment: Is it a causal or casual link?

PubMed

Portaro, Simona; Cacciola, Alberto; Naro, Antonino; Milardi, Demetrio; Morabito, Rosa; Corallo, Francesco; Marino, Silvia; Bramanti, Alessia; Mazzon, Emanuela; Calabrò, Rocco Salvatore

2018-06-01

Myotonia congenita (MC) is a non-dystrophic myotonia inherited either in dominant (Thomsen) or recessive (Becker) form. MC is due to an abnormal functioning of skeletal muscle voltage-gated chloride channel (CLCN1), but the genotype/phenotype correlation remains unclear. A 48-year-old man, from consanguineous parents, presented with a fixed muscle weakness, muscle atrophy, and a cognitive impairment. Notably, his brother presented the same mutation but with a different phenotype, mainly involving cognitive function. The patient was submitted to cognitive assessment, needle electromyography, brain and muscle MRI, and genetic analysis. The Milan Overall Dementia Assessment showed short-term memory, verbal fluency and verbal intelligence impairment. His genetic analysis showed a recessive splice-site mutation in the CLCN1 gene (IVS19+2T>A). Muscle MRI revealed a symmetric and bilateral fat infiltration of the tensor of fascia lata, gluteus medius, and gluteus maximus muscles, associated to mild atrophy. Recessive myotonia congenita was diagnosed. Further studies should establish if and to which extent the CLCN1 mutation is responsible for this c MC phenotype, taking into account a gene-gene and /or a gene-environment.

Genetics Home Reference: nonsyndromic aplasia cutis congenita

MedlinePlus

... are some genetic conditions more common in particular ethnic groups? Genetic Changes Nonsyndromic aplasia cutis congenita can have different causes, and often the cause is unknown. Because the condition is sometimes found in multiple members of a family, it is thought to have a genetic component; ...

RTEL1: functions of a disease-associated helicase.

PubMed

Vannier, Jean-Baptiste; Sarek, Grzegorz; Boulton, Simon J

2014-07-01

DNA secondary structures that arise during DNA replication, repair, and recombination (3R) must be processed correctly to prevent genetic instability. Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles a variety of DNA secondary structures to facilitate 3R processes and to maintain telomere integrity. The past few years have witnessed the emergence of RTEL1 variants that confer increased susceptibility to high-grade glioma, astrocytomas, and glioblastomas. Mutations in RTEL1 have also been implicated in Hoyeraal-Hreidarsson syndrome, a severe form of the bone-marrow failure and cancer predisposition disorder, dyskeratosis congenita. We review these recent findings and highlight its crucial link between DNA secondary-structure metabolism and human disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sodium channel slow inactivation as a therapeutic target for myotonia congenita

PubMed Central

Novak, Kevin R; Norman, Jennifer; Mitchell, Jacob R; Pinter, Martin J; Rich, Mark M

2014-01-01

Objective Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warm-up phenomenon. Our goal was to identify the mechanism underlying warm up and to use this information to guide development of novel therapy. Methods To determine the mechanism underlying warm-up, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warm-up in a mouse model of myotonia congenita. Results Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warm-up. These data suggested enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are FDA-approved for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine’s hypoexcitability side effects. Interpretation We conclude ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita. PMID:25515836

Report of the tenth annual International Pachyonychia Congenita Consortium meeting

PubMed Central

van Steensel, Maurice A.M.; Coulombe, Pierre A.; Kaspar, Roger L.; Milstone, Leonard M.; McLean, W.H. Irwin; Roop, Dennis R.; Smith, Frances J.D.; Sprecher, Eli; Schwartz, Mary E.

2013-01-01

The International Pachyonychia Congenita Consortium (IPCC) was founded in 2004 in Park City, Utah, USA. Its goal is to find a cure for pachyonychia congenita, a rare keratinizing disorder. From February 14th–17th, 2013, the group convened in Park City for their tenth annual meeting. The 2013 meeting focused on how to best move forward with clinical trials and on learning from work in other scientific areas, with an emphasis on understanding mechanisms of pain and hyperkeratosis. Considerable time was spent on discussing the best way to move forward with development of new treatments and how to obtain or develop tools that can measure treatment outcomes in PC. PMID:24518109

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

PubMed Central

Jones, Morgan; Osawa, Gail; Regal, Joshua A.; Weinberg, Daniel N.; Taggart, James; Kocak, Hande; Friedman, Ann; Ferguson, David O.; Keegan, Catherine E.; Maillard, Ivan

2013-01-01

The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors. PMID:24316971

The Short and Long Telomere Syndromes: Paired Paradigms for Molecular Medicine

PubMed Central

Stanley, Susan E.; Armanios, Mary

2016-01-01

Summary Recent advances have defined a role for abnormally short telomeres in a broad spectrum of genetic disorders. They include rare conditions such as dyskeratosis congenita as well pulmonary fibrosis and emphysema. Now, there is new evidence that some familial cancers, such as melanoma, are caused by mutations that lengthen telomeres. Here, we examine the significance of these short and long telomere length extremes for understanding the molecular basis of age-related disease and cancer. PMID:26232116

Myotonia congenita-associated mutations in chloride channel-1 affect zebrafish body wave swimming kinematics.

PubMed

Cheng, Wei; Tian, Jing; Burgunder, Jean-Marc; Hunziker, Walter; Eng, How-Lung

2014-01-01

Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1). Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita.

Myotonia Congenita-Associated Mutations in Chloride Channel-1 Affect Zebrafish Body Wave Swimming Kinematics

PubMed Central

Cheng, Wei; Tian, Jing; Burgunder, Jean-Marc; Hunziker, Walter; Eng, How-Lung

2014-01-01

Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1). Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita. PMID:25083883

A dominantly inherited form of arthrogryposis multiplex congenita with unusual dermatoglyphics.

PubMed

Sack, G H

1978-12-01

A father and daughter with arthrogryposis multiplex congenita and similar dermatoglyphic patterns are described. No evidence was found of chromosomal abnormality, neuropathy or myopathy, and there were no other affected family members. The findings are compatible with autosomal dominant inheritance.

Earliest evidence for arthrogryposis multiplex congenita or Larsen syndrome?

PubMed

Anderson, T

1997-08-08

A sixteenth-century illustrated pamphlet from Great Britain suggests that documentary evidence may permit accurate diagnosis of pathological conditions in earlier societies. The document is of particular importance, since the presented congenital abnormalities, including cleft lip, spina bifida cystica, genu recurvatum, and talipes deformity are reported rarely in archaeological skeletal material. It is suggested that the combination of abnormalities may represent the earliest case of arthrogryposis multiplex congenita or Larsen syndrome.

Genetics Home Reference: X-linked thrombocytopenia

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked thrombocytopenia X-linked thrombocytopenia Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description X-linked thrombocytopenia is a bleeding disorder that primarily ...

The molecular genetic analysis of the expanding pachyonychia congenita case collection

PubMed Central

Wilson, NJ; O'Toole, EA; Milstone, LM; Hansen, CD; Shepherd, AA; Al-Asadi, E; Schwartz, ME; McLean, WHI; Sprecher, E; Smith, FJD

2014-01-01

Background Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Objectives To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years. Methods Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced. Results Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105. Conclusions By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families. PMID:24611874

Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal–Hreidarsson syndrome

PubMed Central

Touzot, Fabien; Callebaut, Isabelle; Soulier, Jean; Gaillard, Laetitia; Azerrad, Chantal; Durandy, Anne; Fischer, Alain; de Villartay, Jean-Pierre; Revy, Patrick

2010-01-01

Telomeres, the protein–DNA complexes at the ends of linear chromosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the β-lactamase/β-CASP family. Impaired telomere protection in humans causes dyskeratosis congenita and Hoyeraal–Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique Apollo splice variant (designated Apollo-Δ) in fibroblasts from a patient with HH syndrome. Apollo-Δ generates a dominant negative form of Apollo lacking the telomeric repeat-binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Δ hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results identify Apollo as a crucial actor in telomere maintenance in vivo, independent of its function as a general DNA repair factor. PMID:20479256

Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome.

PubMed

Touzot, Fabien; Callebaut, Isabelle; Soulier, Jean; Gaillard, Laetitia; Azerrad, Chantal; Durandy, Anne; Fischer, Alain; de Villartay, Jean-Pierre; Revy, Patrick

2010-06-01

Telomeres, the protein-DNA complexes at the ends of linear chromosomes, are protected and regulated by the shelterin molecules, the telomerase complex, and other accessory factors, among which is Apollo, a DNA repair factor of the beta-lactamase/beta-CASP family. Impaired telomere protection in humans causes dyskeratosis congenita and Hoyeraal-Hreidarsson (HH) syndrome, characterized by premature aging, bone marrow failure, and immunodeficiency. We identified a unique Apollo splice variant (designated Apollo-Delta) in fibroblasts from a patient with HH syndrome. Apollo-Delta generates a dominant negative form of Apollo lacking the telomeric repeat-binding factor homology (TRFH)-binding motif (TBM) required for interaction with the shelterin TRF2 at telomeres. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome. These results identify Apollo as a crucial actor in telomere maintenance in vivo, independent of its function as a general DNA repair factor.

Genetics Home Reference: X-linked dilated cardiomyopathy

MedlinePlus

... Twitter Home Health Conditions X-linked dilated cardiomyopathy X-linked dilated cardiomyopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked dilated cardiomyopathy is a form of heart ...

Genetics Home Reference: X-linked myotubular myopathy

MedlinePlus

... Twitter Home Health Conditions X-linked myotubular myopathy X-linked myotubular myopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked myotubular myopathy is a condition that primarily ...

Genetics Home Reference: X-linked sideroblastic anemia

MedlinePlus

... Twitter Home Health Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that ...

[RTEL1 (regulator of telomere elongation helicase 1), a DNA helicase essential for genome stability].

PubMed

Le Guen, Tangui; Jullien, Laurent; Schertzer, Mike; Lefebvre, Axelle; Kermasson, Laetitia; de Villartay, Jean-Pierre; Londoño-Vallejo, Arturo; Revy, Patrick

2013-12-01

RTEL1 (regulator of telomere length helicase 1) is a DNA helicase that has been identified more than 10 years ago. Many works since, mainly in the nematode Caenorhabditis elegans and the mouse, have highlighted its role in chromosomal stability, maintenance of telomere length, and DNA repair. Recently, four laboratories have characterized RTEL1 mutations in patients with dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson (HH) syndrome, a rare and severe variant of DC. We here summarize the current knowledge on RTEL1 and discuss the possible other functions that RTEL1 could play. © 2013 médecine/sciences – Inserm.

Mapping the x-linked lymphoproliferative syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skare, J.C.; Milunsky, A.; Byron, K.S.

1987-04-01

The X-linked lymphoproliferative syndrome is triggered by Epstein-Barr virus infection and results in fatal mononucleosis, immunodeficiency, and lymphoproliferative disorders. This study shows that the mutation responsible for X-linked lymphoproliferative syndrome is genetically linked to a restriction fragment length polymorphism detected with the DXS42 probe (from Xq24-q27). The most likely recombination frequency between the loci is 4%, and the associated logarithm of the odds is 5.26. Haplotype analysis using flanking restriction fragment length polymorphism markers indicates that the locus for X-linked lymphoproliferative syndrome is distal to probe DXS42 but proximal to probe DXS99 (from Xq26-q27). It is now possible to predictmore » which members of a family with X-linked lymphoproliferative syndrome are carrier females and to diagnose the syndrome prenatally.« less

Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Ping; Mobasher, Maral E.; Alawi, Faizan, E-mail: falawi@upenn.edu

Highlights: • Dyskerin depletion triggers cellular senescence in U2OS osteosarcoma cells. • Dyskerin-depleted cells are resistant to apoptosis induced by genotoxic stress. • Chromatin relaxation sensitizes dyskerin-depleted cells to apoptosis. - Abstract: Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However,more » the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.« less

Wong-Type Dermatomyositis Showing Porokeratosis-Like Changes (Columnar Dyskeratosis): A Case Report and Review of the Literature

PubMed Central

Umanoff, Nicole; Fisher, Ari; Carlson, J. Andrew

2015-01-01

Background Wong-type dermatomyositis (DM) exhibits simultaneous pityriasis rubra pilaris (PRP) features. Case Report A 50-year-old woman presented with a heliotrope rash, Gottron's papules, and a poikilodermic, erythematous rash in shawl distribution without evidence of muscle weakness. Despite topical corticosteroids, the eruption progressed 9 months later to include generalized hyperkeratotic follicular papules, islands of sparing, and atrophic macules with a collarette of scale suggestive of porokeratosis. Mild dysphonia was the only sign of muscle weakness. Serology showed positive ANA. Histopathology revealed interface dermatitis with dermal mucin and melanophages, irregular psoriasiform hyperplasia, alternating mounds of para- and orthokeratosis, and tiers of dyskeratotic cells (columnar dyskeratosis). Systemic corticosteroid therapy was not tolerated; acitretin diminished the hyperkeratosis. While hyperpigmentation persisted, no progression of cutaneous or muscular symptoms has occurred after 22 months of follow-up and cessation of the therapy. Overall, her course did not differ from the natural history documented in the literature review of Wong-type DM. The most similar case also exhibited pseudocornoid lamella changes. Conclusion Wong-type DM is a clinicopathologic DM-PRP hybrid that can also exhibit porokeratosis-like features best described as columnar dyskeratosis. Recognizing these types of lesions in DM is warranted in order to make an accurate assessment of their prognostic significance. PMID:27047930

Genetics Home Reference: X-linked severe combined immunodeficiency

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked SCID X-linked severe combined immunodeficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked severe combined immunodeficiency (SCID) is an inherited ...

Genetics Home Reference: X-linked chondrodysplasia punctata 1

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... Home Health Conditions X-linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked chondrodysplasia punctata 1 is a disorder of ...

Cutis Marmorata Telangiectatica Congenita Presenting as a Fetal Hemothorax.

PubMed

Mon, Rodrigo A; Mozurkewich, Ellen; Treadwell, Marjorie C; Berman, Deborah R

2018-05-23

We report a case of a fetus diagnosed at 28 weeks' gestation with a spontaneous prenatal hemothorax. Fetal intervention consisted of 2 thoracenteses with analysis of the pleural effusion. The pregnancy was further complicated by recurrence of the hemothorax, with subsequent mediastinal shift, hydrops, and nonreassuring antenatal testing requiring delivery at 31 weeks' gestation. Postnatal workup established the diagnoses of cutis marmorata telangiectatica congenita (CMTC) and pulmonary lymphangiectasia. The child is currently 4 years old and without any active medical issues or sequelae from the CMTC, pulmonary lymphangiectasia, or prenatal interventions. © 2018 S. Karger AG, Basel.

Kindler syndrome.

PubMed

Kaviarasan, P K; Prasad, P V S; Shradda; Viswanathan, P

2005-01-01

Kindler syndrome is a rare autosomal recessive disorder associated with skin fragility. It is characterized by blistering in infancy, photosensitivity and progressive poikiloderma. The syndrome involves the skin and mucous membrane with radiological changes. The genetic defect has been identified on the short arm of chromosome 20. This report describes an 18-year-old patient with classical features like blistering and photosensitivity in childhood and the subsequent development of poikiloderma. The differential diagnosis of Kindler syndrome includes diseases like Bloom syndrome, Cockayne syndrome, dyskeratosis congenita, epidermolysis bullosa, Rothmund-Thomson syndrome and xeroderma pigmentosum. Our patient had classical cutaneous features of Kindler syndrome with phimosis as a complication.

Genetics Home Reference: X-linked congenital stationary night blindness

MedlinePlus

... Health Conditions X-linked congenital stationary night blindness X-linked congenital stationary night blindness Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked congenital stationary night blindness is a disorder ...

Genetics Home Reference: X-linked lissencephaly with abnormal genitalia

MedlinePlus

... Health Conditions X-linked lissencephaly with abnormal genitalia X-linked lissencephaly with abnormal genitalia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked lissencephaly with abnormal genitalia (XLAG) is a ...

Genetics Home Reference: X-linked sideroblastic anemia and ataxia

MedlinePlus

... Health Conditions X-linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare ...

Genetics Home Reference: X-linked intellectual disability, Siderius type

MedlinePlus

... Health Conditions X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition ...

Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.

PubMed

Levy, Daniel; Neuhausen, Susan L; Hunt, Steven C; Kimura, Masayuki; Hwang, Shih-Jen; Chen, Wei; Bis, Joshua C; Fitzpatrick, Annette L; Smith, Erin; Johnson, Andrew D; Gardner, Jeffrey P; Srinivasan, Sathanur R; Schork, Nicholas; Rotter, Jerome I; Herbig, Utz; Psaty, Bruce M; Sastrasinh, Malinee; Murray, Sarah S; Vasan, Ramachandran S; Province, Michael A; Glazer, Nicole L; Lu, Xiaobin; Cao, Xiaojian; Kronmal, Richard; Mangino, Massimo; Soranzo, Nicole; Spector, Tim D; Berenson, Gerald S; Aviv, Abraham

2010-05-18

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

Genetics Home Reference: X-linked hyper IgM syndrome

MedlinePlus

... Home Health Conditions X-linked hyper IgM syndrome X-linked hyper IgM syndrome Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked hyper IgM syndrome is a condition that ...

Keratin 17 Mutations in Four Families from India with Pachyonychia Congenita

PubMed Central

Agarwala, Manoj; Salphale, Pankaj; Peter, Dincy; Wilson, Neil J; Pulimood, Susanne; Schwartz, Mary E; Smith, Frances J D

2017-01-01

Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. The main features are palmoplantar keratoderma, plantar pain, and nail dystrophy. Cysts of various types, follicular hyperkeratosis, oral leukokeratosis, hyperhidrosis, and natal teeth may also be present. Four unrelated Indian families presented with a clinical diagnosis of PC. This was confirmed by genetic testing; mutations in KRT17 were identified in all affected individuals. PMID:28794556

Genetics Home Reference: X-linked dystonia-parkinsonism

MedlinePlus

... X-linked dystonia-parkinsonism syndrome (XDP): clinical and molecular genetic analysis. Brain Pathol. 1992 Oct;2(4):287-95. Review. Citation on PubMed Kaji R, Goto S, Tamiya G, Ando S, Makino S, Lee LV. Molecular dissection and anatomical basis of dystonia: X-linked ...

Frequency and natural history of inherited bone marrow failure syndromes: the Israeli Inherited Bone Marrow Failure Registry.

PubMed

Tamary, Hannah; Nishri, Daniella; Yacobovich, Joanne; Zilber, Rama; Dgany, Orly; Krasnov, Tanya; Aviner, Shraga; Stepensky, Polina; Ravel-Vilk, Shoshana; Bitan, Menachem; Kaplinsky, Chaim; Ben Barak, Ayelet; Elhasid, Ronit; Kapelusnik, Joseph; Koren, Ariel; Levin, Carina; Attias, Dina; Laor, Ruth; Yaniv, Isaac; Rosenberg, Philip S; Alter, Blanche P

2010-08-01

Inherited bone marrow failure syndromes are rare genetic disorders characterized by bone marrow failure, congenital anomalies, and cancer predisposition. Available single disease registries provide reliable information regarding natural history, efficacy and side effects of treatments, and contribute to the discovery of the causative genes. However, these registries could not shed light on the true incidence of the various syndromes. We, therefore, established an Israeli national registry in order to investigate the relative frequency of each of these syndromes and their complications. Patients were registered by their hematologists in all 16 medical centers in Israel. We included patients with Fanconi anemia, severe congenital neutropenia, Diamond-Blackfan anemia, congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, Shwachman-Diamond syndrome, and thrombocytopenia with absent radii. One hundred and twenty-seven patients diagnosed between 1966 and 2007 were registered. Fifty-two percent were found to have Fanconi anemia, 17% severe congenital neutropenia, 14% Diamond-Blackfan anemia, 6% congenital amegakaryocytic thrombocytopenia, 5% dyskeratosis congenita, 2% Shwachman-Diamond syndrome, and 2% thrombocytopenia with absent radii. No specific diagnosis was made in only 2 patients. Of the thirty patients (24%) developing severe bone marrow failure, 80% had Fanconi anemia. Seven of 9 patients with leukemia had Fanconi anemia, as did all 6 with solid tumors. Thirty-four patients died from their disease; 25 (74%) had Fanconi anemia and 6 (17%) had severe congenital neutropenia. This is the first comprehensive population-based study evaluating the incidence and complications of the different inherited bone marrow failure syndromes. By far the most common disease was Fanconi anemia, followed by severe congenital neutropenia and Diamond-Blackfan anemia. Fanconi anemia carried the worst prognosis, with severe bone marrow failure and cancer susceptibility

Hoyeraal-Hreidarsson syndrome: magnetic resonance imaging findings.

PubMed

Kuwashima, Shigeko

2009-10-01

Hoyeraal-Hreidarsson syndrome (HH) has been defined as a severe variant of dyskeratosis congenita (DKC). We report here a case of a 6-year-old girl with HH who presented with bone marrow hypoplasia, skin pigmentation, nail dystrophy, growth retardation, and bilateral retinal hemorrhage. Brain MRI revealed cerebellar hypoplasia, hypoplasia of the corpus callosum, a small pituitary gland, a small brain stem, and focal long T2 lesions in the thalamus and brain stem. A brain computed tomography scan revealed intracranial calcification as well. To the best of our knowledge, a small pituitary gland and focal long T2 lesions in the thalamus and brain stem have never been reported as a feature of HH.

Asymptomatic myotonia congenita unmasked by severe hypothyroidism.

PubMed

Passeri, Elena; Sansone, Valeria A; Verdelli, Chiara; Mendola, Marco; Corbetta, Sabrina

2014-04-01

Myotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetics Home Reference: alpha thalassemia X-linked intellectual disability syndrome

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... thalassemia X-linked intellectual disability syndrome Alpha thalassemia X-linked intellectual disability syndrome Printable PDF Open All ... view the expand/collapse boxes. Description Alpha thalassemia X-linked intellectual disability syndrome is an inherited disorder ...

FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

PubMed

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-09-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. © 2016 WILEY PERIODICALS, INC.

FARVATX: FAmily-based Rare Variant Association Test for X-linked genes

PubMed Central

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H.; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-01-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease (COPD). Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. PMID:27325607

X-linked congenital panhypopituitarism.

PubMed

Schimke, R N; Spaulding, J J; Hollowell, J G

1971-05-01

Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

Comparative study of pagetoid dyskeratosis between acrochordons and soft fibromas.

PubMed

Piqué-Duran, Enric; Palacios-Llopis, Santiago; Moreno-Ramis, Pedro; Pérez-Cejudo, Juan A; Martínez-Martín, Ma Sol

2006-12-01

Pagetoid dyskeratosis (PD) is considered a casual finding. We can find it in some conditions, including acrochordons and soft fibromas. (1) to compare the presence of PD in soft fibromas and acrochordons and (2) to compare PD positive fibromas and PD negative fibromas. We reviewed all acrochordons and soft fibromas diagnosed in the General Hospital of Lanzarote, Spain, between January 2001 and December 2002. We assessed the presence of PD, size, acanthosis, basal pigmentation, and the presence of pseudohorn cysts. Three hundred sixty one acrochordons and 164 soft fibromas were included in this study. There were striking differences in the presence of PD, size, acanthosis, and basal pigmentation between both entities. PD positive fibromas predominated in axillas. There were no other differences between PD positive fibromas and PD negative fibromas. Although soft fibromas and acrochordons are actually fibroepithelial polyps, including the presence of PD, there are striking differences between them. Thus, both conditions have to be considered as different entities. PD could be related to friction and moisture. PD has to be distinguished from other conditions such as Paget's disease, pagetoid melanoma, koilocytes, clear cell papulosis, among others.

Phenotype-genotype correlations in X linked retinitis pigmentosa.

PubMed Central

Kaplan, J; Pelet, A; Martin, C; Delrieu, O; Aymé, S; Bonneau, D; Briard, M L; Hanauer, A; Larget-Piet, L; Lefrançois, P

1992-01-01

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0). Images PMID:1357178

Sex-specific silencing of X-linked genes by Xist RNA

PubMed Central

Gayen, Srimonta; Maclary, Emily; Hinten, Michael; Kalantry, Sundeep

2016-01-01

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of XΔTsixY male cells displayed ectopic Xist RNA coating compared with XΔTsixX female cells. This increase reflected the inability of XΔTsixY cells to efficiently silence X-linked genes compared with XΔTsixX cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in XΔTsixX female cells relative to XΔTsixY male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating XΔTsixY and 39,XΔTsix (XΔTsixO) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because XΔTsixX female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active XΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing. PMID:26739568

Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay

PubMed Central

Carlson, Jenna C.; Karacz, Chelsea M.; Schwartz, Mary E.; Cross, Michael A.; Marazita, Mary L.

2018-01-01

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita. PMID:29357356

Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.

PubMed

Duverger, Olivier; Carlson, Jenna C; Karacz, Chelsea M; Schwartz, Mary E; Cross, Michael A; Marazita, Mary L; Shaffer, John R; Morasso, Maria I

2018-01-01

Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.

The role of diclofenack on inducing of aplasia cutis congenita: a case report.

PubMed

Pajaziti, Laura; Rexhepi, Syzana; Shatri-Muça, Ylfete; Ferizi, Mybera

2009-10-12

Aplasia cutis congenita is a disorder where e newborn child is missing skin from certain areas. It is a rare condition with no particular race or sex more at risk. May occur by itself or be associated with other physical syndromes or disorders. A classification system exists for aplasia cutis congenital consisting of 9 groups, based on the number and location of the skin defects and the presence or absence of other malformations. Causes of aplasia congenital could be heredity, teratogenic substances, placental infarcts, intrauterine infections, ectodermal dysplasias etc. Diagnosis is made based on the clinical findings. Prognosis depends of the other organs malfunction level and lesions size. Our case was an 22 months old Albanian girl, who was recommended to dermatology for a consultation by a pediatric surgeon because of the changes she had on her parietal part of the scalp with missing hair areas. The child has stenosis congenita ani and to her was installed stoma. In order to investigate other accompanied anomalies of the disease, there are made specific consults by neurologist, orthopedist, cardiologist, nephrologists and citogenetics. It was found out a minor visual discoordination, Sy Floppy, Digiti V superductus pedis bill. Laxitas articularum generalisata. It was a great challenge for us to find out that during the first trimester of the pregnancy (unplanned pregnancy), her mother used Diclofenac. Since there is limited information regarding to teratogenic effects of diclofenac, we considered it interesting to present this case.

The role of diclofenack on inducing of aplasia cutis congenita: a case report

PubMed Central

2009-01-01

Background Aplasia cutis congenita is a disorder where e newborn child is missing skin from certain areas. It is a rare condition with no particular race or sex more at risk. May occur by itself or be associated with other physical syndromes or disorders. A classification system exists for aplasia cutis congenital consisting of 9 groups, based on the number and location of the skin defects and the presence or absence of other malformations. Causes of aplasia congenital could be heredity, teratogenic substances, placental infarcts, intrauterine infections, ectodermal dysplasias etc. Diagnosis is made based on the clinical findings. Prognosis depends of the other organs malfunction level and lesions size. Case report Our case was an 22 months old Albanian girl, who was recommended to dermatology for a consultation by a pediatric surgeon because of the changes she had on her parietal part of the scalp with missing hair areas. The child has stenosis congenita ani and to her was installed stoma. In order to investigate other accompanied anomalies of the disease, there are made specific consults by neurologist, orthopedist, cardiologist, nephrologists and citogenetics. Conclusion It was found out a minor visual discoordination, Sy Floppy, Digiti V superductus pedis bill. Laxitas articularum generalisata. It was a great challenge for us to find out that during the first trimester of the pregnancy (unplanned pregnancy), her mother used Diclofenac. Since there is limited information regarding to teratogenic effects of diclofenac, we considered it interesting to present this case. PMID:19946521

Dental and craniofacial findings in eight miniature schnauzer dogs affected by myotonia congenita: preliminary results.

PubMed

Gracis, M; Keith, D; Vite, C H

2000-09-01

Myotonia is a clinical sign characterized by the delay of skeletal muscle relaxation following the cessation of a voluntary activity or the termination of an electrical or mechanical stimulus. Recently, Miniature Schnauzers with myotonia congenita associated with defective chloride ion conductance across the skeletal muscle membrane were identified. Congenital myotonia in these dogs appears to follow an autosomal recessive mode of inheritance. Craniofacial and dental findings of eight Miniature Schnauzer dogs with myotonia congenita are described in the present paper. These findings include: delayed dental eruption of both deciduous and permanent dentition: persistent deciduous dentition; unerupted or partially erupted permanent teeth: crowding and rotation of premolar and or incisor teeth: missing teeth: increased interproximal space between the maxillary fourth premolar and first molar teeth: decreased interproximal space between the maxillary canine and lateral incisor teeth: inability to fully close the mouth due to malocclusion: distoclusion: and, decreased mandibular range of motion. A long narrow skull with a flattened zygomatic arch and greater mandibular body curvature were also consistent findings in the affected dogs. The small number of dogs studied prevents conclusive statements about the origin of these abnormalities, however it is interesting that only 1 of 45 unaffected Miniature Schnauzer dogs showed similar traits.

[Aplasia cutis congenita associated with epidermolysis bullosa].

PubMed

Muñoz-Guerrero, Félix; Muñoz-Solís, Adrián Antonio; Ornelas-Aguirre, José Manuel

2017-12-01

Aplasia cutis congenita (ACC) is a skin condition of rare presentation, this disease is characterized by absence of skin at birth and associated with facial, skin and bone skull deformities. The diagnosis is mainly clinical. Male 5 days after birth, unique product of primigravida mother and no family history of relevance. Physical examination revealed bilateral and symmetrical skin defects of both lower extremities, the disease is characterized by skin fragility, scabs, and coated pseudomembrane ulcers, decreased interdigital space between toes of the left foot, retraction of the foot and genu varum. It was handled with allograft of epidermis cultured in vitro, general wound care and clinical follow-up. ACC associated with epidermolysis bullosa is one of the rarer forms of presentation. It is necessary to rule out other skin diseases. Clinical management is recommended with biological or synthetic skin cover, infection prevention, early treatment of complications and clinical follow. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes

PubMed Central

Krasovec, Marc; Filatov, Dmitry A.

2018-01-01

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (πx = 0.016; πaut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex. PMID:29751495

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

PubMed

Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

2018-05-03

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

Botulinum toxin in myotonia congenita: it does not help against rigidity and pain.

PubMed

Dressler, Dirk; Adib Saberi, Fereshte

2014-05-01

Botulinum toxin (BT) is a potent local muscle relaxant with analgetic properties. Myotonia congenita (MC) is a genetic disorder producing muscle rigidity and pain. BT injected into the trapezius produced mild paresis, but no effect on rigidity and pain. There were no signs of systemic effects. Lack of BT efficacy on MC rigidity confirms its origin from muscle membrane dysfunction rather than from inappropriate neuromuscular activation. Lack of BT efficacy on pain could be caused by lack of anti-rigidity effect. It could also be due to separate non-muscular pain mechanisms unresponsive to BT.

Macular hole in juvenile X-linked retinoschisis.

PubMed

Al-Swaina, Nayef; Nowilaty, Sawsan R

2013-10-01

An 18 year-old male with no antecedent of trauma, systemic syndrome or myopia was referred for surgical treatment of a full thickness macular hole in the left eye. A more careful inspection revealed discrete foveal cystic changes in the fellow eye and subtle peripheral depigmented retinal pigment epithelial changes in both eyes. A spectral-domain optical coherence tomography (SD-OCT) scan confirmed, in addition to the full thickness macular hole in the left eye, microcystic spaces in the nuclear layers of both retinae. The diagnosis of X-linked retinoschisis was confirmed with a full field electroretinogram displaying the typical negative ERG. Macular holes are uncommon in the young and those complicating X-linked retinoschisis are rare. This report highlights the importance of investigating the presence of a macular hole in a young patient and illustrates the clinical and SD-OCT clues beyond the foveal center which led to the correct diagnosis of X-linked juvenile retinoschisis.

X-linked dominant retinitis pigmentosa in an American family

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 distinctmore » 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.« less

Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia.

PubMed

Baum, Michel; Syal, Ashu; Quigley, Raymond; Seikaly, Mouin

2006-08-01

X-linked hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-linked hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-linked hypophosphatemia is unknown.

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets.

PubMed

Sharkey, Melinda S; Grunseich, Karl; Carpenter, Thomas O

2015-07-01

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Genetics Home Reference: immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MedlinePlus

... Health Conditions IPEX syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome Printable PDF Open All Close All ... expand/collapse boxes. Description Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome primarily affects males and is ...

X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.

PubMed

Christie, P T; Harding, B; Nesbit, M A; Whyte, M P; Thakker, R V

2001-08-01

X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.

Familial Investigations of Childhood Cancer Predisposition

ClinicalTrials.gov

2018-01-03

Acute Leukemia; Adenomatous Polyposis; Adrenocortical Carcinoma; AML; BAP1 Tumor Predisposition Syndrome; Carney Complex; Choroid Plexus Carcinoma; Constitutional Mismatch Repair Deficiency Syndrome; Diamond-Blackfan Anemia; DICER1 Syndrome; Dyskeratosis Congenita; Emberger Syndrome; Familial Acute Myeloid Leukemia; Familial Adenomatous Polyposis; Fanconi Anemia; Familial Cancer; Familial Wilms Tumor; Familial Neuroblastoma; GIST; Hereditary Breast and Ovarian Cancer; Hereditary Paraganglioma-Pheochromocytoma Syndrome; Hodgkin Lymphoma; Juvenile Polyposis; Li-Fraumeni Syndrome; Lynch Syndrome; MDS; Melanoma Syndrome; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Neuroblastoma; Neurofibromatosis Type 1; Neurofibromatosis Type II; Nevoid Basal Cell Carcinoma Syndrome; Non Hodgkin Lymphoma; Noonan Syndrome and Other Rasopathy; Overgrowth Syndromes; Pancreatic Cancer; Peutz-Jeghers Syndrome; Pheochromocytoma/Paraganglioma; PTEN Hamartoma Tumor Syndrome; Retinoblastoma; Rhabdoid Tumor Predisposition Syndrome; Rhabdomyosarcoma; Rothmund-Thomson Syndrome; Tuberous Sclerosis; Von Hippel-Lindau Disease

A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish

NASA Astrophysics Data System (ADS)

Alcaraz-Pérez, Francisca; García-Castillo, Jesús; García-Moreno, Diana; López-Muñoz, Azucena; Anchelin, Monique; Angosto, Diego; Zon, Leonard I.; Mulero, Victoriano; Cayuela, María L.

2014-02-01

Dyskeratosis congenita (DC) is an inherited disorder with mutations affecting telomerase or telomeric proteins. DC patients usually die of bone marrow failure. Here we show that genetic depletion of the telomerase RNA component (TR) in the zebrafish results in impaired myelopoiesis, despite normal development of haematopoietic stem cells (HSCs). The neutropenia caused by TR depletion is independent of telomere length and telomerase activity. Genetic analysis shows that TR modulates the myeloid-erythroid fate decision by controlling the levels of the master myeloid and erythroid transcription factors spi1 and gata1, respectively. The alteration in spi1 and gata1 levels occurs through stimulation of gcsf and mcsf. Our model of TR deficiency in the zebrafish illuminates the non-canonical roles of TR, and could establish therapeutic targets for DC.

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

PubMed

Weinhofer, Isabelle; Zierfuss, Bettina; Hametner, Simon; Wagner, Magdalena; Popitsch, Niko; Machacek, Christian; Bartolini, Barbara; Zlabinger, Gerhard; Ohradanova-Repic, Anna; Stockinger, Hannes; Köhler, Wolfgang; Höftberger, Romana; Regelsberger, Günther; Forss-Petter, Sonja; Lassmann, Hans; Berger, Johannes

2018-05-30

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses

Genetics Home Reference: X-linked spondyloepiphyseal dysplasia tarda

MedlinePlus

... Educational Resources (6 links) Cincinnati Children's Hospital: Coxa Vera Disease InfoSearch: Spondyloepiphyseal dysplasia tarda X-linked Johns ... Free article on PubMed Central Savarirayan R, Thompson E, Gécz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). ...

Atypical amyoplasia congenita in an infant with Leigh syndrome: a mitochondrial cause of severe contractures?

PubMed

Wilnai, Yael; Seaver, Laurie H; Enns, Gregory M

2012-09-01

Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present. Copyright © 2012 Wiley Periodicals, Inc.

siRNAs from an X-linked satellite repeat promote X-chromosome recognition in Drosophila melanogaster.

PubMed

Menon, Debashish U; Coarfa, Cristian; Xiao, Weimin; Gunaratne, Preethi H; Meller, Victoria H

2014-11-18

Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male- specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm(3) satellite related repeats (1.688(X) repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of single-stranded RNAs from 1.688(X) repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688(X) repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688(X) repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin.

Genetics Home Reference: X-linked agammaglobulinemia

MedlinePlus

... Sep;104(3):221-30. Citation on PubMed Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr ... Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

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

Molecular and clinical studies of X-linked deafness among Pakistani families.

PubMed

Waryah, Ali M; Ahmed, Zubair M; Bhinder, Munir A; Binder, Munir A; Choo, Daniel I; Sisk, Robert A; Shahzad, Mohsin; Khan, Shaheen N; Friedman, Thomas B; Riazuddin, Sheikh; Riazuddin, Saima

2011-07-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis.

Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families

PubMed Central

Waryah, Ali M.; Ahmed, Zubair M.; Choo, Daniel I.; Sisk, Robert A.; Binder, Munir A.; Shahzad, Mohsin; Khan, Shaheen N.; Friedman, Thomas B.; Riazuddin, Sheikh; Riazuddin, Saima

2011-01-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132, PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild to profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and molecular epidemiology of hearing loss among Pakistanis. PMID:21633365

X linked mental retardation: a clinical guide.

PubMed

Raymond, F L

2006-03-01

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.

A Simulation of X-Linked Inheritance.

ERIC Educational Resources Information Center

Harrell, Pamela Esprivalo

1997-01-01

Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

PubMed Central

Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R.

2015-01-01

Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. PMID:26395485

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

PubMed

Ballew, Bari J; Joseph, Vijai; De, Saurav; Sarek, Grzegorz; Vannier, Jean-Baptiste; Stracker, Travis; Schrader, Kasmintan A; Small, Trudy N; O'Reilly, Richard; Manschreck, Chris; Harlan Fleischut, Megan M; Zhang, Liying; Sullivan, John; Stratton, Kelly; Yeager, Meredith; Jacobs, Kevin; Giri, Neelam; Alter, Blanche P; Boland, Joseph; Burdett, Laurie; Offit, Kenneth; Boulton, Simon J; Savage, Sharon A; Petrini, John H J

2013-08-01

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

A Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome

PubMed Central

Ballew, Bari J.; Joseph, Vijai; De, Saurav; Sarek, Grzegorz; Vannier, Jean-Baptiste; Stracker, Travis; Schrader, Kasmintan A.; Small, Trudy N.; O'Reilly, Richard; Manschreck, Chris; Harlan Fleischut, Megan M.; Zhang, Liying; Sullivan, John; Stratton, Kelly; Yeager, Meredith; Jacobs, Kevin; Giri, Neelam; Alter, Blanche P.; Boland, Joseph; Burdett, Laurie; Offit, Kenneth; Boulton, Simon J.

2013-01-01

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1. PMID:24009516

Chloride channels in myotonia congenita assessed by velocity recovery cycles.

PubMed

Tan, S Veronica; Z'Graggen, Werner J; Boërio, Delphine; Rayan, Dipa Raja; Norwood, Fiona; Ruddy, Deborah; Howard, R; Hanna, Michael G; Bostock, Hugh

2014-06-01

Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected. MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls. MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation. MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve. Copyright © 2013 Wiley Periodicals, Inc.

Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco.

PubMed

Mostefai, Rahima; Morice-Picard, Fanny; Boralevi, Franck; Sautarel, Michel; Lacombe, Didier; Stasia, Marie José; McGrath, John; Taïeb, Alain

2008-11-01

Three siblings from Morocco consanguineous family presented with cutaneous poikiloderma following postnatal ichthyosiform lesions, associated with papillomatous lesions, palmoplantar keratoderma, pachyonychia of toenails, fragile carious teeth, and lachrymal duct obstruction. Photosensitivity and blistering improved with age. Atrophic scars were prominent on the limbs. Neutropenia developed in the first year secondary to dysmyelopoiesis affecting the granulocyte lineage, associated with a polyclonal hypergammaglobulinemia. Several broncho-pulmonary infectious episodes complicated the evolution, and cystic fibrosis was first considered on the basis of repeated abnormal sweat chloride tests but not confirmed by molecular analyses. This autosomal recessive disorder matches that described originally as poikiloderma with neutropenia-Clericuzio type in Navajo Indians (OMIM 604173). It is discussed within the group of the major hereditary poikiloderma disorders, that is, Rothmund-Thomson syndrome, dyskeratosis congenita, and Kindler syndrome. Copyright 2008 Wiley-Liss, Inc.

The C-terminal extension of human RTEL1, mutated in Hoyeraal-Hreidarsson syndrome, contains harmonin-N-like domains.

PubMed

Faure, Guilhem; Revy, Patrick; Schertzer, Michael; Londono-Vallejo, Arturo; Callebaut, Isabelle

2014-06-01

Several studies have recently shown that germline mutations in RTEL1, an essential DNA helicase involved in telomere regulation and DNA repair, cause Hoyeraal-Hreidarsson syndrome (HHS), a severe form of dyskeratosis congenita. Using original new softwares, facilitating the delineation of the different domains of the protein and the identification of remote relationships for orphan domains, we outline here that the C-terminal extension of RTEL1, downstream of its catalytic domain and including several HHS-associated mutations, contains a yet unidentified tandem of harmonin-N-like domains, which may serve as a hub for partner interaction. This finding highlights the potential critical role of this region for the function of RTEL1 and gives insights into the impact that the identified mutations would have on the structure and function of these domains. © 2013 Wiley Periodicals, Inc.

Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease.

PubMed

Horn, Morten A; Erichsen, Martina M; Wolff, Anette S B; Månsson, Jan-Eric; Husebye, Eystein S; Tallaksen, Chantal M E; Skjeldal, Ola H

2013-09-01

X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. © 2013 John Wiley & Sons Ltd.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

PubMed

Wu, An-Lun; Wang, Jung-Pan; Tseng, Yun-Ju; Liu, Laura; Kang, Yu-Chuan; Chen, Kuan-Jen; Chao, An-Ning; Yeh, Lung-Kun; Chen, Tun-Lu; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun; Wang, Nan-Kai

2018-05-01

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

Genetics Home Reference: X-linked lymphoproliferative disease

MedlinePlus

... infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... severe susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome XLP Related Information How ...

Interbrachial Pinch by Trapezius Transfer in Amyoplasia Congenita: A Case Report

PubMed Central

Thione, Alessandro; Cavadas, Pedro C.; Rubi, Carlo G.

2017-01-01

Summary: Amyoplasia congenita, or “classic distal arthrogryposis,” is the most common disorder among the congenital, non-progressive, multiple joint contractural conditions named arthrogryposis. The cause remains unknown, and it occurs sporadically. Abnormal neurological examination indicates that movement in utero was diminished as a result of an abnormality of the central or peripheral nervous system, the motor end plate, or muscle. The absence of central neural pathology indicates the origin in akinetic fetal condition. Three weeks are enough to cause muscle weakness and joint fibrosis. Joint contractures in amyoplasia are often rigid and refractory to nonoperative treatment such as passive stretching. Surgery is focused on each patient's need respecting adaptive maneuvers to accomplish daily tasks. We present a case in which pectoral major muscle had no strength for pinching; a trapezius muscle transfer was planned to obtain an interbrachial pinch useful for grasping. PMID:28607845

X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria

PubMed Central

Brancaleoni, V.; Balwani, M.; Granata, F.; Graziadei, G.; Missineo, P.; Fiorentino, V.; Fustinoni, S.; Cappellini, M.D.; Naik, H.; Desnick, R.J.; Di Pierro, E.

2015-01-01

X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

Linkage localization of X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Trofatter, J.; Haines, J.L.

1993-02-01

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived frommore » work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.« less

X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pegoraro, E.; Hoffman, E.P.; Carelli, V.

1996-02-02

Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model ofmore » mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.« less

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility.

PubMed

Lu, Xuemei; Shapiro, Joshua A; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-08-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

[No X-chromosome linked juvenile foveal retinoschisis].

PubMed

Pérez Alvarez, M J; Clement Fernández, F

2002-08-01

To describe the clinical characteristics of two cases of juvenile foveal retinoschisis in women with an atypical hereditary pattern, no X-chromosome linked. An autosomal recessive inheritance is proposed. Two generations of a family (5 members) in which only two sisters were evaluated. The complete examination of these two cases includes retinography, fluorescein angiography, automated perimetry, color vision testing, electroretinogram, electrooculogram and visually evoked potentials. Comparing our cases with the classic form of X-linked juvenile retinoschisis, they are less severely affected. The best visual acuity and the less disturbed or even normal electroretinogram confirm this fact. We emphasise the existence of isolated plaques of retinal pigment epithelium atrophy with perivascular pigment clumps without foveal schisis in one patient, which could represent an evolved form of this entity. The hereditary foveal juvenile retinoschisis in women suggests an autosomal inheritance (autosomal recessive in our cases) and presents less severe involvement (Arch Soc Esp Oftalmol 2002; 77: 443-448).

Unraveling the Pathogenesis of Hoyeraal-Hreidarsson Syndrome, a Complex Telomere Biology Disorder

PubMed Central

Glousker, Galina; Touzot, Fabien; Revy, Patrick; Tzfati, Yehuda; Savage, Sharon A.

2015-01-01

SUMMARY Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita (DC). The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease. PMID:25940403

Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

PubMed

Le Guen, Tangui; Jullien, Laurent; Touzot, Fabien; Schertzer, Michael; Gaillard, Laetitia; Perderiset, Mylène; Carpentier, Wassila; Nitschke, Patrick; Picard, Capucine; Couillault, Gérard; Soulier, Jean; Fischer, Alain; Callebaut, Isabelle; Jabado, Nada; Londono-Vallejo, Arturo; de Villartay, Jean-Pierre; Revy, Patrick

2013-08-15

Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

The Role of Nuclear Receptor Coactivators in Recurrent Prostate Cancer

DTIC Science & Technology

2006-02-01

hyp- oplasia congenita and hypogonadotropic hypogonadism (34). From an evolutionary perspective, the AR AF2 region of the ligand binding domain is more...linked adrenal hypoplasia congenita and hypogo- nadotropic hypogonadism . Nature 372:672–676. 35. Muscatelli, F., A. P. Walker, E. De Plaen, A. N

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility

PubMed Central

Lu, Xuemei; Shapiro, Joshua A.; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J.; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-01-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible. PMID:20511493

Genetics Home Reference: X-linked cardiac valvular dysplasia

MedlinePlus

... inflammation of the inner lining of the heart (endocarditis), abnormal blood clots, or sudden death. X-linked ... Johns Hopkins Medicine: Mitral Valve Prolapse MedlinePlus Encyclopedia: Endocarditis MedlinePlus Encyclopedia: Mitral Valve Prolapse General Information from ...

Clinical and genetic features in autosomal recessive and X-linked Alport syndrome.

PubMed

Wang, Yanyan; Sivakumar, Vanessa; Mohammad, Mardhiah; Colville, Deb; Storey, Helen; Flinter, Frances; Dagher, Hayat; Savige, Judy

2014-03-01

This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport syndrome. All patients had the diagnosis of Alport syndrome and the mode of inheritance confirmed by genetic testing, and underwent examination at a single centre. Patients comprised 9 males and 6 females with autosomal recessive Alport syndrome, and 18 males and 22 females with X-linked disease. Fourteen (93 %) individuals with autosomal recessive Alport syndrome developed early end-stage renal failure, all 15 had hearing loss, and most had lenticonus (12, 80 %), and a central (13, 87 %) or peripheral (13, 87 %) retinopathy. These features occurred as often as in males with X-linked disease. Females with autosomal recessive inheritance were less likely to have an affected family member in another generation (p = 0.01) than females with X-linked disease. They were more likely to have renal failure (p = 0.003), hearing loss (p = 0.02) and lenticonus (p < 0.001). Fifty percent had a central retinopathy compared with 18 % with X-linked disease (p = 0.14), but peripheral retinopathy prevalence was not different (p = 0.64). Nonsense mutations accounted for 67 % (8/12) of these disease-causing mutations. Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy.

X-linked mental retardation associated with macro-orchidism.

PubMed Central

Turner, G; Eastman, C; Casey, J; McLeay, A; Procopis, P; Turner, B

1975-01-01

Two families are described with an X-linked form of mental retardation in whom the affected males were found to have bilateral enlargement of the testes. No conclusive evidence of any endocrinological disturbance was found. Images PMID:1240971

Editorial: X-chromosome-linked Kallmann's syndrome: Pathology at the molecular level

DOE Office of Scientific and Technical Information (OSTI.GOV)

Prager, D.; Braunstein, G.D.

Kallmann's syndrome or olfactogenital dysplasia refers to a disorder characterized by hypogonadotropic hypogonadism and anosmia or hyposmia which can occur sporadically or in a familial setting. Originally described in 1856, the first familial cases were reported by Kallmann et al., in 1944. Based on segregation analysis of multiple families, three modes of transmission have been documented: X-linked, autosomal dominant with variable penetrance, and autosomal recessive. Kallmann's syndrome occurs in less than 1 in 10,000 male births, with a 5-fold excess of affected males to females, suggesting that the X-linked form is the most frequent. By genetic linkage analysis the X-linkedmore » form of Kallmann's syndrome was localized to Xp22.3. This was confirmed by the description of patients with contiguous gene syndromes due to deletions of various portions of the distal short arm of the X-chromosome. Such patients present with complex phenotypes characterized by a combination of Kallmann's syndrome with X-linked icthyosis due to steroid sulfatase deficiency, chondrodysplasia punctata, short stature, and mental retardation. DNA analysis has identified and mapped the genes responsible for these disorders. 10 refs., 1 fig., 1 tab.« less

ZC4H2 Mutations Are Associated with Arthrogryposis Multiplex Congenita and Intellectual Disability through Impairment of Central and Peripheral Synaptic Plasticity

PubMed Central

Hirata, Hiromi; Nanda, Indrajit; van Riesen, Anne; McMichael, Gai; Hu, Hao; Hambrock, Melanie; Papon, Marie-Amélie; Fischer, Ute; Marouillat, Sylviane; Ding, Can; Alirol, Servane; Bienek, Melanie; Preisler-Adams, Sabine; Grimme, Astrid; Seelow, Dominik; Webster, Richard; Haan, Eric; MacLennan, Alastair; Stenzel, Werner; Yap, Tzu Ying; Gardner, Alison; Nguyen, Lam Son; Shaw, Marie; Lebrun, Nicolas; Haas, Stefan A.; Kress, Wolfram; Haaf, Thomas; Schellenberger, Elke; Chelly, Jamel; Viot, Géraldine; Shaffer, Lisa G.; Rosenfeld, Jill A.; Kramer, Nancy; Falk, Rena; El-Khechen, Dima; Escobar, Luis F.; Hennekam, Raoul; Wieacker, Peter; Hübner, Christoph; Ropers, Hans-Hilger; Gecz, Jozef; Schuelke, Markus; Laumonnier, Frédéric; Kalscheuer, Vera M.

2013-01-01

Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC. PMID:23623388

The multifocal electroretinogram in X-linked juvenile retinoschisis.

PubMed

Huang, Shizhou; Wu, Dezheng; Jiang, Futian; Luo, Guangwei; Liang, Jiongji; Wen, Feng; Yu, Minzhong; Long, Shixian; Wu, Lezheng

2003-05-01

To measure and compare the multifocal electroretinography in normal control and X-linked juvenile retinoschisis, 13 cases (13 right eyes) of normal control and nine cases (17 eyes) of X-linked juvenile retinoschisis were measured with VERIS Science 4.0. Four cases (eight eyes) out of the nine retinoschisis cases were tested with Ganzfeld ERG at the same day. The results showed statistically significant difference of average response densities and latencies in six ring retinal regions between the normal control and retinoschisis. The trace array and 3-D topography of multifocal ERG showed multi-area amplitude decrease with absence or reduction of central peak amplitude in patients with retinoschisis. The P1/N1 ratio of multifocal ERG average response densities in six ring retinal regions was different from the b/a ratio of Ganzfeld ERG. The multifocal ERG and Ganzfeld ERG each had its advantage in the diagnosis of retinoschisis.

Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita.

PubMed

Nishio, Nobuhiro; Takahashi, Yoshiyuki; Ohashi, Haruhiko; Doisaki, Sayoko; Muramatsu, Hideki; Hama, Asahito; Shimada, Akira; Yagasaki, Hiroshi; Kojima, Seiji

2011-03-01

DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen. © 2010 John Wiley & Sons A/S.

Spondyloepiphseal dysplasia congenita in siblings born to unaffected parents: ? germ line mosaicism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mulla, W.; McDonald-McGinn, D.; Zackai, E.

1994-09-01

Germ line mosaicism has been used to explain the birth of more than one child affected with a dominantly inherited disorder born to unaffected parents. Furthermore, it has been confirmed clinically in families where recurrence in siblings was originally thought to be autosomal recessive, but were affected individuals have reproduced affected offspring. Firm evidence of germ line mosaicism using mutation analysis by molecular methods exists for some autosomal disorders. We present two siblings with spondyloepipheseal dysplasia congenita (SEDC) born to unaffected parents. This suggests the presence of germ line mosaicism in this entity. Patient 1 was born at 32 weeksmore » gestation to a G1P1 Puerto Rican mother. The pregnancy was complicated by polyhydramnios. The neonate, a short-limbed dwarf, died at 15 hours of age from respiratory distress and a compromised thoracic cavity. Patient 2, the sibling of patient 1 was born at 37 weeks gestation after a pregnancy complicated by polyhydramnios and prenatal ultrasound diagnosis of short-limbed dwarfism. The diagnosis of SEDC was made and, after review of the sibling`s postmortem X-rays, it was felt that she was similarly affected. The family history reveals no history of dwarfism or consanguinity. The SEDC is described as an autosomal dominant form of dwarfism with variable presentation including some cases that have been lethal in the neonatal period. SEDC is now believed to represent a family of collagen II mutations. Sporadic cases that have arisen in families with no history have been ascribed to new heterozygous mutations. Other families in which SEDC and SEMD recurred without a family history most likely represent germ line mosaicism. In these cases molecular studies should be pursued to document a collagen II mutation. We believe that germ line mosaicism is the most plausible explanation for recurrence in our family.« less

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family

PubMed Central

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-01

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children. PMID:26823236

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family.

PubMed

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursey, Terry G; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-29

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers.

PubMed

Lourenço, Charles Marques; Simão, Gustavo Novelino; Santos, Antonio Carlos; Marques, Wilson

2012-07-01

X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia.

PubMed

Kasper, Burkhard S; Kurzbuch, Katrin; Chang, Bernard S; Pauli, Elisabeth; Hamer, Hajo M; Winkler, Jürgen; Hehr, Ute

2013-06-01

Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH. Copyright © 2013 Wiley Periodicals, Inc.

Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population.

PubMed

Fedick, A M; Shi, L; Jalas, C; Treff, N R; Ekstein, J; Kornreich, R; Edelmann, L; Mehta, L; Savage, S A

2015-08-01

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Neovascular glaucoma in a patient with X-linked juvenile retinoschisis.

PubMed

Zuo, Chengguo; Chen, Changzheng; Xing, Yiqiao; Du, Lei

2005-09-01

To report the rubeosis iridis and neovascular glaucoma findings in one patient of X-linked juvenile retinoschisis(XLRS). Color fundus photography, fluorescein angiography (FFA), OCT and B-scan were performed in a patient with X-linked juvenile retinoschisis complicated with neovascular glaucoma. Color fundus photography, fluorescein angiography (FFA), OCT and B-scan unveiled a rare condition of XLRS complicated with neovascular glaucoma. XLRS may complicate with neovascular glaucoma. It is necessary to test OCT, FFA, ERG and carefully examine the fundus of the follow eye when it comes to uncertain neovascular glaucoma of youth and child. And only in this way, can we exclude XLRS.

Genotypic analysis of X-linked retinoschisis in Western Australia.

PubMed

Lamey, Tina; Laurin, Sarina; Chelva, Enid; De Roach, John

2010-01-01

X-linked Retinoschisis is a leading cause of juvenile macular degeneration. Four Western Australian families affected by X-Linked Retinoschisis were analysed using DNA and clinical information from the Australian Inherited Retinal Disease (IRD) Register and DNA Bank. By direct sequencing of the RS1 gene, three genetic variants were identified; 52+1G > T, 289T > G and 416delA. 289T > G has not been previously reported and is likely to cause a substitution of a membrane binding residue (W92G) in the functional discoidin domain. All clinically diagnosed individuals showed typical electronegative ERGs. The 52+1G > T obligate carrier also recorded a bilaterally abnormal rod ERG and mildly abnormal photopic responses. mfERG trace arrays showed reduced response densities in the paramacular region extending futher temporally for each eye.

Pyoderma Gangrenosum–Like Ulcer in a Patient With X-Linked Agammaglobulinemia

PubMed Central

Murray, Patrick R.; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L.

2011-01-01

Background Pyoderma gangrenosum–like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient’s culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum–like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum–like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. PMID:20479300

Transcription map of Xq27: candidates for several X-linked diseases.

PubMed

Zucchi, I; Jones, J; Affer, M; Montagna, C; Redolfi, E; Susani, L; Vezzoni, P; Parvari, R; Schlessinger, D; Whyte, M P; Mumm, S

1999-04-15

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found. Copyright 1999 Academic Press.

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

PubMed

Jonsson, Kenneth B; Zahradnik, Richard; Larsson, Tobias; White, Kenneth E; Sugimoto, Toshitsugu; Imanishi, Yasuo; Yamamoto, Takehisa; Hampson, Geeta; Koshiyama, Hiroyuki; Ljunggren, Osten; Oba, Koichi; Yang, In Myung; Miyauchi, Akimitsu; Econs, Michael J; Lavigne, Jeffrey; Jüppner, Harald

2003-04-24

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic

Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis.

PubMed

Dodds, Jodi A; Srivastava, Anand K; Holden, Kenton R

2006-04-01

X-linked juvenile retinoschisis is a rare progressive vitreoretinal degenerative process that appears in early childhood, results in decreased visual acuity and blindness (if severe), and is caused by various mutations within the XLRS1 gene at Xp22.2. We report an affected family of Western European ancestry with X-linked juvenile retinoschisis. The family was found to carry a 304C-->T substitution in exon 4 of the XLRS1 gene, resulting in an Arg102Trp amino acid substitution. Two of the four available clinical cases in this family were found to carry the mutation. All available mothers of affected males were found to be unaffected carriers of the mutation, a typical feature of X-linked diseases. Two new female carriers, sisters of affected males, were identified and counseled accordingly. Questionnaires on visual functioning were given to the affected family members to examine the psychologic and sociologic impact of X-linked juvenile retinoschisis, which documented an associated stigma even when affected with a "mild" phenotype.

Expression pattern of X-linked genes in sex chromosome aneuploid bovine cells.

PubMed

Basrur, Parvathi K; Farazmand, Ali; Stranzinger, Gerald; Graphodatskaya, Daria; Reyes, Ed R; King, W Allan

2004-01-01

Expression of the X-inactive specific transcript (XIST) gene is a prerequisite step for dosage compensation in mammals, accomplished by silencing one of the two X chromosomes in normal female diploid cells or all X chromosomes in excess of one in sex chromosome aneuploids. Our previous studies showing that XIST expression does not eventuate the inactivation of X-linked genes in fetal bovine testis had suggested that XIST expression may not be an indicator of X inactivation in this species. In this study, we used a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) approach on cultures of bovine cells with varying sex chromosome constitution (XY, XX, XXY and XXX) to test whether the levels of XIST expressed conform to the number of late replicating (inactive) X chromosomes displayed by proliferating cells in these cultures. Expression patterns of four X-linked genes, including hypoxanthine phosphorybosyl transferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), zinc finger protein locus on the X (ZFX). and 'selected mouse cDNA on the X' (SMCX), in all these cells were also tested. Results showed that XIST expression was significantly higher (p < 0.05) in XXX cells compared to XX and XXY cells and that G6PD. HPRT, and SMCX loci are subject to X inactivation. The significantly higher levels of ZFX expressed in XXX cells compared to XX and XXY cells (p < 0.05) confirmed that this bovine locus, as human ZFX, escapes X inactivation. However, the levels of XIST and ZFX expressed were not proportional to the X chromosome load in these cells suggesting that X-linked loci escaping inactivation may be regulated at transcription (or post-transcription) level by mechanisms that prevent gene-specific product accumulation beyond certain levels in sex chromosome aneuploids.

X-linked cardiomyopathy is heterogeneous

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of amore » large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.« less

X-Linked Intellectual Disability: Unique Vulnerability of the Male Genome

ERIC Educational Resources Information Center

Stevenson, Roger E.; Schwartz, Charles E.

2009-01-01

X-linked intellectual disability (XLID) accounts for approximately 16% of males with intellectual disability (ID). This is, in part, related to the fact that males have a single X chromosome. Progress in the clinical and molecular characterization of XLID has outpaced progress in the delineation of ID due to genes on the other 22 chromosomes.…

Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation

PubMed Central

Royo, Hélène; Seitz, Hervé; ElInati, Elias; Peters, Antoine H. F. M.; Stadler, Michael B.; Turner, James M. A.

2015-01-01

During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein-coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions. PMID:26509798

Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cherryson, A.K.; Yeung, L.; Kennerson, M.L.

1994-09-01

Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We havemore » identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).« less

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

PubMed

Lefebvre, Mathilde; Dufernez, Fabienne; Bruel, Ange-Line; Gonzales, Marie; Aral, Bernard; Saint-Onge, Judith; Gigot, Nadège; Desir, Julie; Daelemans, Caroline; Jossic, Frédérique; Schmitt, Sébastien; Mangione, Raphaele; Pelluard, Fanny; Vincent-Delorme, Catherine; Labaune, Jean-Marc; Bigi, Nicole; D'Olne, Dominique; Delezoide, Anne-Lise; Toutain, Annick; Blesson, Sophie; Cormier-Daire, Valérie; Thevenon, Julien; El Chehadeh, Salima; Masurel-Paulet, Alice; Joyé, Nicole; Vibert-Guigue, Claude; Rigonnot, Luc; Rousseau, Thierry; Vabres, Pierre; Hervé, Philippe; Lamazière, Antonin; Rivière, Jean-Baptiste; Faivre, Laurence; Laurent, Nicole; Thauvin-Robinet, Christel

2015-07-01

Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations. © 2015 John Wiley & Sons, Ltd.

Genetics Home Reference: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia

MedlinePlus

... Share: Email Facebook Twitter Home Health Conditions XMEN X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ... Javascript to view the expand/collapse boxes. Description X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ...

Pachyonychia Congenita (K16) with Unusual Features and Good Response to Acitretin

PubMed Central

Almutawa, Fahad; Thusaringam, Thusanth; Watters, Kevin; Gayden, Tenzin; Jabado, Nada; Sasseville, Denis

2015-01-01

Background Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new classification is based on genetic variants with mutations in keratin KRT6A, KRT6B, KRT6C, KRT16, KRT17, and an unknown mutation. Here, we present a case of PC with unusual clinical and histological features and a favorable response to oral acitretin. Case A 49-year-old male presented with diffuse and striate palmoplantar keratoderma, thickened nails, knuckle pads, and pseudoainhum. Histology showed compact hyperkeratosis, prominent irregular acanthosis, and extensive epidermolytic hyperkeratosis, suggestive of Vörner's palmoplantar keratoderma. However, keratin 9 and 1 were not mutated, and full exome sequencing showed heterozygous missense mutation in type I keratin K16. Conclusion To our knowledge, epidermolytic hyperkeratosis has not been previously described with PC. Our patient had an excellent response, maintained over the last 5 years, to a low dose of acitretin. We wish to emphasize the crucial role of whole exome sequencing in establishing the correct diagnosis. PMID:26464567

Molecular genetic analysis of patients with sporadic and X-linked infantile nystagmus

PubMed Central

Zhao, Hui; Huang, Xiu-Feng; Zheng, Zhi-Li; Deng, Wen-Li; Lei, Xin-Lan; Xing, Dong-Jun; Ye, Liang; Xu, Su-Zhong; Chen, Jie; Zhang, Fang; Yu, Xin-Ping; Jin, Zi-Bing

2016-01-01

Objectives Infantile nystagmus (IN) is a genetically heterogeneous condition characterised by involuntary rhythmic oscillations of the eyes accompanied by different degrees of vision impairment. Two genes have been identified as mainly causing IN: FRMD7 and GPR143. The aim of our study was to identify the genetic basis of both sporadic IN and X-linked IN. Design Prospective analysis. Patients Twenty Chinese patients, including 15 sporadic IN cases and 5 from X-linked IN families, were recruited and underwent molecular genetic analysis. We first performed PCR-based DNA sequencing of the entire coding region and the splice junctions of the FRMD7 and GPR143 genes in participants. Mutational analysis and co-segregation confirmation were then performed. Setting All clinical examinations and genetic experiments were performed in the Eye Hospital of Wenzhou Medical University. Results Two mutations in the FRMD7 gene, including one novel nonsense mutation (c.1090C>T, p.Q364X) and one reported missense mutation (c.781C>G, p.R261G), were identified in two of the five (40%) X-linked IN families. However, none of putative mutations were identified in FRMD7 or GPR143 in any of the sporadic cases. Conclusions The results suggest that mutations in FRMD7 appeared to be the major genetic cause of X-linked IN, but not of sporadic IN. Our findings provide further insights into FRMD7 mutations, which could be helpful for future genetic diagnosis and genetic counselling of Chinese patients with nystagmus. PMID:27036142

Gene Expression Profiling in Pachyonychia Congenita Skin

PubMed Central

Cao, Yu-An; Hickerson, Robyn P.; Seegmiller, Brandon L.; Grapov, Dmitry; Gross, Maren M.; Bessette, Marc R.; Phinney, Brett S.; Flores, Manuel A.; Speaker, Tycho J.; Vermeulen, Annaleen; Bravo, Albert A.; Bruckner, Anna L.; Milstone, Leonard M.; Schwartz, Mary E.; Rice, Robert H.; Kaspar, Roger L.

2015-01-01

Background Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear. Objective To better understand PC pathogenesis. Methods RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples. Results A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis. Conclusion Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics. PMID:25656049

X-linked intellectual disability update 2017.

PubMed

Neri, Giovanni; Schwartz, Charles E; Lubs, Herbert A; Stevenson, Roger E

2018-04-25

The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function. © 2018 Wiley Periodicals, Inc.

A family study of congenital X linked sideroblastic anaemia.

PubMed Central

Holmes, J; May, A; Geddes, D; Jacobs, A

1990-01-01

We report on the cytogenetic findings in a family study of pyridoxine responsive, X linked sideroblastic anaemia. An increase in the number of X chromosomes was observed in a small proportion of metaphases prepared from five female members, but these findings did not strictly correlate with the carrier status of the condition. No consistent cytogenetic abnormality could be identified or associated with this rare familial condition. The diagnosis and counselling of carriers of this condition is discussed. Images PMID:2308152

Use of topical dorzolamide for patients with X-linked juvenile retinoschisis: case report.

PubMed

Bastos, André Luís Carvalho de Moura; Freitas, Bruno de Paula; Villas Boas, Oscar; Ramiro, Alexandre Campelo

2008-01-01

X-linked juvenile retinoschisis (XLRS) is a recessively inherited vitreoretinal degeneration characterized by macular pathology and splitting of the neuroretinal layers that is associated with alterations in the XLRS1 gene. There have been no therapeutic interventions known to be effective for patients with X-linked juvenile retinoschisis, but some studies are trying to determine the importance of dorzolamide for the treatment of foveal lesions in this disease. The authors, using optical coherence tomography, describe findings in a patient with X-linked juvenile retinoschisis, before and after a topical use of dorzolamide. Besides the improvement in his visual acuity, further studies are required to elucidate the real prevalence of nonresponse to dorzolamide and the frequency with which there may be a recurrence of foveal cystic changes during continued treatment.

Lamellar macular hole in X linked retinoschisis

PubMed Central

Kumar, Vinod; Goel, Neha

2016-01-01

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. PMID:27170611

Optical coherence tomography in the diagnosis of juvenile X-linked retinoschisis.

PubMed

Eriksson, Urban; Larsson, Eva; Holmström, Gerd

2004-04-01

To describe the value of optical coherence tomography (OCT) as a diagnostic tool in the diagnosis of X-linked retinoschisis. We report three boys aged between 8 and 17 years, diagnosed with X-linked retinoschisis. During investigations they were examined with OCT (Zeiss Humphrey OCT 1, upgraded version). Single scans of the central posterior pole and the region around the vascular arcades were obtained. Two of the boys underwent full-field ERG according to ISCEV standards. Genetic analysis was performed in all three boys, with sequencing of the XLRS gene. The OCT results revealed a pattern with a cleavage of the retina in two distinct planes, one deep (outer retina) and one superficial. This was very obvious in one patient and a similar but not as pronounced pattern was seen in the other two cases. The two layers were superficially connected with thin-walled, vertical palisades, separated by low reflective, cystoid spaces, confluent and most prominent in the foveal region. Full-field ERG and/or DNA analysis are well known methods used for diagnosis of X-linked juvenile retinoschisis. In this paper, we suggest that OCT can also be a helpful diagnostic tool.

X-linked cataract and Nance-Horan syndrome are allelic disorders.

PubMed

Coccia, Margherita; Brooks, Simon P; Webb, Tom R; Christodoulou, Katja; Wozniak, Izabella O; Murday, Victoria; Balicki, Martha; Yee, Harris A; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J; Maher, Eamonn R; Moore, Anthony T; Russell-Eggitt, Isabelle M; Hardcastle, Alison J

2009-07-15

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.

X-linked cataract and Nance-Horan syndrome are allelic disorders

PubMed Central

Coccia, Margherita; Brooks, Simon P.; Webb, Tom R.; Christodoulou, Katja; Wozniak, Izabella O.; Murday, Victoria; Balicki, Martha; Yee, Harris A.; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K.; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J.; Maher, Eamonn R.; Moore, Anthony T.; Russell-Eggitt, Isabelle M.; Hardcastle, Alison J.

2009-01-01

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved. PMID:19414485

Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

PubMed

Favor, J; Pretsch, W

1990-01-01

Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

Human X-Linked genes regionally mapped utilizing X-autosome translocations and somatic cell hybrids.

PubMed Central

Shows, T B; Brown, J A

1975-01-01

Human genes coding for hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8; IMP:pyrophosphate phosphoribosyltransferase), glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49; D-glucose-6-phosphate:NADP+ 1-oxidoreductase), and phosphoglycerate kinase (PGK, EC 2.7.2.3; ATP:3-phospho-D-glycerate 1-phosphotransferase) have been assigned to specific regions on the long arm of the X chromosome by somatic cell gentic techniques. Gene assignment and linear order were determined by employing human somatic cells possessing an X/9 translocation or an X/22 translocation in man-mouse cell hybridization studies. The X/9 translocation involved the majority of the X long arm translocated to chromosome 9 and the X/22 translocation involved the distal half of the X long arm translocated to 22. In each case these rearrangements appeared to be reciprocal. Concordant segregation of X-linked enzymes and segments of the X chromosome generated by the translocations indicated assignment of the PGK gene to a proximal long arm region (q12-q22) and the HPRT and G6PD genes to the distal half (q22-qter) of the X long arm. Further evidence suggests a gene order on the X long arm of centromere-PGK-HPRT-G6PD. Images PMID:1056018

Lamellar macular hole in X linked retinoschisis.

PubMed

Kumar, Vinod; Goel, Neha

2016-05-11

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. 2016 BMJ Publishing Group Ltd.

A major X-linked locus affects kidney function in mice

PubMed Central

Leduc, Magalie S.; Savage, Holly S.; Stearns, Timothy M.; Cario, Clinton L.; Walsh, Kenneth A.; Paigen, Beverly; Berndt, Annerose

2012-01-01

Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance. We used KK/HlJ, an albuminuria-sensitive strain, and C57BL/6J, an albuminuria-resistant strain, to perform a quantitative trait locus (QTL) cross to identify the genetic basis for chronic kidney failure. Albumin-creatinine-ratio (ACR) was measured in 130 F2 male offspring. One significant QTL was identified on chromosome (Chr) X and four suggestive QTLs were found on Chrs 6, 7, 12, and 13. Narrowing of the QTL region was focused on the X-linked QTL and performed by incorporating genotype and expression analyses for genes located in the region. From the 485 genes identified in the X-linked QTL region, a few candidate genes were identified using a combination of bioinformatic evidence based on genomic comparison of the parental strains and known function in urine homeostasis. Finally, this study demonstrates the significance of the X chromosome in the genetic determination of albuminuria. PMID:23011808

Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fain, P.R.; Barker, D.F.; Chance, P.F.

1994-02-01

Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

X-linked Alport syndrome caused by splicing mutations in COL4A5.

PubMed

Nozu, Kandai; Vorechovsky, Igor; Kaito, Hiroshi; Fu, Xue Jun; Nakanishi, Koichi; Hashimura, Yuya; Hashimoto, Fusako; Kamei, Koichi; Ito, Shuichi; Kaku, Yoshitsugu; Imasawa, Toshiyuki; Ushijima, Katsumi; Shimizu, Junya; Makita, Yoshio; Konomoto, Takao; Yoshikawa, Norishige; Iijima, Kazumoto

2014-11-07

X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism. In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities. Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics. This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked

X linked exudative vitreoretinopathy: clinical features and genetic linkage analysis.

PubMed

Fullwood, P; Jones, J; Bundey, S; Dudgeon, J; Fielder, A R; Kilpatrick, M W

1993-03-01

A four generation family in which familial exudative vitreoretinopathy is inherited as an X linked condition is described. Essentially the condition is one of abnormal vascularisation and signs at birth are those of a retinopathy superficially resembling retinopathy of prematurity, retinal folds, or, in advanced cases, enophthalmos or even phthisis. Prognosis depends on the progression of the retinal changes. The family members, including seven affected males and five obligate carrier females, have been types for 20 DNA markers, and linkage analysis suggests a gene locus either at Xq21.3 or at Xp11. As the latter region includes the locus for the gene for Norrie disease, it is possible that this and X linked vitreoretinopathy are allelic. We can further speculate that the differences in severity of the clinical manifestations are dependent only upon the timing of the insult.

A family with X-linked anophthalmia: exclusion of SOX3 as a candidate gene.

PubMed

Slavotinek, Anne; Lee, Stephen S; Hamilton, Steven P

2005-10-01

We report on a four-generation family with X-linked anophthalmia in four affected males and show that this family has LOD scores consistent with linkage to Xq27, the third family reported to be linked to the ANOP1 locus. We sequenced the SOX3 gene at Xq27 as a candidate gene for the X-linked anophthalmia based on the high homology of this gene to SOX2, a gene previously mutated in bilateral anophthlamia. However, no amino acid sequence alterations were identified in SOX3. We have improved the definition of the phenotype in males with anophthalmia linked to the ANOP1 locus, as microcephaly, ocular colobomas, and severe renal malformations have not been described in families linked to ANOP1. (c) 2005 Wiley-Liss, Inc.

CAPILLARY NETWORK ALTERATIONS IN X-LINKED RETINOSCHISIS IMAGED ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PubMed

Romano, Francesco; Arrigo, Alessandro; Chʼng, Soon Wai; Battaglia Parodi, Maurizio; Manitto, Maria Pia; Martina, Elisabetta; Bandello, Francesco; Stanga, Paulo E

2018-06-05

To assess foveal and parafoveal vasculature at the superficial capillary plexus, deep capillary plexus, and choriocapillaris of patients with X-linked retinoschisis by means of optical coherence tomography angiography. Six patients with X-linked retinoschisis (12 eyes) and seven healthy controls (14 eyes) were recruited and underwent complete ophthalmologic examination, including best-corrected visual acuity, dilated fundoscopy, and 3 × 3-mm optical coherence tomography angiography macular scans (DRI OCT Triton; Topcon Corp). After segmentation and quality review, optical coherence tomography angiography slabs were imported into ImageJ 1.50 (NIH; Bethesda) and digitally binarized. Quantification of vessel density was performed after foveal avascular zone area measurement and exclusion. Patients were additionally divided into "responders" and "nonresponders" to dorzolamide therapy. Foveal avascular zone area resulted markedly enlarged at the deep capillary plexus (P < 0.001), particularly in nonresponders. Moreover, patients disclosed a significant deep capillary plexus rarefaction, when compared with controls (P: 0.04); however, a subanalysis revealed that this damage was limited to the fovea (P: 0.006). Finally, the enlargement of foveal avascular zone area positively correlated with a decline in best-corrected visual acuity (P: 0.01). Prominent foveal vascular impairment is detectable in the deep capillary plexus of patients with X-linked retinoschisis. Our results correlate with functional outcomes, suggesting a possible vascular role in X-linked retinoschisis clinical manifestations.

Therapeutic siRNAs for dominant genetic skin diseases including pachyonychia congenita

PubMed Central

Leachman, Sancy A.; Hickerson, Robyn P.; Hull, Peter R.; Smith, Frances J. D.; Milstone, Leonard M.; Lane, E. Birgitte; Bale, Sherri J.; Roop, Dennis R.; McLean, W. H. Irwin; Kaspar, Roger L.

2008-01-01

The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been genetically defined, but little progress has been made with respect to the clinical application of this knowledge. A notable exception to this exists for pachyonychia congenita (PC), a rare, dominant negative keratin disorder. The establishment of a non-profit organization, PC Project, has led to an unprecedented coalescence of patients, scientists, and physicians with a unified vision of developing novel therapeutics for PC. Utilizing the technological by-products of the human genome project, such as RNA interference (RNAi) and quantitative RT-PCR (qRT-PCR), physicians and scientists have collaborated to create a candidate siRNA therapeutic that selectively inhibits a mutant allele of KRT6A, the most commonly affected PC keratin. In vitro investigation of this siRNA demonstrates potent inhibition of the mutant allele and reversal of the cellular aggregation phenotype. In parallel, an allele-specific quantitative real time RT-PCR assay has been developed and validated on patient callus samples in preparation for clinical trials. If clinical efficacy is ultimately demonstrated, this “first-in-skin” siRNA may herald a paradigm shift in the treatment of dominant negative genetic disorders. PMID:18495438

Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita.

PubMed

Leachman, Sancy A; Hickerson, Robyn P; Hull, Peter R; Smith, Frances J D; Milstone, Leonard M; Lane, E Birgitte; Bale, Sherri J; Roop, Dennis R; McLean, W H Irwin; Kaspar, Roger L

2008-09-01

The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been genetically defined, but little progress has been made with respect to the clinical application of this knowledge. A notable exception to this exists for pachyonychia congenita (PC), a rare, dominant-negative keratin disorder. The establishment of a non-profit organization, PC Project, has led to an unprecedented coalescence of patients, scientists, and physicians with a unified vision of developing novel therapeutics for PC. Utilizing the technological by-products of the human genome project, such as RNA interference (RNAi) and quantitative RT-PCR (qRT-PCR), physicians and scientists have collaborated to create a candidate siRNA therapeutic that selectively inhibits a mutant allele of KRT6A, the most commonly affected PC keratin. In vitro investigation of this siRNA demonstrates potent inhibition of the mutant allele and reversal of the cellular aggregation phenotype. In parallel, an allele-specific quantitative real-time RT-PCR assay has been developed and validated on patient callus samples in preparation for clinical trials. If clinical efficacy is ultimately demonstrated, this "first-in-skin" siRNA may herald a paradigm shift in the treatment of dominant-negative genetic disorders.

X-linked Acrogigantism (X-LAG) Syndrome: Clinical Profile and Therapeutic Responses

PubMed Central

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J.; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H.; Bours, Vincent; Liu, Pengfei; De Herder, Wouter; Pellegata, Natalia; Lupski, James R.; Daly, Adrian F.; Stratakis, Constantine A.

2015-01-01

X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

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

A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

PubMed

Zhou, Qi; Yao, Fengxia; Wang, Feng; Li, Hui; Chen, Rui; Sui, Ruifang

2018-01-01

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. © 2017 Wiley Periodicals, Inc.

Foveomacular schisis in juvenile X-linked retinoschisis: an optical coherence tomography study.

PubMed

Yu, Jia; Ni, Yingqin; Keane, Pearse A; Jiang, Chunhui; Wang, Wenji; Xu, Gezhi

2010-06-01

To explore the structural features of juvenile X-linked retinoschisis using spectral-domain optical coherence tomography (OCT). Retrospective, observational cross-sectional study. Eighteen male patients (34 eyes) who were diagnosed with juvenile X-linked retinoschisis at the Eye & ENT Hospital of Fudan University over an 18-month period were included. Their OCT images, which were obtained using spectral-domain OCT (Cirrus HD-OCT; Carl Zeiss Meditec), were analyzed. The anatomic location of the schisis cavity in juvenile X-linked retinoschisis was characterized by direct inspection of OCT images. On OCT, the schisis cavity was visible at the fovea in all 34 eyes, and it was associated with increased retinal thickness. Schisis was present at the retinal nerve fiber layer in 4 eyes, at the inner nuclear layer in 29 eyes, and at the outer nuclear layer/outer plexiform layer in 22 eyes. In most cases, widespread foveomacular schisis was detected using OCT; however, in 9 eyes (6 patients), the schisis was confined to the fovea. Schisis of the inner nuclear layer and outer nuclear layer/outer plexiform layer almost always involved the foveal center, but retinal nerve fiber layer schisis was seen only in the parafoveal area. Despite conventional wisdom, in patients with X-linked retinoschisis, the schisis cavity can occur in a number of different layers of the neurosensory retina (retinal nerve fiber layer, inner nuclear layer, and outer nuclear layer/outer plexiform layer). In addition, different forms of schisis may affect different locations in the macula (foveal vs parafoveal), and, in most eyes, the schisis involves the entire foveomacular region. Copyright 2010 Elsevier Inc. All rights reserved.

A Novel Mutation in the XLRS1 Gene in a Korean Family with X-linked Retinoschisis

PubMed Central

Jwa, Nam Soo; Kim, Sung Soo; Lee, Sung Chul; Kwon, Oh Woong

2006-01-01

Purpose To report a novel missense mutation in the XLRS1 gene in a Korean family with X-linked retinoschisis. Methods Observation case report of a family with a proband with X-linked retinoschisis underwent complete ophthalmologic examination. Genomic DNA was excluded from the family's blood and all exons of the XLRS1 gene were amplified by polymerase chain reaction and analyzed using a direct sequencing method. Results A novel Leu103Phe missense mutation was identified. Conclusions A novel Leu103Phe mutation is an additional missense mutation which is responsible for the pathogenesis of X-linked retinoschisis. PMID:16768192

X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.

PubMed Central

Bichet, D G; Arthus, M F; Lonergan, M; Hendy, G N; Paradis, A J; Fujiwara, T M; Morgan, K; Gregory, M C; Rosenthal, W; Didwania, A

1993-01-01

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene. Images PMID:8104196

Burosumab Therapy in Children with X-Linked Hypophosphatemia.

PubMed

Carpenter, Thomas O; Whyte, Michael P; Imel, Erik A; Boot, Annemieke M; Högler, Wolfgang; Linglart, Agnès; Padidela, Raja; Van't Hoff, William; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; Kakkis, Emil; San Martin, Javier; Portale, Anthony A

2018-05-24

X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both

The forensic value of X-linked markers in mixed-male DNA analysis.

PubMed

He, HaiJun; Zha, Lagabaiyila; Cai, JinHong; Huang, Jian

2018-05-04

Autosomal genetic markers and Y chromosome markers have been widely applied in analysis of mixed stains at crime scenes by forensic scientists. However, true genotype combinations are often difficult to distinguish using autosomal markers when similar amounts of DNA are contributed by multiple donors. In addition, specific individuals cannot be determined by Y chromosomal markers because male relatives share the same Y chromosome. X-linked markers, possessing characteristics somewhere intermediate between autosomes and the Y chromosome, are less universally applied in criminal casework. In this paper, X markers are proposed to apply to male mixtures because their true genes can be more easily and accurately recognized than the decision of the genotypes of AS markers. In this study, an actual two-man mixed stain from a forensic case file and simulated male-mixed DNA were examined simultaneously with the X markers and autosomal markers. Finally, the actual mixture was separated successfully by the X markers, although it was unresolved by AS-STRs, and the separation ratio of the simulated mixture was much higher using Chr X tools than with AS methods. We believe X-linked markers provide significant advantages in individual discrimination of male mixtures that should be further applied to forensic work.

Variation in the X-Linked EFHC2 Gene Is Associated with Social Cognitive Abilities in Males

PubMed Central

Startin, Carla M.; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H.

2015-01-01

Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID:26107779

A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2.

PubMed

Katz, Bradley J; Zhao, Yu; Warner, Judith E A; Tong, Zongzhong; Yang, Zhenglin; Zhang, Kang

2006-10-15

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic atrophy. Clinical features of ADOA include a slowly progressive bilateral loss of visual acuity, constriction of peripheral visual fields, central scotomas, and color vision abnormalities. Although ADOA is the most commonly inherited optic atrophy, autosomal recessive, X-linked, mitochondrial, and sporadic forms have also been reported. Four families with X-linked optic atrophy (XLOA) were previously described. One family was subsequently linked to Xp11.4-Xp11.2 (OPA2). This investigation studied one multi-generation family with an apparently X-linked form of optic atrophy and compared their clinical characteristics with those of the previously described families, and determined whether this family was linked to the same genetic locus. Fifteen individuals in a three-generation Idaho family underwent complete eye examination, color vision testing, automated perimetry, and fundus photography. Polymorphic markers were used to genotype each individual and to determine linkage. Visual acuities ranged from 20/30 to 20/100. All affected subjects had significant optic nerve pallor. Obligate female carriers were clinically unaffected. Preliminary linkage analysis (LOD score = 1.8) revealed that the disease gene localized to the OPA2 locus on Xp11.4-Xp11.2. Four forms of inherited optic neuropathy, ADOA, autosomal recessive optic atrophy (Costeff Syndrome), Leber hereditary optic neuropathy, and Charcot-Marie-Tooth disease with optic atrophy, are associated with mitochondrial dysfunction. Future identification of the XLOA gene will reveal whether this form of optic atrophy is also associated with a mitochondrial defect. Identification of the XLOA gene will advance our understanding of the inherited optic neuropathies and perhaps suggest treatments for these diseases. An improved understanding of inherited optic neuropathies may in turn advance our understanding of acquired optic nerve diseases, such

Telomere-driven diseases and telomere-targeting therapies

PubMed Central

2017-01-01

Telomeres, the protective ends of linear chromosomes, shorten throughout an individual’s lifetime. Telomere shortening is proposed to be a primary molecular cause of aging. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, and trigger the development of age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as telomere syndromes, including Hoyeraal-Hreidarsson syndrome, dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis. Telomere shortening induces chromosomal instability that, in the absence of functional tumor suppressor genes, can contribute to tumorigenesis. In addition, mutations in telomere length maintenance genes and in shelterin components, the protein complex that protects telomeres, have been found to be associated with different types of cancer. These observations have encouraged the development of therapeutic strategies to treat and prevent telomere-associated diseases, namely aging-related diseases, including cancer. Here we review the molecular mechanisms underlying telomere-driven diseases and highlight recent advances in the preclinical development of telomere-targeted therapies using mouse models. PMID:28254828

Application of carrier testing to genetic counseling for X-linked agammaglobulinemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allen, R.C.; Nachtman, R.G.; Belmont, J.W.

Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19[sup +] peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLAmore » demonstrated >95% skewing of X inactivation in peripheral blood CD19[sup +] cells but not in CD19[sup [minus

Meiotic drive impacts expression and evolution of x-linked genes in stalk-eyed flies.

PubMed

Reinhardt, Josephine A; Brand, Cara L; Paczolt, Kimberly A; Johns, Philip M; Baker, Richard H; Wilkinson, Gerald S

2014-01-01

Although sex chromosome meiotic drive has been observed in a variety of species for over 50 years, the genes causing drive are only known in a few cases, and none of these cases cause distorted sex-ratios in nature. In stalk-eyed flies (Teleopsis dalmanni), driving X chromosomes are commonly found at frequencies approaching 30% in the wild, but the genetic basis of drive has remained elusive due to reduced recombination between driving and non-driving X chromosomes. Here, we used RNAseq to identify transcripts that are differentially expressed between males carrying either a driving X (XSR) or a standard X chromosome (XST), and found hundreds of these, the majority of which are X-linked. Drive-associated transcripts show increased levels of sequence divergence (dN/dS) compared to a control set, and are predominantly expressed either in testes or in the gonads of both sexes. Finally, we confirmed that XSR and XST are highly divergent by estimating sequence differentiation between the RNAseq pools. We found that X-linked transcripts were often strongly differentiated (whereas most autosomal transcripts were not), supporting the presence of a relatively large region of recombination suppression on XSR presumably caused by one or more inversions. We have identified a group of genes that are good candidates for further study into the causes and consequences of sex-chromosome drive, and demonstrated that meiotic drive has had a profound effect on sequence evolution and gene expression of X-linked genes in this species.

Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?

PubMed Central

Jonsson, J J; Renieri, A; Gallagher, P G; Kashtan, C E; Cherniske, E M; Bruttini, M; Piccini, M; Vitelli, F; Ballabio, A; Pober, B R

1998-01-01

We describe a family with four members, a mother, two sons, and a daughter, who show clinical features consistent with X linked Alport syndrome. The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis. The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability and rigidity was normal on ektacytometry. Molecular characterisation suggests a submicroscopic X chromosome deletion encompassing the entire COL4A5 gene. We propose that the additional abnormalities found in the affected males of this family are attributable to deletion or disruption of X linked recessive genes adjacent to the COL4A5 gene and that this constellation of findings may represent a new X linked contiguous gene deletion syndrome. Images PMID:9598718

Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

PubMed

Russell-Eggitt, I M

2000-12-01

When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR.

PubMed

Riveiro-Alvarez, Rosa; Trujillo-Tiebas, Maria José; Gimenez-Pardo, Ascension; Garcia-Hoyos, Maria; Cantalapiedra, Diego; Lorda-Sanchez, Isabel; Rodriguez de Alba, Marta; Ramos, Carmen; Ayuso, Carmen

2005-09-02

Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 DXS538more » 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.« less

[Prenatal diagnosis of X-linked anhidrotic ectodermal dysplasia with X-chromosome inversion].

PubMed

Shi, Hui-juan; Fang, Qun; Wang, Lian-tang

2005-07-13

To investigate the possibility of prenatal diagnosis of the fetal suspected to be affected by anhidrotic ectodermal dysplasia (EDA) in a family with X-linked EDA so as to provide a basis for prenatal diagnosis and genetic counseling of this disorder. Pedigree analysis and genetic counseling were performed in a family after a proband was diagnosed with EDA. The peripheral blood samples were collected from the proband, a 12-year-old boy, his mother, and his 2 aunts, one being pregnant, to undergo chromosome karyotype analysis. The fetus Puncture of umbilical vein was performed to collect the blood of fetus for chromosome examination. Induced abortion was conducted due to the diagnosis of the fetus with EDA. Autopsy, immunohistochemistry of the skin tissues of face, breast, epigastrium, and thigh, and X-ray photography of the lower jawbone were made. Pericentric inversion occurring at one of the X-chromosome [inv (x) (p22q13)] was found in the proband and his nephew (the fetus), both patients, and his mother and his second aunt (the pregnant woman), both carriers. Autopsy of the fetus showed epidermis dysplasia and deficiency of hair follicle and sebaceous gland. Immunohistochemistry showed that epithelial membrane antigen and cytokeratin were negatively expressed in the fetal skin tissues. Pedigree analysis and genetic counseling for the family members of EDA patients and prenatal and postpartum examination for the fetus help diagnose EDA.

A Complex Genetic Basis to X-Linked Hybrid Male Sterility Between Two Species of House Mice

PubMed Central

Good, Jeffrey M.; Dean, Matthew D.; Nachman, Michael W.

2008-01-01

The X chromosome plays a central role in the evolution of reproductive isolation, but few studies have examined the genetic basis of X-linked incompatibilities during the early stages of speciation. We report the results of a large experiment focused on the reciprocal introgression of the X chromosome between two species of house mice, Mus musculus and M. domesticus. Introgression of the M. musculus X chromosome into a wild-derived M. domesticus genetic background produced male-limited sterility, qualitatively consistent with previous experiments using classic inbred strains to represent M. domesticus. The genetic basis of sterility involved a minimum of four X-linked factors. The phenotypic effects of major sterility QTL were largely additive and resulted in complete sterility when combined. No sterility factors were uncovered on the M. domesticus X chromosome. Overall, these results revealed a complex and asymmetric genetic basis to X-linked hybrid male sterility during the early stages of speciation in mice. Combined with data from previous studies, we identify one relatively narrow interval on the M. musculus X chromosome involved in hybrid male sterility. Only a handful of spermatogenic genes are within this region, including one of the most rapidly evolving genes on the mouse X chromosome. PMID:18689897

A complex genetic basis to X-linked hybrid male sterility between two species of house mice.

PubMed

Good, Jeffrey M; Dean, Matthew D; Nachman, Michael W

2008-08-01

The X chromosome plays a central role in the evolution of reproductive isolation, but few studies have examined the genetic basis of X-linked incompatibilities during the early stages of speciation. We report the results of a large experiment focused on the reciprocal introgression of the X chromosome between two species of house mice, Mus musculus and M. domesticus. Introgression of the M. musculus X chromosome into a wild-derived M. domesticus genetic background produced male-limited sterility, qualitatively consistent with previous experiments using classic inbred strains to represent M. domesticus. The genetic basis of sterility involved a minimum of four X-linked factors. The phenotypic effects of major sterility QTL were largely additive and resulted in complete sterility when combined. No sterility factors were uncovered on the M. domesticus X chromosome. Overall, these results revealed a complex and asymmetric genetic basis to X-linked hybrid male sterility during the early stages of speciation in mice. Combined with data from previous studies, we identify one relatively narrow interval on the M. musculus X chromosome involved in hybrid male sterility. Only a handful of spermatogenic genes are within this region, including one of the most rapidly evolving genes on the mouse X chromosome.

Localisation of the gene for X-linked reticulate pigmentary disorder with systemic manifestations (PDR), previously known as X-linked cutaneous amyloidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gedeon, A.K.; Mulley, J.C.; Kozman, H.

1994-08-01

X-linked reticulate pigmentary disorder (PDR), previously reported as X-linked cutaneous amyloidosis (MIM No. 301220), is characterized by brown pigmentation of the skin which follows the lines of Blaschko in females but appears as reticulate sheets in males. Males may suffer severe gastrointestinal disorders in infancy with failure to thrive and early death. Nowadays symptomatic treatment allows survival and other manifestations may appear such as corneal dystrophy with severe photophobia or chronic respiratory disease. Amyloid deposition in the skin may be no more than an age-dependent secondary manifestation. The PDR gene was localized by linkage analysis to Xp21-p22. The background geneticmore » map is Xpter-DXS996-22.5-DXS207-3.3-DXS999-3.3-DXS365-14.2-DXS989-4.1-3`DMD-3.5-DXS997-1.0-STR44-9.3-DYSI-2.3-DXS1068-11.0-DXS228 with distances between markers given in cM. Recombinants detected with DXS999 distally and DXS228 proximally, define the limits to the localization. Linkage was found with several markers within this interval. Peak lod scores of 3.21 at {theta} = 0.0 were obtained between PDR and DXS989 and between PDR and 5`DYSI within the dystrophin locus. 29 refs., 2 figs., 2 tabs.« less

MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome

PubMed Central

Siew, Wei-Hong; Tan, Kai-Leng; Babaei, Maryam Abbaspour; Cheah, Pike-See; Ling, King-Hwa

2013-01-01

Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)]. PMID:23596395

[Clinical and molecular study in a child with X-linked hypohidrotic ectodermal dysplasia].

PubMed

Callea, Michele; Yavuz, Izzet; Clarich, Gabriella; Cammarata-Scalisi, Francisco

2015-12-01

Ectodermal dysplasia encompasses more than 200 clinically distinct entities, which affect at least two structures derived from the ectoderm, including the skin, hair, nails, teeth, sweat glands, and sebaceous glands. X-linked hypohidrotic ectodermal dysplasia is the most common type and is caused by mutation of the EDA gene that encodes Ectodysplasin-A. It occurs in less than 1 in 100 000 individuals and is clinically characterized by hypodontia, hypohidrosis, hypotrichosis, and eye dis orders. We present a child evaluated in a multidisciplinary manner with clinical and molecular diagnosis of X-linked hypohidrotic ectodermal dysplasia with type missense mutation c.1133C> T; p.T378M in EDA gene.

Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes

PubMed Central

Kerns, Michelle L.; Hakim, Jill M.C.; Lu, Rosemary G.; Guo, Yajuan; Berroth, Andreas; Kaspar, Roger L.

2016-01-01

Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16–/– mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid–derived 2 related factor 2–dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16–/– mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16–/– footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16–/– mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment. PMID:27183391

Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance Horan syndrome, on the mouse X chromosome.

PubMed

Stambolian, D; Favor, J; Silvers, W; Avner, P; Chapman, V; Zhou, E

1994-07-15

The Xcat mutation in the mouse, an X-linked inherited disorder, is characterized by the congenital onset of cataracts. The cataracts have morphologies similar to those of cataracts found in the human Nance Horan (X-linked cataract dental) syndrome, suggesting that Xcat is an animal model for Nance Horan. The Xcat mutation provides an opportunity to investigate, at the molecular level, the pathogenesis of cataract. As a first step to cloning the Xcat gene, we report the localization of the Xcat mutation with respect to known molecular markers on the mouse X chromosome. Back-cross progeny carrying the Xcat mutation were obtained from an interspecific cross. Genomic DNA from each mouse was subjected to Southern and PCR analysis to identify restriction fragment length polymorphisms and simple sequence length polymorphisms, respectively. Our results refine the location of Xcat to a 2-cM region, eliminate several genes from consideration as the Xcat mutation, identify molecular probes tightly linked with Xcat, and suggest candidate genes responsible for the Xcat phenotype.

Assessing interethnic admixture using an X-linked insertion-deletion multiplex.

PubMed

Ribeiro-Rodrigues, Elzemar Martins; dos Santos, Ney Pereira Carneiro; dos Santos, Andrea Kely Campos Ribeiro; Pereira, Rui; Amorim, António; Gusmão, Leonor; Zago, Marco Antonio; dos Santos, Sidney Emanuel Batista

2009-01-01

In this study, a PCR multiplex was optimized, allowing the simultaneous analysis of 13 X-chromosome Insertion/deletion polymorphisms (INDELs). Genetic variation observed in Africans, Europeans, and Native Americans reveals high inter-population variability. The estimated proportions of X-chromosomes in an admixed population from the Brazilian Amazon region show a predominant Amerindian contribution (approximately 41%), followed by European (approximately 32%) and African (approximately 27%) contributions. The proportion of Amerindian contribution based on X-linked data is similar to the expected value based on mtDNA and Y-chromosome information. The accuracy for assessing interethnic admixture, and the high differentiation between African, European, and Native American populations, demonstrates the suitability of this INDEL set to measure ancestry proportions in three-hybrid populations, as it is the case of Latin American populations.

The rapid evolution of X-linked male-biased gene expression and the large-X effect in Drosophila yakuba, D. santomea, and their hybrids.

PubMed

Llopart, Ana

2012-12-01

The X chromosome has a large effect on hybrid dysfunction, particularly on hybrid male sterility. Although the evidence for this so-called large-X effect is clear, its molecular causes are not yet fully understood. One possibility is that, under certain conditions, evolution proceeds faster in X-linked than in autosomal loci (i.e., faster-X effect) due to both natural selection and their hemizygosity in males, an effect that is expected to be greatest in genes with male-biased expression. Here, I study genome-wide variation in transcript abundance between Drosophila yakuba and D. santomea, within these species and in their hybrid males to evaluate both the faster-X and large-X effects at the level of expression. I find that in X-linked male-biased genes (MBGs) expression evolves faster than in their autosomal counterparts, an effect that is accompanied by a unique reduction in expression polymorphism. This suggests that Darwinian selection is driving expression differences between species, likely enhanced by the hemizygosity of the X chromosome in males. Despite the recent split of the two sister species under study, abundant changes in both cis- and trans-regulatory elements underlie expression divergence in the majority of the genes analyzed, with significant differences in allelic ratios of transcript abundance between the two reciprocal F(1) hybrid males. Cis-trans coevolution at molecular level, evolved shortly after populations become isolated, may therefore contribute to explain the breakdown of the regulation of gene expression in hybrid males. Additionally, the X chromosome plays a large role in this hybrid male misexpression, which affects not only MBG but also, to a lesser degree, nonsex-biased genes. Interestingly, hybrid male misexpression is concentrated mostly in autosomal genes, likely facilitated by the rapid evolution of sex-linked trans-acting factors. I suggest that the faster evolution of X-linked MBGs, at both protein and expression levels

X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene.

PubMed

Lagresle-Peyrou, Chantal; Luce, Sonia; Ouchani, Farid; Soheili, Tayebeh Shabi; Sadek, Hanem; Chouteau, Myriam; Durand, Amandine; Pic, Isabelle; Majewski, Jacek; Brouzes, Chantal; Lambert, Nathalie; Bohineust, Armelle; Verhoeyen, Els; Cosset, François-Loïc; Magerus-Chatinet, Aude; Rieux-Laucat, Frédéric; Gandemer, Virginie; Monnier, Delphine; Heijmans, Catherine; van Gijn, Marielle; Dalm, Virgil A; Mahlaoui, Nizar; Stephan, Jean-Louis; Picard, Capucine; Durandy, Anne; Kracker, Sven; Hivroz, Claire; Jabado, Nada; de Saint Basile, Geneviève; Fischer, Alain; Cavazzana, Marina; André-Schmutz, Isabelle

2016-12-01

We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8 + T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

A Novel Mutation in CLCN1 Associated with Feline Myotonia Congenita

PubMed Central

Gandolfi, Barbara; Daniel, Rob J.; O'Brien, Dennis P.; Guo, Ling T.; Youngs, Melanie D.; Leach, Stacey B.; Jones, Boyd R.; Shelton, G. Diane; Lyons, Leslie A.

2014-01-01

Myotonia congenita (MC) is a skeletal muscle channelopathy characterized by inability of the muscle to relax following voluntary contraction. Worldwide population prevalence in humans is 1∶100,000. Studies in mice, dogs, humans and goats confirmed myotonia associated with functional defects in chloride channels and mutations in a skeletal muscle chloride channel (CLCN1). CLCN1 encodes for the most abundant chloride channel in the skeletal muscle cell membrane. Five random bred cats from Winnipeg, Canada with MC were examined. All cats had a protruding tongue, limited range of jaw motion and drooling with prominent neck and proximal limb musculature. All cats had blepharospasm upon palpebral reflex testing and a short-strided gait. Electromyograms demonstrated myotonic discharges at a mean frequency of 300 Hz resembling the sound of a ‘swarm of bees’. Muscle histopathology showed hypertrophy of all fiber types. Direct sequencing of CLCN1 revealed a mutation disrupting a donor splice site downstream of exon 16 in only the affected cats. In vitro translation of the mutated protein predicted a premature truncation and partial lack of the highly conserved CBS1 (cystathionine β-synthase) domain critical for ion transport activity and one dimerization domain pivotal in channel formation. Genetic screening of the Winnipeg random bred population of the cats' origin identified carriers of the mutation. A genetic test for population screening is now available and carrier cats from the feral population can be identified. PMID:25356766

Novel XLRS1 gene mutations cause X-linked juvenile retinoschisis in Chinese families.

PubMed

Ma, Xiang; Li, Xiaoxin; Wang, Lihua

2008-01-01

To investigate various XLRS1 (RS1) gene mutations in Chinese families with X-linked juvenile retinoschisis (XLRS or RS). Genomic DNA was isolated from leukocytes of 29 male patients with X-linked juvenile retinoschisis, 38 female carriers, and 100 normal controls. All 6 exons of the RS1 gene were amplified by polymerase chain reaction, and the RS1 gene mutations were determined by direct sequencing. Eleven different RS1 mutations in 12 families were identified in the 29 male patients. The mutations comprised eight missense, two frameshift, and one splice donor site mutation. Four of these mutations, one frameshift mutation (26 del T) in exon 1, one frameshift mutation (488 del G) in exon 5, Asp145His and Arg156Gly in exon 5, have not been previously described. One novel non-disease-related polymorphism, 576C to T (Pro192Pro) in exon 6, was also found. Six recurrent mutations, Ser73Pro and Arg102Gln mutations in exon 4 and Arg200Cys, Arg209His, Arg213Gln, and Cys223Arg mutations in exon 6, were also identified in this study. RS1 gene mutations caused X-linked juvenile retinoschisis in these Chinese families.

Defining the cause of skewed X-chromosome inactivation in X-linked mental retardation by use of a mouse model.

PubMed

Muers, Mary R; Sharpe, Jacqueline A; Garrick, David; Sloane-Stanley, Jacqueline; Nolan, Patrick M; Hacker, Terry; Wood, William G; Higgs, Douglas R; Gibbons, Richard J

2007-06-01

Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal female population but is observed frequently in carriers of some X-linked mutations. Recently, it has been shown that various forms of X-linked mental retardation (XLMR) have a strong association with skewed XCI in female carriers, but the mechanisms underlying this skewing are unknown. ATR-X syndrome, caused by mutations in a ubiquitously expressed, chromatin-associated protein, provides a clear example of XLMR in which phenotypically normal female carriers virtually all have highly skewed XCI biased against the X chromosome that harbors the mutant allele. Here, we have used a mouse model to understand the processes causing skewed XCI. In female mice heterozygous for a null Atrx allele, we found that XCI is balanced early in embryogenesis but becomes skewed over the course of development, because of selection favoring cells expressing the wild-type Atrx allele. Unexpectedly, selection does not appear to be the result of general cellular-viability defects in Atrx-deficient cells, since it is restricted to specific stages of development and is not ongoing throughout the life of the animal. Instead, there is evidence that selection results from independent tissue-specific effects. This illustrates an important mechanism by which skewed XCI may occur in carriers of XLMR and provides insight into the normal role of ATRX in regulating cell fate.

X-linked recessive primary retinal dysplasia is linked to the Norrie disease locus.

PubMed

Ravia, Y; Braier-Goldstein, O; Bat-Miriam, K M; Erlich, S; Barkai, G; Goldman, B

1993-08-01

X-linked primary retinal dysplasia (PRD) refers to an abnormal proliferation of retinal tissue causing either its neural elements or its glial tissue to form folds, giving rise to gliosis. A Jewish family of oriental origin was previously reported by Godel and Goodman, in which a total of five males suffer from different degrees of blindness. The authors postulated that the described findings are distinguished from Norrie disease, since in this case no clinical findings, other than those associated with the eyes, were noticed in the affected males. In addition, two of the carrier females exhibit minimal eye changes. We have performed linkage analysis of the family using the L1.28, p58-1 and m27 beta probes, and DXS426 and MAOB associated microsatellites. Our results map the gene responsible for the disorder between the MAOB and DXS426, m27 beta and p58-1 loci, on the short arm of the X chromosome at Xp11.3, which suggest the possibility that the same gene is responsible for both primary retinal dysplasia and Norrie disease.

Congenital cataracts and other abnormalities in a female with 46.X, del(X)(q26q28)mat: A new locus for X-linked congenital cataract?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Babul, R.; Chitayat, D.; Teshima, I.

1994-09-01

Three forms of X-linked congenital cataracts have been delineated: congenital cataract with posterior Y-sutural opacities in heterozygotes, congenital cataract and microcornea or microphthalmia and congenital cataract-dental syndrome (Nance-Horan syndrome). Of these, only the Nance-Horan syndrome has been mapped to Xp22.3-p21.1. However, Warburg has suggested that these different forms of X-linked congenital cataracts are due to deletions of varying sizes, placing them in the vicinity of the Nance-Horan syndrome region. We report on a female patient born to a 29-year-old primigravida woman who at birth was found to have hypotonia, dysmorphic facial features, hydrocephalus and dense white congenital bilateral cataracts. Othermore » ophthalmological findings included bilateral nystagmus and shallow orbits. Chromosome analysis revealed 46,X,del(X)(q26q28)mat. The mother, however, is phenotypically normal. Brain CT scan on the female infant revealed communicating hydrocephalus and a muscle biopsy showed congenital muscle fiber disproportion. An EMG and NCV were normal. At 4 years of age, her height and weight were below -3SD and her OFC was +2SD. Molecular studies using DNA markers located in Xq26-qter have revealed that the proximal breakpoint in the patient and her mother is defined by the HPRT locus while the distal breakpoint is defined by the locus DXS1108. This indicates that the deletion is not terminal but rather interstitial, retaining sequences proximal to the telomeric region. Other molecular studies are in progress to determine the X-inactivation status of the deleted chromosome in our patient and her mother as a possible explanation for the variation in the phenotype. These clinical and molecular findings suggest that another locus for X-linked congenital cataract exists at Xq26-28.« less

X-linked juvenile retinoschisis in females and response to carbonic anhydrase inhibitors: case report and review of the literature.

PubMed

Ali, Syed; Seth, Rajeev

2013-01-01

A 63 year old woman was referred to the retina clinic after her vision failed to improve in her left eye after cataract surgery. X-linked retinoschisis was diagnosed in the patient after her retina exam revealed an area of retinoschisis and a foveal cyst. The OCT confirmed the macular cyst and the ERG showed loss of B waves. The florescein angiogram showed no significant perifoveal leakage. Her foveal cyst resolved after treatment with carbonic anhydrase inhibitors. The patient's son was examined and his ophthalmologic exam, ERG and imaging findings were consistent with X-linked retinoschisis. However, his bilateral foveal cysts did not respond to treatment with carbonic anhydrase inhibitors. X-linked retinoschisis is a very rare disease in women due to its X-linked recessive inheritance and the foveal cysts associated with it can respond to carbonic anhydrase inhibitors.

[X-linked adrenoleukodystrophy: a report of three cases. The importance of early diagnosis].

PubMed

López Úbeda, Marta; de Arriba Muñoz, Antonio; Ferrer Lozano, Marta; Labarta Aizpún, José I; García Jiménez, María C

2017-10-01

X-linked adrenoleukodystrophy is the most common peroxisomal disorder. This disease is caused by a defect in the ABCD1 gen. Saturated very long chain fatty acids are accumulated in serum, adrenal cortex and central nervous system white matter. The clinical spectrum is characterized by progressive neurological dysfunction and adrenal insufficiency with a devastating prognosis. We report a first case of X-linked adrenoleukodystrophy with fatal evolution which identified two asymptomatic family members and established a preventive treatment. Although there is no definitive cure, we stress the importance of family study and evaluation of the individual in situation of risk to establish an early preventive treatment and to give in each particular situation suitable professional advice. Sociedad Argentina de Pediatría.

Patulous Subarachnoid Space of the Optic Nerve Associated with X-Linked Hypophosphatemic Rickets.

PubMed

Galvez-Ruiz, Alberto; Chaudhry, Imtiaz

2013-01-01

Although the deficiency forms are the most common manifestations of rickets, there are other forms of rickets that are resistant to vitamin D. Of these, the most common is X-linked hypophosphatemic rickets. Rickets represents a group of multiple cranial bone disorders-craniosynostosis and the presence of Chari I malformation being the most notable-that explain the increase in intracranial pressure. We present a 4-year-old patient with an unusual association of X-linked hypophosphataemic rickets, bilateral proptosis, and prominent bilateral widening of the optic nerve sheaths. Although the association between intracranial hypertension and rickets is known, to the best of our knowledge, such a prominent distention of the subarachnoid space of the optic nerve without papilloedema has not been previously described.

Retinal detachment 7 years after prophylactic schisis cavity excision in juvenile X-linked retinoschisis.

PubMed

Sobrin, Lucia; Berrocal, Audina M; Murray, Timothy G

2003-01-01

A 7-year-old boy with X-linked juvenile retinoschisis developed a retinal detachment at the site of previous prophylactic excision of a schisis cavity. The patient underwent a scleral buckle procedure, pars plana vitrectomy, membrane peel, and silicone oil injection with successful reattachment. At last follow-up, the visual acuity was 20/400 and the retina was attached. Prophylactic excision of a schisis cavity may be complicated by retinal detachment several years after the surgery. Given the favorable natural history of schisis cavities in X-linked juvenile retinoschisis, the decision to perform prophylactic excision should be undertaken cautiously after full consideration of the potential complications.

Autosomal Genes of Autosomal/X-Linked Duplicated Gene Pairs and Germ-Line Proliferation in Caenorhabditis elegans

PubMed Central

Maciejowski, John; Ahn, James Hyungsoo; Cipriani, Patricia Giselle; Killian, Darrell J.; Chaudhary, Aisha L.; Lee, Ji Inn; Voutev, Roumen; Johnsen, Robert C.; Baillie, David L.; Gunsalus, Kristin C.; Fitch, David H. A.; Hubbard, E. Jane Albert

2005-01-01

We report molecular genetic studies of three genes involved in early germ-line proliferation in Caenorhabditis elegans that lend unexpected insight into a germ-line/soma functional separation of autosomal/X-linked duplicated gene pairs. In a genetic screen for germ-line proliferation-defective mutants, we identified mutations in rpl-11.1 (L11 protein of the large ribosomal subunit), pab-1 [a poly(A)-binding protein], and glp-3/eft-3 (an elongation factor 1-α homolog). All three are members of autosome/X gene pairs. Consistent with a germ-line-restricted function of rpl-11.1 and pab-1, mutations in these genes extend life span and cause gigantism. We further examined the RNAi phenotypes of the three sets of rpl genes (rpl-11, rpl-24, and rpl-25) and found that for the two rpl genes with autosomal/X-linked pairs (rpl-11 and rpl-25), zygotic germ-line function is carried by the autosomal copy. Available RNAi results for highly conserved autosomal/X-linked gene pairs suggest that other duplicated genes may follow a similar trend. The three rpl and the pab-1/2 duplications predate the divergence between C. elegans and C. briggsae, while the eft-3/4 duplication appears to have occurred in the lineage to C. elegans after it diverged from C. briggsae. The duplicated C. briggsae orthologs of the three C. elegans autosomal/X-linked gene pairs also display functional differences between paralogs. We present hypotheses for evolutionary mechanisms that may underlie germ-line/soma subfunctionalization of duplicated genes, taking into account the role of X chromosome silencing in the germ line and analogous mammalian phenomena. PMID:15687263

A novel mutation in FRMD7 causing X-linked idiopathic congenital nystagmus in a large family

PubMed Central

He, Xiang; Gu, Feng; Wang, Yujing; Yan, Jinting; Zhang, Meng; Huang, Shangzhi

2008-01-01

Purpose To identify the gene responsible for causing an X-linked idiopathic congenital nystagmus (XLICN) in a six-generation Chinese family. Methods Forty-nine members of an XLICN family were recruited and examined after obtaining informed consent. Affected male individuals were genotyped with microsatellite markers around the FRMD7 locus. Mutations were comprehensively screened by direct sequencing using gene specific primers. An X-inactivation pattern was investigated by X chromosome methylation analysis. Results The patients showed phenotypes consistent with XLICN. Genotype analysis showed that male affected individuals in the family shared a common haplotype with the selected markers. Sequencing FRMD7 revealed a G>T transversion (c.812G>T) in exon 9, which caused a conservative substitution of Cys to Phe at codon 271 (p.C271F). This mutation co-segregated with all affected individuals and was present in the obligate, non-penetrant female carriers. However, the mutation was not observed in unaffected familial males or 400 control males. Females with the mutant gene could be affected or carrier and they shared the same inactivated X chromosome harboring the mutation in blood cells, which showed there is no clear causal link between X-inactivation pattern and phenotype. Conclusions We identified a novel mutation in FRMD7 and confirmed the role of this mutation in the pathogenesis of X-linked congenital nystagmus. PMID:18246032

Microsatellites within the feline androgen receptor are suitable for X chromosome-linked clonality testing in archival material.

PubMed

Farwick, Nadine M; Klopfleisch, Robert; Gruber, Achim D; Weiss, Alexander Th A

2017-04-01

Objectives A hallmark of neoplasms is their origin from a single cell; that is, clonality. Many techniques have been developed in human medicine to utilise this feature of tumours for diagnostic purposes. One approach is X chromosome-linked clonality testing using polymorphisms of genes encoded by genes on the X chromosome. The aim of this study was to determine if the feline androgen receptor gene was suitable for X chromosome-linked clonality testing. Methods The feline androgen receptor gene was characterised and used to test clonality of feline lymphomas by PCR and polyacrylamide gel electrophoresis, using archival formalin-fixed, paraffin-embedded material. Results Clonality of the feline lymphomas under study was confirmed and the gene locus was shown to represent a suitable target in clonality testing. Conclusions and relevance Because there are some pitfalls of using X chromosome-linked clonality testing, further studies are necessary to establish this technique in the cat.

X-linked agammaglobulinemia in northern Thailand.

PubMed

Trakultivakorn, Muthita; Ochs, Hans D

2006-03-01

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by a failure to generate immunoglobulins of all isotypes due to the absence of mature B cells and plasma cells, secondary to mutations in the Bruton's tyrosine kinase (Btk) gene. We report six patients with XLA, confirmed by mutation analysis, from northern Thailand. The mean age of onset was 2.5 years and the mean age at diagnosis was 7.3 years. All patients had a history of otitis media, pneumonia and arthritis at the time of diagnosis, five patients had developed bronchiectasis and 3 patients septicemia. Other infections reported included sinusitis (5/6), pericarditis (1/6), meningitis (1/6) and pyoderma (1/6). Haemophilus influenzae, Streptococcus pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus were isolated on multiple occasions. One patient died of sepsis at the age of 16 years. These observations demonstrate that early diagnosis and treatment can improve prognosis and quality of life.

A CLINICIAN'S GUIDE TO X-LINKED HYPOPHOSPHATEMIA

PubMed Central

Carpenter, Thomas O.; Imel, Erik A.; Holm, Ingrid A.; Jan de Beur, Suzanne M.; Insogna, Karl L.

2011-01-01

X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and XLH support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the “Advances in Rare Bone Diseases Scientific Conference,” held at the National Institutes of Health in October 2008. We briefly review the clinical and pathophysiologic features of the disorder, and offer this guide in response to the conference recommendation, base on our collective accumulated experience in the management of this complex disorder. PMID:21538511

Fatal hepatic hemorrhage by peliosis hepatis in X-linked myotubular myopathy: a case report.

PubMed

Motoki, T; Fukuda, M; Nakano, T; Matsukage, S; Fukui, A; Akiyoshi, S; Hayashi, Y K; Ishii, E; Nishino, I

2013-11-01

We report a 5-year-old boy with X-linked myotubular myopathy complicated by peliosis hepatis. At birth, he was affected with marked generalized muscle hypotonia and weakness, which required permanent ventilatory support, and was bedridden for life. He died of acute fatal hepatic hemorrhage after using a mechanical in-exsufflator. Peliosis hepatis, defined as multiple, variable-sized, cystic blood-filled spaces through the liver parenchyma, was confirmed by autopsy. To avoid fatal hepatic hemorrhage by peliosis hepatis, routine hepatic function tests and abdominal imaging tests should be performed for patients with X-linked myotubular myopathy, especially at the time of using artificial respiration. Copyright © 2013 Elsevier B.V. All rights reserved.

X-linked ocular albinism in Blacks. Ocular albinism cum pigmento.

PubMed

O'Donnell, F E; Green, W R; Fleischman, J A; Hambrick, G W

1978-07-01

X-linked ocular albinism can be an unsuspected cause of congenital nystagmus in blacks. In this study, eight of ten black ocular albinos from two kindreds had nonalbinotic, moderately pigmented fundi and no transillumination of the iris. We refer to this paradoxical condition as "ocular albinism cum pigmento." The only constant ophthalmoscopic feature was a foveal hypoplasia. Biopsy of clinically normal skin to demonstrate giant pigment granules is the most accurate means of diagnosis.

X-linked juvenile retinoschisis in a consanguineous family: phenotypic variability and report of a homozygous female patient.

PubMed

Gliem, Martin; Holz, Frank G; Stöhr, Heidi; Weber, Bernhard H F; Charbel Issa, Peter

2014-12-01

To describe the phenotypic variability in a consanguineous family with genetically confirmed X-linked retinoschisis. Five patients, including one homozygous female, were characterized by clinical examination, optical coherence tomography, fundus autofluorescence, mapping of macular pigment optical density, electroretinography, and DNA testing. The 36-year-old male index patient showed a ring of enhanced autofluorescence and outer retinal atrophy on optical coherence tomography. Electroretinography testing revealed a reduced a/b ratio. His mother presented with a central atrophic retina with markedly reduced autofluorescence signal and a surrounding ring of enhanced autofluorescence. The 40-year-old brother of the index patient and his 2 sons showed characteristic signs for X-linked retinoschisis, including retinal schisis and a reduced a/b ratio. Genetic testing revealed a c.293C>A mutation in the RS1 gene in all affected family members while the mother of the index patient was homozygous for this mutation. X-linked retinoschisis can present with a wide phenotypic variability. Here, detailed family history and genetic testing established the diagnosis of X-linked retinoschisis despite striking differences in phenotypic presentation in affected subjects, homozygosity of one affected female, and seemingly dominant inheritance in three subsequent generations because of multiple consanguinity.

Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension.

PubMed

Porreca, Rosa M; Glousker, Galina; Awad, Aya; Matilla Fernandez, Maria I; Gibaud, Anne; Naucke, Christian; Cohen, Scott B; Bryan, Tracy M; Tzfati, Yehuda; Draskovic, Irena; Londoño-Vallejo, Arturo

2018-05-18

Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase.

X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

PubMed

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

2015-06-01

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. © 2015 Society for Endocrinology.

Linkage and candidate gene analysis of X-linked familial exudative vitreoretinopathy.

PubMed

Shastry, B S; Hejtmancik, J F; Plager, D A; Hartzer, M K; Trese, M T

1995-05-20

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder characterized by avascularity of the peripheral retina, retinal exudates, tractional detachment, and retinal folds. The disorder is most commonly transmitted as an autosomal dominant trait, but X-linked transmission also occurs. To initiate the process of identifying the gene responsible for the X-linked disorder, linkage analysis has been performed with three previously unreported three- or four-generation families. Two-point analysis showed linkage to MAOA (Zmax = 2.1, theta max = 0) and DXS228 (Zmax = 0.5, theta max = 0.11), and this was further confirmed by multipoint analysis with these same markers (Zmax = 2.81 at MAOA), which both lie near the gene causing Norrie disease. Molecular genetic analysis further reveals a missense mutation (R121W) in the third exon of the Norrie's disease gene that perfectly cosegregates with the disease through three generations in one family. This mutation was not detected in the unaffected family members and six normal unrelated controls, suggesting that it is likely to be the pathogenic mutation. Additionally, a polymorphic missense mutation (H127R) was detected in a severely affected patient.

Vitreoretinal surgery without schisis cavity excision for the management of juvenile X linked retinoschisis.

PubMed

García-Arumí, J; Corcóstegui, I A; Navarro, R; Zapata, M A; Berrocal, M H

2008-11-01

Juvenile X linked retinoschisis (XLRS) is a congenital X linked recessive retinal disorder characterised by cystic maculopathy and peripheral schisis. This study presents the case of an 8-month-old boy with a documented positive family history of XLRS, with a large retinoschisis cavity affecting the macula, first in the left eye and 1 year later in the right eye. The patient underwent pars plana vitrectomy in both eyes using 23-G instruments, posterior hyaloid dissection, a small retinotomy, fluid drainage with a 42-G cannula, infrared diode laser and silicone oil as internal tamponade. The anatomical and functional outcomes at 3 years following the first surgery are described. To the authors' knowledge, there is no previously reported experience with this technique in patients with XLRS.

Molecular characterization of a novel X-linked syndrome involving developmental delay and deafness.

PubMed

Hildebrand, Michael S; de Silva, Michelle G; Tan, Tiong Yang; Rose, Elizabeth; Nishimura, Carla; Tolmachova, Tanya; Hulett, Joanne M; White, Susan M; Silver, Jeremy; Bahlo, Melanie; Smith, Richard J H; Dahl, Hans-Henrik M

2007-11-01

X-linked syndromes associated with developmental delay and sensorineural hearing loss (SNHL) have been characterized at the molecular level, including Mohr-Tranebjaerg syndrome and Norrie disease. In this study we report on a novel X-linked recessive, congenital syndrome in a family with developmental delay and SNHL that maps to a locus associated with mental retardation (MR) for which no causative gene has been identified. The X-linked recessive inheritance and congenital nature of the syndrome was confirmed by detailed clinical investigation and the family history. Linkage mapping of the X-chromosome was conducted to ascertain the disease locus and candidate genes were screened by direct sequencing and STRP analysis. The recessive syndrome was mapped to Xp11.3-q21.32 and a deletion was identified in a regulatory region upstream of the POU3F4 gene in affected family members. Since mutations in POU3F4 cause deafness at the DFN3 locus, the deletion is the likely cause of the SNHL in this family. The choroideremia (CHM) gene was also screened and a novel missense change was identified. The alteration changes the serine residue at position 89 in the Rab escort 1 protein (REP-1) to a cysteine (S89C). Prenylation of Rab proteins was investigated in patients and the location of REP-1 expression in the brain determined. However, subsequent analysis revealed that this change in CHM was polymorphic having no effect on REP-1 function. Although the causative gene at the MR locus in this family has not been identified, there are a number of genes involved in syndromic and nonsyndromic forms of MR that are potential candidates. Copyright 2007 Wiley-Liss, Inc.

Unique Variants in OPN1LW Cause Both Syndromic and Nonsyndromic X-Linked High Myopia Mapped to MYP1.

PubMed

Li, Jiali; Gao, Bei; Guan, Liping; Xiao, Xueshan; Zhang, Jianguo; Li, Shiqiang; Jiang, Hui; Jia, Xiaoyun; Yang, Jianhua; Guo, Xiangming; Yin, Ye; Wang, Jun; Zhang, Qingjiong

2015-06-01

MYP1 is a locus for X-linked syndromic and nonsyndromic high myopia. Recently, unique haplotypes in OPN1LW were found to be responsible for X-linked syndromic high myopia mapped to MYP1. The current study is to test if such variants in OPN1LW are also responsible for X-linked nonsyndromic high myopia mapped to MYP1. The proband of the family previously mapped to MYP1 was initially analyzed using whole-exome sequencing and whole-genome sequencing. Additional probands with early-onset high myopia were analyzed using whole-exome sequencing. Variants in OPN1LW were selected and confirmed by Sanger sequencing. Long-range and second PCR were used to determine the haplotype and the first gene of the red-green gene array. Candidate variants were further validated in family members and controls. The unique LVAVA haplotype in OPN1LW was detected in the family with X-linked nonsyndromic high myopia mapped to MYP1. In addition, this haplotype and a novel frameshift mutation (c.617_620dup, p.Phe208Argfs*51) in OPN1LW were detected in two other families with X-linked high myopia. The unique haplotype cosegregated with high myopia in the two families, with a maximum LOD score of 3.34 and 2.31 at θ = 0. OPN1LW with the variants in these families was the first gene in the red-green gene array and was not present in 247 male controls. Reevaluation of the clinical data in both families with the unique haplotype suggested nonsyndromic high myopia. Our study confirms the findings that unique variants in OPN1LW are responsible for both syndromic and nonsyndromic X-linked high myopia mapped to MYP1.

X-linked juvenile retinoschisis (XLRS): a review of genotype-phenotype relationships.

PubMed

Kim, David Y; Mukai, Shizuo

2013-01-01

X-linked juvenile retinoschisis (XLRS) is one of the most common genetic causes of juvenile progressive retinal-vitreal degeneration in males. To date, more than 196 different mutations of the RS1 gene have been associated with XLRS. The mutation spectrum is large and the phenotype variable. This review will focus on the clinical features of XLRS and examine the relationship between phenotype and genotype.

A Novel Mutation in a Kazakh Family with X-Linked Alport Syndrome

PubMed Central

Rakhimova, Saule E.; Nigmatullina, Nazym B.; Momynaliev, Kuvat T.; Ramanculov, Yerlan M.

2015-01-01

Alport syndrome is a genetic condition that results in hematuria, progressive renal impairment, hearing loss, and occasionally lenticonus and retinopathy. Approximately 80% of Alport syndrome cases are caused by X-linked mutations in the COL4A5 gene encoding type IV collagen. The objective of this study was to define the SNP profiles for COL4A5 in patients with hereditary nephritis and hematuria. For this, we examined four subjects from one Kazakh family clinically affected with X-linked Alport syndrome due to COL4A5 gene mutations. All 51 exons of the COL4A5 gene were screened by linkage analysis and direct DNA sequencing, resulting in the identification of a novel mutation (G641E) in exon 25. The mutation was found only in two affected family individuals but was not present in healthy family members or 200 unrelated healthy controls. This result demonstrates that this novel mutation is pathogenic and has meaningful implications for the diagnosis of patients with Alport syndrome. PMID:26168235

A Novel Mutation in a Kazakh Family with X-Linked Alport Syndrome.

PubMed

Baikara, Barshagul T; Zholdybayeva, Elena V; Rakhimova, Saule E; Nigmatullina, Nazym B; Momynaliev, Kuvat T; Ramanculov, Yerlan M

2015-01-01

Alport syndrome is a genetic condition that results in hematuria, progressive renal impairment, hearing loss, and occasionally lenticonus and retinopathy. Approximately 80% of Alport syndrome cases are caused by X-linked mutations in the COL4A5 gene encoding type IV collagen. The objective of this study was to define the SNP profiles for COL4A5 in patients with hereditary nephritis and hematuria. For this, we examined four subjects from one Kazakh family clinically affected with X-linked Alport syndrome due to COL4A5 gene mutations. All 51 exons of the COL4A5 gene were screened by linkage analysis and direct DNA sequencing, resulting in the identification of a novel mutation (G641E) in exon 25. The mutation was found only in two affected family individuals but was not present in healthy family members or 200 unrelated healthy controls. This result demonstrates that this novel mutation is pathogenic and has meaningful implications for the diagnosis of patients with Alport syndrome.

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.

PubMed

Schneider, Holm; Faschingbauer, Florian; Schuepbach-Mallepell, Sonia; Körber, Iris; Wohlfart, Sigrun; Dick, Angela; Wahlbuhl, Mandy; Kowalczyk-Quintas, Christine; Vigolo, Michele; Kirby, Neil; Tannert, Corinna; Rompel, Oliver; Rascher, Wolfgang; Beckmann, Matthias W; Schneider, Pascal

2018-04-26

Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).

Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis

PubMed Central

Bush, Ronald A.; Wei, Lisa L.; Sieving, Paul A.

2015-01-01

Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS. PMID:26101206

Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects.

PubMed

Bauters, Marijke; Frints, Suzanna G; Van Esch, Hilde; Spruijt, Liesbeth; Baldewijns, Marcella M; de Die-Smulders, Christine E M; Fryns, Jean-Pierre; Marynen, Peter; Froyen, Guy

2014-08-01

Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1 Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism. The duplication was mapped from 138.7 to 139.8 Mb, harboring only two annotated genes, SOX3 and ATP11C, and was shown to be a direct tandem copy number gain. Unexpectedly, the microduplication did not fully segregate with the disease in this family suggesting that SOX3 duplications have variable penetrance for X-linked hypopituitarism. In the same family, a female fetus presenting with a neural tube defect was also shown to carry the SOX3 copy number gain. Since we also demonstrated increased SOX3 mRNA levels in amnion cells derived from an unrelated t(X;22)(q27;q11) female fetus with spina bifida, we propose that increased levels of SOX3 could be a risk factor for neural tube defects. © 2014 Wiley Periodicals, Inc.

Gastrointestinal Manifestations in X-linked Agammaglobulinemia

PubMed Central

Barmettler, Sara; Otani, Iris M.; Minhas, Jasmit; Abraham, Roshini S.; Chang, Yenhui; Dorsey, Morna J.; Ballas, Zuhair K.; Bonilla, Francisco A.; Ochs, Hans D.; Walter, Jolan E.

2017-01-01

Purpose X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in XLA, the spectrum of gastrointestinal manifestations has not previously been fully explored. Methods We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the USIDNet, a national registry of primary immunodeficiencies. Results In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide-ranging, and management strategies were diverse and mainly experimental. Conclusions Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients. PMID:28236219

Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder.

PubMed

Yanagi, Kumiko; Kaname, Tadashi; Wakui, Keiko; Hashimoto, Ohiko; Fukushima, Yoshimitsu; Naritomi, Kenji

2012-01-01

Mutations in the X-linked genes neuroligin 3 (NLGN3) and neuroligin 4X (NLGN4X) were first implicated in the pathogenesis of X-linked autism in Swedish families. However, reports of mutations in these genes in autism spectrum disorder (ASD) patients from various ethnic backgrounds present conflicting results regarding the etiology of ASD, possibly because of genetic heterogeneity and/or differences in their ethnic background. Additional mutation screening study on another ethnic background could help to clarify the relevance of the genes to ASD. We scanned the entire coding regions of NLGN3 and NLGN4X in 62 Japanese patients with ASD by polymerase chain reaction-high-resolution melting curve and direct sequencing analyses. Four synonymous substitutions, one in NLGN3 and three in NLGN4X, were identified in four of the 62 patients. These substitutions were not present in 278 control X-chromosomes from unrelated Japanese individuals and were not registered in the database of Single Nucleotide Polymorphisms build 132 or in the Japanese Single Nucleotide Polymorphisms database, indicating that they were novel and specific to ASD. Though further analysis is necessary to determine the physiological and clinical importance of such substitutions, the possibility of the relevance of both synonymous and nonsynonymous substitutions with the etiology of ASD should be considered.

Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder

PubMed Central

Yanagi, Kumiko; Kaname, Tadashi; Wakui, Keiko; Hashimoto, Ohiko; Fukushima, Yoshimitsu; Naritomi, Kenji

2012-01-01

Mutations in the X-linked genes neuroligin 3 (NLGN3) and neuroligin 4X (NLGN4X) were first implicated in the pathogenesis of X-linked autism in Swedish families. However, reports of mutations in these genes in autism spectrum disorder (ASD) patients from various ethnic backgrounds present conflicting results regarding the etiology of ASD, possibly because of genetic heterogeneity and/or differences in their ethnic background. Additional mutation screening study on another ethnic background could help to clarify the relevance of the genes to ASD. We scanned the entire coding regions of NLGN3 and NLGN4X in 62 Japanese patients with ASD by polymerase chain reaction-high-resolution melting curve and direct sequencing analyses. Four synonymous substitutions, one in NLGN3 and three in NLGN4X, were identified in four of the 62 patients. These substitutions were not present in 278 control X-chromosomes from unrelated Japanese individuals and were not registered in the database of Single Nucleotide Polymorphisms build 132 or in the Japanese Single Nucleotide Polymorphisms database, indicating that they were novel and specific to ASD. Though further analysis is necessary to determine the physiological and clinical importance of such substitutions, the possibility of the relevance of both synonymous and nonsynonymous substitutions with the etiology of ASD should be considered. PMID:22934180

MHC class 2 deficiency and X-linked agammaglobulinaemia in a consanguineous extended family.

PubMed

Broides, A; Shubinsky, G; Parvari, R; Grimbacher, B; Somech, R; Garty, B Z; Levy, J

2009-08-01

Manifestations of immunodeficiency within the same family are presumed to be the same disease. We report a consanguineous extended family where four patients have immunodeficiency, three have X-linked agammaglobulinaemia and one has major histocompatibility complex class 2 deficiency. Within one family, two rare genetic diseases with similar clinical manifestations can occur.

Dysregulation of X-linked gene expression in Klinefelter's syndrome and association with verbal cognition.

PubMed

Vawter, Marquis P; Harvey, Philip D; DeLisi, Lynn E

2007-09-05

Klinefelter's Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini-Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression-cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = -0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition-gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis. Copyright 2007 Wiley-Liss, Inc.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

PubMed Central

Carpinelli, Marina R.; Wicks, Ian P.; Sims, Natalie A.; O’Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J.; Bahlo, Melanie; Alexander, Warren S.; Hilton, Douglas J.

2002-01-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G1) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease. PMID:12414538

An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.

PubMed

Carpinelli, Marina R; Wicks, Ian P; Sims, Natalie A; O'Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J; Bahlo, Melanie; Alexander, Warren S; Hilton, Douglas J

2002-11-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia.

PubMed

Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B; Liberton, Denise K; Landan, Maya; Wang, Zhifeng; Boekelheide, Anne; Langham, Margaret; Mushegyan, Vagan; Oberoi, Snehlata; Brao, Rosalie; Wen, Timothy; Johnson, Ramsey; Huttner, Kenneth; Grange, Dorothy K; Spritz, Richard A; Hallgrímsson, Benedikt; Jheon, Andrew H; Klein, Ophir D

2014-09-01

Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.

X-linked recessive nephrogenic diabetes insipidus: a clinico-genetic study.

PubMed

Hong, Che Ry; Kang, Hee Gyung; Choi, Hyun Jin; Cho, Min Hyun; Lee, Jung Won; Kang, Ju Hyung; Park, Hye Won; Koo, Ja Wook; Ha, Tae-Sun; Kim, Su-Yung; Il Cheong, Hae

2014-01-01

A retrospective genotype and phenotype analysis of X-linked congenital nephrogenic diabetes insipidus (NDI) was conducted on a nationwide cohort of 25 (24 male, 1 female) Korean children with AVPR2 gene mutations, comparing non-truncating and truncating mutations. In an analysis of male patients, the median age at diagnosis was 0.9 years old. At a median follow-up of 5.4 years, urinary tract dilatations were evident in 62% of patients and their median glomerular filtration rate was 72 mL/min/1.73 m2. Weights and heights were under the 3rd percentile in 22% and 33% of patients, respectively. One patient had low intelligence quotient and another developed end-stage renal disease. No statistically significant genotype-phenotype correlation was found between non-truncating and truncating mutations. One patient was female; she was analyzed separately because inactivation and mosaicism of the X chromosome may influence clinical manifestations in female patients. Current unsatisfactory long-term outcome of congenital NDI necessitates a novel therapeutic strategy.

Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX Trial)

PubMed Central

Hoffman, Dennis R.; Hughbanks-Wheaton, Dianna K.; Pearson, N. Shirlene; Fish, Gary E.; Spencer, Rand; Takacs, Alison; Klein, Martin; Locke, Kirsten G.; Birch, David G.

2016-01-01

IMPORTANCE X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100 000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. OBJECTIVE To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTS A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non–X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). INTERVENTIONS All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURES The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. RESULTS Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse

Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis.

PubMed

Bradshaw, K D; Carr, B R

1986-07-01

PSD-X-linked ichthyosis are manifestations of a similar disorder of an inborn error of metabolism characterized by a deficiency of steroid sulfatase. The decreased enzyme activity is due to the absence of the expression of enzyme (steroid sulfatase) protein. Affected individuals with this disorder are males (X-linked inheritance) with a frequency of 1/2000 to 1/6000 births. Homozygous females from cosanguineous marriages have been reported with this disorder. The diagnosis is suspected and confirmed by: Low estriol excretion; Negative DHEAS loading test Increased DHEAS in amnionic fluid; Normal DHEAS in cord plasma; Possible delayed or abnormal labor patterns; Decreased sulfatase activity in the placenta, fibroblast, erythrocytes, lymphocytes or leukocytes of affected individuals; Development of ichthyosis in male infants at 2 to 3 months of age.

A recoding scheme for X-linked and pseudoautosomal loci to be used with computer programs for autosomal LOD-score analysis.

PubMed

Strauch, Konstantin; Baur, Max P; Wienker, Thomas F

2004-01-01

We present a recoding scheme that allows for a parametric multipoint X-chromosomal linkage analysis of dichotomous traits in the context of a computer program for autosomes that can use trait models with imprinting. Furthermore, with this scheme, it is possible to perform a joint multipoint analysis of X-linked and pseudoautosomal loci. It is required that (1) the marker genotypes of all female nonfounders are available and that (2) there are no male nonfounders who have daughters in the pedigree. The second requirement does not apply if the trait locus is pseudoautosomal. The X-linked marker loci are recorded by adding a dummy allele to the males' hemizygous genotypes. For modelling an X-linked trait locus, five different liability classes are defined, in conjunction with a paternal imprinting model for male nonfounders. The formulation aims at the mapping of a diallelic trait locus relative to an arbitrary number of codominant markers with known genetic distances, in cases where a program for a genuine X-chromosomal analysis is not available. 2004 S. Karger AG, Basel.

Genetics Home Reference: myotonia congenita

MedlinePlus

... Manual Consumer Version: Congenital Myopathies Orphanet: Thomsen and Becker disease Patient Support and Advocacy Resources (3 links) Muscular Dystrophy Association National Organization for Rare Disorders (NORD) Resource ...

Indocyanine green angiography of juvenile X-linked retinoschisis.

PubMed

Souied, Eric H; Goritsa, Anna; Querques, Giuseppe; Coscas, Gabriel; Soubrane, Gisele

2005-09-01

In juvenile X-linked retinoschisis (XLRS), fluorescein angiography is usually unremarkable and contributes poorly to the diagnosis. However, indocyanine green (ICG) angiography features in eyes that are affected with XLRS were not yet described. Retrospective observational case series. A complete ophthalmologic examination that included ICG angiography was performed on three unrelated male patients (six eyes) who were 15, 22, and 48 years old. A distinct hyperfluorescent stellate pattern in the macular area that was associated with radial lines of hypofluorescence that were centered on the foveola was observed on the early phase of ICG examination (six of six eyes). This feature disappeared on the late phase of ICG examination. On these six XLRS eyes, early phases of ICG examination revealed an unusual radial aspect on the macula. This finding suggests that ICG angiography may be useful for the diagnosis of XLRS.

Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.

PubMed

Naito, E; Ito, M; Yokota, I; Saijo, T; Matsuda, J; Osaka, H; Kimura, S; Kuroda, Y

1997-08-01

We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency in a patient with an X-linked form of Leigh syndrome. PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP) concentration (0.4 mmol/L). However, in the presence of a low concentration (1 x 10(-4) mmol/L) of TPP, the activity was significantly decreased, indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP. The patient's older brother also was diagnosed as PDHC deficiency with Leigh syndrome, suggesting that PDHC deficiency in these two brothers was not a de novo mutation. Sequencing of the X-linked PDHC E1 alpha subunit revealed a C-->G point mutation at nucleotide 787, resulting in a substitution of glycine for arginine 263. Restriction enzyme analysis of the E1 alpha gene revealed that the mother was a heterozygote, indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance.

Combination of a Haploidentical Stem Cell Transplant With Umbilical Cord Blood for Cerebral X-Linked Adrenoleukodystrophy.

PubMed

Jiang, Hua; Jiang, Min-Yan; Liu, Sha; Cai, Yan-Na; Liang, Cui-Li; Liu, Li

2015-08-01

Childhood cerebral X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disorder that affects central nervous system myelin and the adrenal cortex. Hematopoietic stem cell transplantation is the best available curative therapy if performed during the early stages of disease. Only 30% of patients who might benefit from a hematopoietic stem cell transplant will have a full human leukocyte antigen-matched donor, which is considered to be the best choice. We present a 5-year-old boy with cerebral X-linked adrenoleukodystrophy whose brain magnetic resonance imaging severity score was 7 and who needed an immediate transplantation without an available full human leukocyte antigen-matched donor. We combined haploidentical and umbilical cord blood sources for transplantation and saw encouraging results. After transplantation, the patient showed neurological stability for 6 months and the level of very long chain fatty acids had decreased. By 1 year, the patient appeared to gradually develop cognition, motor, and visual disturbances resulting from possible mix chimerism. Transplantation of haploidentical stem cells combined with the infusion of umbilical cord blood is a novel approach for treating cerebral X-linked adrenoleukodystrophy. It is critical to monitor posttransplant chimerism and carry out antirejection therapy timely for a beneficial clinical outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Inherent X-Linked Genetic Variability and Cellular Mosaicism Unique to Females Contribute to Sex-Related Differences in the Innate Immune Response.

PubMed

Spolarics, Zoltan; Peña, Geber; Qin, Yong; Donnelly, Robert J; Livingston, David H

2017-01-01

Females have a longer lifespan and better general health than males. Considerable number of studies also demonstrated that, after trauma and sepsis, females present better outcomes as compared to males indicating sex-related differences in the innate immune response. The current notion is that differences in the immuno-modulatory effects of sex hormones are the underlying causative mechanism. However, the field remains controversial and the exclusive role of sex hormones has been challenged. Here, we propose that polymorphic X-linked immune competent genes, which are abundant in the population are important players in sex-based immuno-modulation and play a key role in causing sex-related outcome differences following trauma or sepsis. We describe the differences in X chromosome (ChrX) regulation between males and females and its consequences in the context of common X-linked polymorphisms at the individual as well as population level. We also discuss the potential pathophysiological and immune-modulatory aspects of ChrX cellular mosaicism, which is unique to females and how this may contribute to sex-biased immune-modulation. The potential confounding effects of ChrX skewing of cell progenitors at the bone marrow is also presented together with aspects of acute trauma-induced de novo ChrX skewing at the periphery. In support of the hypothesis, novel observations indicating ChrX skewing in a female trauma cohort as well as case studies depicting the temporal relationship between trauma-induced cellular skewing and the clinical course are also described. Finally, we list and discuss a selected set of polymorphic X-linked genes, which are frequent in the population and have key regulatory or metabolic functions in the innate immune response and, therefore, are primary candidates for mediating sex-biased immune responses. We conclude that sex-related differences in a variety of disease processes including the innate inflammatory response to injury and infection may be

Evidence for Phex haploinsufficiency in murine X-linked hypophosphatemia.

PubMed

Wang, L; Du, L; Ecarot, B

1999-04-01

Mutations in the PHEX gene (phosphate-regulating gene with homology to endopeptidases on the X-chromosome) are responsible for X-linked hypophosphatemia (HYP). We previously reported the full-length coding sequence of murine Phex cDNA and provided evidence of Phex expression in bone and tooth. Here, we report the cloning of the entire 3.5-kb 3'UTR of the Phex gene, yielding a total of 6248 bp for the Phex transcript. Southern blot and RT-PCR analyses revealed that the 3' end of the coding sequence and the 3'UTR of the Phex gene, spanning exons 16 to 22, are deleted in Hyp, the mouse model for HYP. Northern blot analysis of bone revealed lack of expression of stable Phex mRNA from the mutant allele and expression of Phex transcripts from the wild-type allele in Hyp heterozygous females. Expression of the Phex protein in heterozygotes was confirmed by Western analysis with antibodies raised against a COOH-terminal peptide of the mouse Phex protein. Taken together, these results indicate that the dominant pattern of Hyp inheritance in mice is due to Phex haploinsufficiency.

Inflammatory profile in X-linked adrenoleukodystrophy patients: Understanding disease progression.

PubMed

Marchetti, Desirèe Padilha; Donida, Bruna; Jacques, Carlos Eduardo; Deon, Marion; Hauschild, Tatiane Cristina; Koehler-Santos, Patricia; de Moura Coelho, Daniella; Coitinho, Adriana Simon; Jardim, Laura Bannach; Vargas, Carmen Regla

2018-01-01

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro- and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro-inflammatory cytokines IL-1β, IL-2, IL-8, and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti-inflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL-2, IL-6, and IFN-γ), Th2 (IL-4 and IL-10), and macrophages response (TNF-α and IL-1β) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X-ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression. © 2017 Wiley Periodicals, Inc.

Imprinted and X-linked non-coding RNAs as potential regulators of human placental function

PubMed Central

Buckberry, Sam; Bianco-Miotto, Tina; Roberts, Claire T

2014-01-01

Pregnancy outcome is inextricably linked to placental development, which is strictly controlled temporally and spatially through mechanisms that are only partially understood. However, increasing evidence suggests non-coding RNAs (ncRNAs) direct and regulate a considerable number of biological processes and therefore may constitute a previously hidden layer of regulatory information in the placenta. Many ncRNAs, including both microRNAs and long non-coding transcripts, show almost exclusive or predominant expression in the placenta compared with other somatic tissues and display altered expression patterns in placentas from complicated pregnancies. In this review, we explore the results of recent genome-scale and single gene expression studies using human placental tissue, but include studies in the mouse where human data are lacking. Our review focuses on the ncRNAs epigenetically regulated through genomic imprinting or X-chromosome inactivation and includes recent evidence surrounding the H19 lincRNA, the imprinted C19MC cluster microRNAs, and X-linked miRNAs associated with pregnancy complications. PMID:24081302

Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood.

PubMed

Ouvrier, Robert; Geevasingha, Nimeshan; Ryan, Monique M

2007-08-01

The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing.

Treatment of Chronic Enterovirus Encephalitis With Fluoxetine in a Patient With X-Linked Agammaglobulinemia.

PubMed

Gofshteyn, Jacqueline; Cárdenas, Ana María; Bearden, David

2016-11-01

Enterovirus may result in a devastating chronic encephalitis in immunocompromised patients, particularly in patients with X-linked agammaglobulinemia. Prognosis for patients with chronic enterovirus encephalitis is poor, almost invariably resulting in mortality without specific treatment. There are currently no approved antiviral agents for enterovirus, but the antidepressant drug fluoxetine has been identified through library-based compound screening as a potential anti-enteroviral agent in vitro. However, use of fluoxetine has not previously been studied in humans with enteroviral disease. A five year old boy with X-linked agammaglobulinemia presented with progressive neurological deterioration and was found to have chronic enterovirus encephalitis by brain biopsy. He failed to respond to standard treatment with high dose intravenous immunoglobulin, but showed stabilization and improvement following treatment with fluoxetine. This is the first report to describe the use of fluoxetine as a potential therapy for chronic enterovirus infection. Further investigation of fluoxetine as a treatment option for chronic enterovirus encephalitis is necessary. Copyright © 2016 Elsevier Inc. All rights reserved.

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

PubMed

Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

PubMed Central

Madrigal, I; Rodríguez-Revenga, L; Armengol, L; González, E; Rodriguez, B; Badenas, C; Sánchez, A; Martínez, F; Guitart, M; Fernández, I; Arranz, JA; Tejada, MI; Pérez-Jurado, LA; Estivill, X; Milà, M

2007-01-01

Background Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). Conclusion This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients. PMID:18047645

Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. 1988.

PubMed

Neri, G; Marini, R; Cappa, M; Borrelli, P; Opitz, J M

2013-11-01

The following paper by Professor GiovanniNeri and colleagues was originally published in 1988, American Journal of Medical Genetics 30:287–299. This paper represented a seminal work at the time of publication as it not only reported a new family with a disorder that had been called the “gigantism-dysplasia syndrome”, but also suggested naming the condition the Simpson-Golabi-Behmel syndrome. This eponym has clearly stood “the test of time”, and that designation is now widely accepted. This paper is graciously republished by Wiley-Blackwell in the Special Festschrift issue honoring Professor Neri. We report on another family with the so-called "gigantism-dysplasia syndrome", an X-linked condition characterized by pre-and postnatal overgrowth, characteristic face with apparent coarseness, dysplastic changes in several tissues, and mild intellectual impairment. This condition has been called the Golabi-Rosen syndrome; however, we agree that is the same entity as that described, in a milder form, by Simpson et al. in 1975 and by Behmel et al. in 1984. Therefore, we suggest that this entity be designated the Simpson-Golabi-Behmel syndrome. The manifestations in affected individuals suggest that this condition represents an X-linked encephalo-tropho-schisis syndrome. © 2013 Wiley Periodicals, Inc.

Connexin mutations in X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Scherer, S.S.; Wang, S.

1993-12-24

X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry techniques, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32more » plays an important role in peripheral nerve.« less

Molecular population genetics of X-linked genes in Drosophila pseudoobscura.

PubMed Central

Kovacevic, M; Schaeffer, S W

2000-01-01

This article presents a nucleotide sequence analysis of 500 bp determined in each of five X-linked genes, runt, sisterlessA, period, esterase 5, and Heat-shock protein 83, in 40 Drosophila pseudoobscura strains collected from two populations. Estimates of the neutral migration parameter for the five loci show that gene flow among D. pseudoobscura populations is sufficient to homogenize inversion frequencies across the range of the species. Nucleotide diversity at each locus fails to reject a neutral model of molecular evolution. The sample of 40 chromosomes included six Sex-ratio inversions, a series of three nonoverlapping inversions that are associated with a strong meiotic drive phenotype. The selection driven by the Sex-ratio meiotic drive element has not fixed variation across the X chromosome of D. pseudoobscura because, while significant linkage disequilibrium was observed within the sisterlessA, period, and esterase 5 genes, we did not find evidence for nonrandom association among loci. The Sex-ratio chromosome was estimated to be 25,000 years old based on the decomposition of linkage disequilibrium between esterase 5 and Heat-shock protein 83 or 1 million years old based on the net divergence of esterase 5 between Standard and Sex-ratio chromosomes. Genetic diversity was depressed within esterase 5 within Sex-ratio chromosomes, while the four other genes failed to show a reduction in heterozygosity in the Sex-ratio background. The reduced heterogeneity in esterase 5 is due either to its location near one of the Sex-ratio inversion breakpoints or that it is closely linked to a gene or genes responsible for the Sex-ratio meiotic drive system. PMID:10978282

1 Tb/s x km multimode fiber link combining WDM transmission and low-linewidth lasers.

PubMed

Gasulla, I; Capmany, J

2008-05-26

We have successfully demonstrated an error-free transmission of 10 x 20 Gb/s 200 GHz-spaced ITU channels through a 5 km link of 62.5-microm core-diameter graded-index multimode silica fiber. The overall figure corresponds to an aggregate bit rate per length product of 1 Tb/s x km, the highest value ever reported to our knowledge. Successful transmission is achieved by a combination of low-linewidth DFB lasers and the central launch technique.

Sex-linked dominant

MedlinePlus

Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase

PubMed Central

Parry, Erin M.; Alder, Jonathan K.; Qi, Xiaodong; Chen, Julian J.-L.

2011-01-01

Mutations in the essential telomerase components hTERT and hTR cause dyskeratosis congenita, a bone marrow failure syndrome characterized by mucocutaneous features. Some (∼ 3%) sporadic aplastic anemia (AA) and idiopathic pulmonary fibrosis cases also carry mutations in hTERT and hTR. Even though it can affect clinical outcome, because the mutation frequency is rare, genetic testing is not standard. We examined whether the cooccurrence of bone marrow failure and pulmonary fibrosis in the same individual or family enriches for the presence of a telomerase mutation. Ten consecutive individuals with a total of 36 family members who fulfilled these criteria carried a germline mutant telomerase gene (100%). The mean age of onset for individuals with AA was significantly younger than that for those with pulmonary fibrosis (14 vs 51; P < .0001). Families displayed autosomal dominant inheritance and there was an evolving pattern of genetic anticipation, with the older generation primarily affected by pulmonary fibrosis and successive generations by bone marrow failure. The cooccurrence of AA and pulmonary fibrosis in a single patient or family is highly predictive for the presence of a germline telomerase defect. This diagnosis affects the choice of bone marrow transplantation preparative regimen and can prevent morbidity. PMID:21436073

Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension

PubMed Central

Porreca, Rosa M; Glousker, Galina; Awad, Aya; Matilla Fernandez, Maria I; Gibaud, Anne; Naucke, Christian; Cohen, Scott B; Bryan, Tracy M; Tzfati, Yehuda; Draskovic, Irena; Londoño-Vallejo, Arturo

2018-01-01

Abstract Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase. PMID:29522136

Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation.

PubMed Central

Stevenson, R E; Häne, B; Arena, J F; May, M; Lawrence, L; Lubs, H A; Schwartz, C E

1997-01-01

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively. Images PMID:9192265

Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation.

PubMed

Stevenson, R E; Häne, B; Arena, J F; May, M; Lawrence, L; Lubs, H A; Schwartz, C E

1997-06-01

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively.

Dysregulation of X-Linked Gene Expression in Klinefelter’s Syndrome and Association With Verbal Cognition

PubMed Central

Vawter, Marquis P.; Harvey, Philip D.; DeLisi, Lynn E.

2007-01-01

Klinefelter’s Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini–Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression–cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = −0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition–gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis. PMID:17347996

X-linked hypophosphataemia: a homologous disorder in humans and mice.

PubMed

Tenenhouse, H S

1999-02-01

X-linked hypophosphatemia is an inherited disorder of phosphate (Pi) homeostasis characterized by growth retardation, rickets and osteomalacia, hypophosphataemia, and aberrant renal Pi reabsorption and vitamin D metabolism. Studies in murine Hyp and Gy homologues have identified a specific defect in Na+-Pi cotransport at the brush border membrane, abnormal regulation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) synthesis and degradation, and an intrinsic defect in bone mineralization. The mutant gene has been identified in XLH patients, by positional cloning, and in Hyp and Gy mice, and was designated PHEX/Phex to signify a PHosphate-regulating gene with homology to Endopeptidases on the X chromosome. PHEX/Phex is expressed in bones and teeth but not in kidney and efforts are under way to elucidate how loss of PHEX/Phex function elicits the mutant phenotype. Based on its homology to endopeptidases, it is postulated that PHEX/Phex is involved in the activation or inactivation of a peptide hormone(s) which plays a key role in the regulation of bone mineralization, renal Pi handling and vitamin D metabolism.

Role of ALDP (ABCD1) and Mitochondria in X-Linked Adrenoleukodystrophy

PubMed Central

McGuinness, M. C.; Lu, J.-F.; Zhang, H.-P.; Dong, G.-X.; Heinzer, A. K.; Watkins, P. A.; Powers, J.; Smith, K. D.

2003-01-01

Peroxisomal disorders have been associated with malfunction of peroxisomal metabolic pathways, but the pathogenesis of these disorders is largely unknown. X-linked adrenoleukodystrophy (X-ALD) is associated with elevated levels of very-long-chain fatty acids (VLCFA; C>22:0) that have been attributed to reduced peroxisomal VLCFA β-oxidation activity. Previously, our laboratory and others have reported elevated VLCFA levels and reduced peroxisomal VLCFA β-oxidation in human and mouse X-ALD fibroblasts. In this study, we found normal levels of peroxisomal VLCFA β-oxidation in tissues from ALD mice with elevated VLCFA levels. Treatment of ALD mice with pharmacological agents resulted in decreased VLCFA levels without a change in VLCFA β-oxidation activity. These data indicate that ALDP does not determine the rate of VLCFA β-oxidation and that VLCFA levels are not determined by the rate of VLCFA β-oxidation. The rate of peroxisomal VLCFA β-oxidation in human and mouse fibroblasts in vitro is affected by the rate of mitochondrial long-chain fatty acid β-oxidation. We hypothesize that ALDP facilitates the interaction between peroxisomes and mitochondria, resulting, when ALDP is deficient in X-ALD, in increased VLCFA accumulation despite normal peroxisomal VLCFA β-oxidation in ALD mouse tissues. In support of this hypothesis, mitochondrial structural abnormalities were observed in adrenal cortical cells of ALD mice. PMID:12509471

Pyoderma gangrenosum-like ulcer in a patient with X-linked agammaglobulinemia: identification of Helicobacter bilis by mass spectrometry analysis.

PubMed

Murray, Patrick R; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B; Ecker, David J; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L

2010-05-01

Pyoderma gangrenosum-like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient's culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when subcultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum-like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum-like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy.

BTKbase, mutation database for X-linked agammaglobulinemia (XLA).

PubMed Central

Vihinen, M; Brandau, O; Brandén, L J; Kwan, S P; Lappalainen, I; Lester, T; Noordzij, J G; Ochs, H D; Ollila, J; Pienaar, S M; Riikonen, P; Saha, B K; Smith, C I

1998-01-01

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 463 mutation entries from 406 unrelated families showing 303 unique molecular events. In addition to mutations, the database also lists variants or polymorphisms. Each patient is given a unique patient identity number (PIN). Information is included regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites that code for arginine residues. The putative structural implications of all the missense mutations are given in the database. The improved version of the registry having a number of new features is available at http://www. helsinki.fi/science/signal/btkbase.html PMID:9399844

Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chalmers, R.M.; Davis, M.B.; Sweeney, M.G.

1996-07-01

Pedigree analysis of British families with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skewing of X inactivation. Linkage analysis in British and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studied. Further, there was no excess skewing of X inactivation in affectedmore » females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of incomplete penetrance and male predominance in LHON remains unclear. 27 refs., 1 fig., 3 tabs.« less

X-linked Charcot-Marie-Tooth disease predominates in a cohort of multiethnic Malaysian patients.

PubMed

Shahrizaila, Nortina; Samulong, Sarimah; Tey, Shelisa; Suan, Liaw Chiew; Meng, Lao Kah; Goh, Khean Jin; Ahmad-Annuar, Azlina

2014-02-01

Data regarding Charcot-Marie-Tooth disease is lacking in Southeast Asian populations. We investigated the frequency of the common genetic mutations in a multiethnic Malaysian cohort. Patients with features of Charcot-Marie-Tooth disease or hereditary liability to pressure palsies were investigated for PMP22 duplication, deletion, and point mutations and GJB1, MPZ, and MFN2 point mutations. Over a period of 3 years, we identified 25 index patients. A genetic diagnosis was reached in 60%. The most common were point mutations in GJB1, accounting for X-linked Charcot-Marie-Tooth disease (24% of the total patient population), followed by PMP22 duplication causing Charcot-Marie-Tooth disease type 1A (20%). We also discovered 2 novel GJB1 mutations, c.521C>T (Proline174Leucine) and c.220G>A (Valine74Methionine). X-linked Charcot-Marie-Tooth disease was found to predominate in our patient cohort. We also found a better phenotype/genotype correlation when applying a more recently recommended genetic approach to Charcot-Marie-Tooth disease. Copyright © 2013 Wiley Periodicals, Inc.

High-resolution mapping of the x-linked hypohidrotic ectodermal dysplasia (EDA) locus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zonana, J.; Jones, M.; Litt, M.

1992-11-01

The X-linked hypohidrotic ectodermal dysplasia (EDA) locus has been previously localized to the subchromosomal region Xq11-q21.1. The authors have extended previous linkage studies and analyzed linkage between the EDA locus and 10 marker loci, including five new loci, in 41 families. Four of the marker loci showed no recombination with the EDA locus, and six other loci were also linked to the EDA locus with recombination fractions of .009-.075. Multipoint analysis gave support to the placement of the PGK1P1 locus proximal to the EDA locus and the DXS453 and PGK1 loci distal to EDA. Further ordering of the loci couldmore » be inferred from a human-rodent somatic cell hybrid derived from an affected female with EDA and an X;9 translocation and from studies of an affected male with EDA and a submicroscopic deletion. Three of the proximal marker loci, which showed no recombination with the EDA locus, when used in combination, were informative in 92% of females. The closely linked flanking polymorphic loci DXS339 and DXS453 had heterozygosites of 72% and 76%, respectively, and when used jointly, they were doubly informative in 52% of females. The human DXS732 locus was defined by a conserved mouse probe pcos169E/4 (DXCrc169 locus) that consegregates with the mouse tabby (Ta) locus, a potential homologue to the EDA locus. The absence of recombination between EDA and the DXSA732 locus lends support to the hypothesis that the DXCrc169 locus in the mouse and the DXS732 locus in humans may contain candidate sequences for the Ta and EDA genes, respectively. 36 refs., 1 fig., 5 tabs.« less

Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia

USDA-ARS?s Scientific Manuscript database

Focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular, and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and fou...

Effects of oxygen stoichiometry on the scaling behaviors of YBa2Cu3O(x) grain boundary weak-links

NASA Technical Reports Server (NTRS)

Wu, K. H.; Fu, C. M.; Jeng, W. J.; Juang, J. Y.; Uen, T. M.; Gou, Y. S.

1995-01-01

The effects of oxygen stoichiometry on the transport properties of the pulsed laser deposited YBa2Cu3O(x) bicrystalline grain boundary weak-link junctions were studied. It is found that not only the cross boundary resistive transition foot structure can be manipulated repeatedly with oxygen annealing processes but the junction behaviors are also altered in accordance. In the fully oxygenated state i.e with x = 7.0 in YBa2Cu3O(x) stoichiometry, the junction critical current exhibits a power of 2 scaling behavior with temperature. In contrast, when annealed in the conditions of oxygen-deficient state (e.g with x = 6.9 in YBa2Cu3O(x) stoichiometry) the junction critical current switches to a linear temperature dependence behavior. The results are tentatively attributed to the modification of the structure in the boundary area upon oxygen annealing, which, in turn, will affect the effective dimension of the geometrically constrained weak-link bridges. The detailed discussion on the responsible physical mechanisms as well as the implications of the present results on device applications will be given.

7 Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy

PubMed Central

Ratai, Eva; Kok, Trina; Wiggins, Christopher; Wiggins, Graham; Grant, Ellen; Gagoski, Borjan; O'Neill, Gilmore; Adalsteinsson, Elfar; Eichler, Florian

2010-01-01

Background Adult patients with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging. Objective To test the hypothesis that neurochemistry in normal appearing brain differs among adult phenotypes of X-ALD, and that neurochemical changes correlate with the severity of symptoms. Patients and Methods Using a 7 Tesla scanner we performed structural and proton MRSI in 13 adult patients with X-ALD, including 4 patients with adult cerebral ALD (ACALD), 5 with adrenomyeloneuropathy (AMN) and 4 female heterozygotes. Studies were also performed in nine healthy controls. Results Among adult X-ALD phenotypes, MI/Cr was 46% higher and Cho/Cr 21% higher in normal appearing white matter of ACALD compared to AMN (p < 0.05). Both NAA/Cr and Glu/Cr ratios were lower in AMN patients (p = 0.028 and p = 0.036, respectively) than in controls. There were no significant differences between AMN and female heterozygotes. In cortex, ACALD patients had lower values of NAA/Cr compared to female heterozygotes and controls (p = 0.022). The global MI/Cr ratio demonstrated a significant association with the EDSS (Spearman ρ = 0.66, p = 0.039). Conclusion 7 Tesla proton MRSI reveals differences in the neurochemistry of ACALD but is unable to distinguish AMN from female heterozygotes. MI/Cr correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD. PMID:19001168

Regulatory divergence of X-linked genes and hybrid male sterility in mice.

PubMed

Oka, Ayako; Shiroishi, Toshihiko

2014-01-01

Postzygotic reproductive isolation is the reduction of fertility or viability in hybrids between genetically diverged populations. One example of reproductive isolation, hybrid male sterility, may be caused by genetic incompatibility between diverged genetic factors in two distinct populations. Genetic factors involved in hybrid male sterility are disproportionately located on the X chromosome. Recent studies showing the evolutionary divergence in gene regulatory networks or epigenetic effects suggest that the genetic incompatibilities occur at much broader levels than had previously been thought (e.g., incompatibility of protein-protein interactions). The latest studies suggest that evolutionary divergence of transcriptional regulation causes genetic incompatibilities in hybrid animals, and that such incompatibilities preferentially involve X-linked genes. In this review, we focus on recent progress in understanding hybrid sterility in mice, including our studies, and we discuss the evolutionary significance of regulatory divergence for speciation.

X-linked adult-onset adrenoleukodystrophy: Psychiatric and neurological manifestations

PubMed Central

Shamim, Daniah; Alleyne, Karen

2017-01-01

Adult-onset adrenoleukodystrophy is a rare x-linked inborn error of metabolism occurring predominantly in males with onset in early 30s. Here, we report a 34-year-old male with first signs of disease in early 20s manifesting as a pure psychiatric disorder. Prior to onset of neurological symptoms, this patient demonstrated a schizophrenia and bipolar-like presentation. The disease progressed over the next 10–13 years and his memory and motor problems became evident around the age of 33 years. Subsequently, diagnostic testing showed the typical magnetic resonance imaging and lab findings for adult-onset adrenoleukodystrophy. This case highlights adult-onset adrenoleukodystrophy which may present as a pure psychiatric disturbance in early adulthood and briefly discusses the prolonged time between the onset of psychiatric symptoms and the onset of neurological disease. PMID:29201369

X-linked adult-onset adrenoleukodystrophy: Psychiatric and neurological manifestations.

PubMed

Shamim, Daniah; Alleyne, Karen

2017-01-01

Adult-onset adrenoleukodystrophy is a rare x-linked inborn error of metabolism occurring predominantly in males with onset in early 30s. Here, we report a 34-year-old male with first signs of disease in early 20s manifesting as a pure psychiatric disorder. Prior to onset of neurological symptoms, this patient demonstrated a schizophrenia and bipolar-like presentation. The disease progressed over the next 10-13 years and his memory and motor problems became evident around the age of 33 years. Subsequently, diagnostic testing showed the typical magnetic resonance imaging and lab findings for adult-onset adrenoleukodystrophy. This case highlights adult-onset adrenoleukodystrophy which may present as a pure psychiatric disturbance in early adulthood and briefly discusses the prolonged time between the onset of psychiatric symptoms and the onset of neurological disease.

A novel AVPR2 splice site mutation leads to partial X-linked nephrogenic diabetes insipidus in two brothers.

PubMed

Schernthaner-Reiter, Marie Helene; Adams, David; Trivellin, Giampaolo; Ramnitz, Mary Scott; Raygada, Margarita; Golas, Gretchen; Faucz, Fabio R; Nilsson, Ola; Nella, Aikaterini A; Dileepan, Kavitha; Lodish, Maya; Lee, Paul; Tifft, Cynthia; Markello, Thomas; Gahl, William; Stratakis, Constantine A

2016-05-01

X-linked nephrogenic diabetes insipidus (NDI, OMIM#304800) is caused by mutations in the arginine vasopressin (AVP, OMIM*192340) receptor type 2 (AVPR2, OMIM*300538) gene. A 20-month-old boy and his 8-year-old brother presented with polyuria, polydipsia, and failure to thrive. Both boys demonstrated partial DDAVP (1-desamino-8-D AVP or desmopressin) responses; thus, NDI diagnosis was delayed. While routine sequencing of AVPR2 showed a potential splice site variant, it was not until exome sequencing confirmed the AVPR2 splice site variant and did not reveal any more likely candidates that the patients' diagnosis was made and proper treatment was instituted. Both patients were hemizygous for two AVPR2 variants predicted in silico to affect AVPR2 messenger RNA (mRNA) splicing. A minigene assay revealed that the novel AVPR2 c.276A>G mutation creates a novel splice acceptor site leading to 5' truncation of AVPR2 exon 2 in HEK293 human kidney cells. Both patients have been treated with high-dose DDAVP with a remarkable improvement of their symptoms and accelerated linear growth and weight gain. We present here a unique case of partial X-linked NDI due to an AVPR2 splice site mutation; patients with diabetes insipidus of unknown etiology may harbor splice site mutations that are initially underestimated in their pathogenicity on sequence analysis. • X-linked nephrogenic diabetes insipidus is caused by AVPR2 mutations, and disease severity can vary depending on the functional effect of the mutation. What is New: • We demonstrate here that a splice site mutation in AVPR2 leads to partial X-linked NDI in two brothers. • Treatment with high-dose DDAVP led to improvement of polyuria and polydipsia, weight gain, and growth.

INTRAGROUP AND GALAXY-LINKED DIFFUSE X-RAY EMISSION IN HICKSON COMPACT GROUPS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Desjardins, Tyler D.; Gallagher, Sarah C.; Tzanavaris, Panayiotis

2013-02-15

Isolated compact groups (CGs) of galaxies present a range of dynamical states, group velocity dispersions, and galaxy morphologies with which to study galaxy evolution, particularly the properties of gas both within the galaxies and in the intragroup medium. As part of a large, multiwavelength examination of CGs, we present an archival study of diffuse X-ray emission in a subset of nine Hickson compact groups (HCGs) observed with the Chandra X-Ray Observatory. We find that seven of the groups in our sample exhibit detectable diffuse emission. However, unlike large-scale emission in galaxy clusters, the diffuse features in the majority of themore » detected groups are linked to the individual galaxies, in the form of both plumes and halos likely as a result of vigourous star formation or activity in the galaxy nucleus, as well as in emission from tidal features. Unlike previous studies from earlier X-ray missions, HCGs 31, 42, 59, and 92 are found to be consistent with the L{sub X} -T relationship from clusters within the errors, while HCGs 16 and 31 are consistent with the cluster L{sub X} -{sigma} relation, though this is likely coincidental given that the hot gas in these two systems is largely due to star formation. We find that L{sub X} increases with decreasing group H I to dynamical-mass ratio with tentative evidence for a dependence in X-ray luminosity on H I morphology whereby systems with intragroup H I indicative of strong interactions are considerably more X-ray luminous than passively evolving groups. We also find a gap in the L{sub X} of groups as a function of the total group specific star formation rate. Our findings suggest that the hot gas in these groups is not in hydrostatic equilibrium and these systems are not low-mass analogs of rich groups or clusters, with the possible exception of HCG 62.« less

Intragroup and Galaxy-linked Diffuse X-ray Emission In Hickson Compact Groups

NASA Technical Reports Server (NTRS)

Desjardins, Tyler D.; Gallagher, Sarah C.; Tzanavaris, Panayiotis; Mulchaey, John S.; Brandt, William N.; Charlton, Jane C.; Garmire, Gordon P.; Gronwall, Caryl; Cardiff, Ann; Johnson, Kelsey E.;

Juvenile X-linked retinoschisis responsive to intravitreal corticosteroids.

PubMed

Ansari, Waseem H; Browne, Andrew W; Singh, Rishi P

2017-04-01

To report the case of an adult male with X-linked retinoschisis (XLRS) who presented with cystoid macular edema (CME) that responded consistently to treatment with intravitreal steroids. A 39 year old male with unilateral presentation of CME after repair of a retinal detachment secondary to XLRS responded initially to an injection of intravitreal triamcinolone acetonide (IVTA). Central subfield thickness on OCT was reduced. Three months later, the CME recurred and he was unresponsive to topical treatment so repeat IVTA was given, and the CME once again was reduced dramatically. After the next recurrence, intravitreal dexamethasone implant treatment was initiated and successful at treating recurrences in 3 month intervals for 5 additional injections. Finally, an intravitreal fluocinolone acetonide implant was surgically placed with control of CME. Corticosteroids have never been reported to be effective in CME related to XLRS. Here, we document a case of a man who successfully had decrease of intraretinal fluid and schisis with treatment of intravitreal corticosteroids as demonstrated by spectral domain optical coherence tomography.

Deletion of the X-linked opsin gene array locus control region (LCR) results in disruption of the cone mosaic.

PubMed

Carroll, Joseph; Rossi, Ethan A; Porter, Jason; Neitz, Jay; Roorda, Austin; Williams, David R; Neitz, Maureen

2010-09-15

Blue cone monochromacy (BCM) is an X-linked condition in which long- (L) and middle- (M) wavelength-sensitive cone function is absent. Due to the X-linked nature of the condition, female carriers are spared from a full manifestation of the associated defects but can show visual symptoms, including abnormal cone electroretinograms. Here we imaged the cone mosaic in four females carrying an L/M array with deletion of the locus control region, resulting in an absence of L/M opsin gene expression (effectively acting as a cone opsin knockout). On average, they had cone mosaics with reduced density and disrupted organization compared to normal trichromats. This suggests that the absence of opsin in a subset of cones results in their early degeneration, with X-inactivation the likely mechanism underlying phenotypic variability in BCM carriers. Copyright 2010 Elsevier Ltd. All rights reserved.

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento.

PubMed

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing.

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.

PubMed

Xue, Shifeng; Maluenda, Jérôme; Marguet, Florent; Shboul, Mohammad; Quevarec, Loïc; Bonnard, Carine; Ng, Alvin Yu Jin; Tohari, Sumanty; Tan, Thong Teck; Kong, Mung Kei; Monaghan, Kristin G; Cho, Megan T; Siskind, Carly E; Sampson, Jacinda B; Rocha, Carolina Tesi; Alkazaleh, Fawaz; Gonzales, Marie; Rigonnot, Luc; Whalen, Sandra; Gut, Marta; Gut, Ivo; Bucourt, Martine; Venkatesh, Byrappa; Laquerrière, Annie; Reversade, Bruno; Melki, Judith

2017-04-06

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Single-Exome sequencing identified a novel RP2 mutation in a child with X-linked retinitis pigmentosa.

PubMed

Lim, Hassol; Park, Young-Mi; Lee, Jong-Keuk; Taek Lim, Hyun

2016-10-01

To present an efficient and successful application of a single-exome sequencing study in a family clinically diagnosed with X-linked retinitis pigmentosa. Exome sequencing study based on clinical examination data. An 8-year-old proband and his family. The proband and his family members underwent comprehensive ophthalmologic examinations. Exome sequencing was undertaken in the proband using Agilent SureSelect Human All Exon Kit and Illumina HiSeq 2000 platform. Bioinformatic analysis used Illumina pipeline with Burrows-Wheeler Aligner-Genome Analysis Toolkit (BWA-GATK), followed by ANNOVAR to perform variant functional annotation. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation. Analysis of exome sequence data identified a novel frameshift mutation in RP2 gene resulting in a premature stop codon (c.665delC, p.Pro222fsTer237). Sanger sequencing revealed this mutation co-segregated with the disease phenotype in the child's family. We identified a novel causative mutation in RP2 from a single proband's exome sequence data analysis. This study highlights the effectiveness of the whole-exome sequencing in the genetic diagnosis of X-linked retinitis pigmentosa, over the conventional sequencing methods. Even using a single exome, exome sequencing technology would be able to pinpoint pathogenic variant(s) for X-linked retinitis pigmentosa, when properly applied with aid of adequate variant filtering strategy. Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Novel domain-specific POU3F4 mutations are associated with X-linked deafness: examples from different populations.

PubMed

Bademci, Guney; Lasisi, Akeem; Yariz, Kemal O; Montenegro, Paola; Menendez, Ibis; Vinueza, Rodrigo; Paredes, Rosario; Moreta, Germania; Subasioglu, Asli; Blanton, Susan; Fitoz, Suat; Incesulu, Armagan; Sennaroglu, Levent; Tekin, Mustafa

2015-02-25

Mutations in the POU3F4 gene cause X-linked deafness type 3 (DFN3), which is characterized by inner ear anomalies. Three Turkish, one Ecuadorian, and one Nigerian families were included based on either inner ear anomalies detected in probands or X-linked family histories. Exome sequencing and/or Sanger sequencing were performed in order to identify the causative DNA variants in these families. Four novel, c.707A>C (p.(Glu236Ala)), c.772delG (p.(Glu258ArgfsX30)), c.902C>T (p.(Pro301Leu)), c.987T>C (p.(Ile308Thr)), and one previously reported mutation c.346delG (p.(Ala116ProfsX26)) in POU3F4, were identified. All mutations identified are predicted to affect the POU-specific or POU homeo domains of the protein and co-segregated with deafness in all families. Expanding the spectrum of POU3F4 mutations in different populations along with their associated phenotypes provides better understanding of their clinical importance and will be helpful in clinical evaluation and counseling of the affected individuals.

X-linked Alport syndrome: An SSCP-based mutation survey over all 51 exons of the COL4A5 gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renieri, A.; Bruttini, M.; Galli, L.

1996-06-01

The COL4A5 gene encodes the {alpha}5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 startmore » codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the {alpha}5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. 44 refs., 3 figs., 4 tabs.« less

Genetics Home Reference: spondyloepiphyseal dysplasia congenita

MedlinePlus

... feet. Abnormal curvature of the spine ( kyphoscoliosis and lordosis ) becomes more severe during childhood. Instability of the ... Resources (4 links) MedlinePlus Encyclopedia: Clubfoot MedlinePlus Encyclopedia: ... Detachment MedlinePlus Encyclopedia: Scoliosis General ...

Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links with Pragmatic Language

ERIC Educational Resources Information Center

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2013-01-01

This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 27 with typical development (TD), aged 4-15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did…

Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease

PubMed Central

Bustamante, Jacinta; Arias, Andres A; Vogt, Guillaume; Picard, Capucine; Galicia, Lizbeth Blancas; Prando, Carolina; Grant, Audrey V; Marchal, Christophe C; Hubeau, Marjorie; Chapgier, Ariane; de Beaucoudrey, Ludovic; Puel, Anne; Feinberg, Jacqueline; Valinetz, Ethan; Jannière, Lucile; Besse, Céline; Boland, Anne; Brisseau, Jean-Marie; Blanche, Stéphane; Lortholary, Olivier; Fieschi, Claire; Emile, Jean-François; Boisson-Dupuis, Stéphanie; Al-Muhsen, Saleh; Woda, Bruce; Newburger, Peter E; Condino-Neto, Antonio; Dinauer, Mary C; Abel, Laurent; Casanova, Jean-Laurent

2011-01-01

Germline mutations in CYBB, the human gene encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This ‘experiment of nature’ indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria. PMID:21278736

Novel RS1 mutations associated with X-linked juvenile retinoschisis

PubMed Central

YI, JUNHUI; LI, SHIQIANG; JIA, XIAOYUN; XIAO, XUESHAN; WANG, PANFENG; GUO, XIANGMING; ZHANG, QINGJIONG

2012-01-01

To identify mutations in the retinoschisin (RS1) gene in families with X-linked retinoschisis (XLRS). Twenty families with XLRS were enrolled in this study. All six coding exons and adjacent intronic regions of RS1 were amplified by polymerase chain reaction (PCR). The nucleotide sequences of the amplicons were determined by Sanger sequencing. Ten hemizygous mutations in RS1 were detected in patients from 14 of the 20 families. Four of the ten mutations were novel, including c:176G>A (p:Cys59Tyr) in exon 3, c:531T>G (p:Tyr177X), c:607C>G (p:Pro203Ala) and c:668G>A (p:Cys223Tyr) in exon 6. These four novel mutations were not present in 176 normal individuals. The remaining six were recurrent mutations, including c:214G>A (p:Glu72Lys), c:304C>T (p:Arg102Trp), c:436G>A (p:Glu146Lys), c:544C>T (p:Arg182Cys), c:599G>A (p:Arg200His) and c:644A>T (p:Glu215Val). Our study expanded the mutation spectrum of RS1 and enriches our understanding of the molecular basis of XLRS. PMID:22245991

Novel RS1 mutations associated with X-linked juvenile retinoschisis.

PubMed

Yi, Junhui; Li, Shiqiang; Jia, Xiaoyun; Xiao, Xueshan; Wang, Panfeng; Guo, Xiangming; Zhang, Qingjiong

2012-04-01

To identify mutations in the retinoschisin (RS1) gene in families with X-linked retinoschisis (XLRS). Twenty families with XLRS were enrolled in this study. All six coding exons and adjacent intronic regions of RS1 were amplified by polymerase chain reaction (PCR). The nucleotide sequences of the amplicons were determined by Sanger sequencing. Ten hemizygous mutations in RS1 were detected in patients from 14 of the 20 families. Four of the ten mutations were novel, including c:176G>A (p:Cys59Tyr) in exon 3, c:531T>G (p:Tyr177X), c:607C>G (p:Pro203Ala) and c:668G>A (p:Cys223Tyr) in exon 6. These four novel mutations were not present in 176 normal individuals. The remaining six were recurrent mutations, including c:214G>A (p:Glu72Lys), c:304C>T (p:Arg102Trp), c:436G>A (p:Glu146Lys), c:544C>T (p:Arg182Cys), c:599G>A (p:Arg200His) and c:644A>T (p:Glu215Val). Our study expanded the mutation spectrum of RS1 and enriches our understanding of the molecular basis of XLRS.

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento

PubMed Central

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing. PMID:28611923

Hunting for Novel X-Linked Breast Cancer Suppressor Genes in Mouse and Human

DTIC Science & Technology

2007-03-01

display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE (DD-MM-YYYY) 01/03/07 2 . REPORT TYPE...and correlated significantly with HER- 2 over-expression, regardless of the status of HER- 2 amplification. In toto, the data demonstrate that FOXP3...is an X-linked breast cancer suppressor gene and an important regulator of the HER- 2 /ErbB2 oncogene. 15. SUBJECT TERMS No subject terms provided 16

X-Linked Glomerulopathy Due to COL4A5 Founder Variant.

PubMed

Barua, Moumita; John, Rohan; Stella, Lorenzo; Li, Weili; Roslin, Nicole M; Sharif, Bedra; Hack, Saidah; Lajoie-Starkell, Ginette; Schwaderer, Andrew L; Becknell, Brian; Wuttke, Matthias; Köttgen, Anna; Cattran, Daniel; Paterson, Andrew D; Pei, York

2018-03-01

Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c.T665G; rs281874761) of the coding DNA predicted to lead to a cysteine to phenylalanine substitution at amino acid 222, which was not seen in databases cataloguing natural human genetic variation, including dbSNP138, 1000 Genomes Project release version 01-11-2004, Exome Sequencing Project 21-06-2014, or ExAC 01-11-2014. Review of the literature identified 2 additional families with the same COL4A5 variant leading to similar atypical histopathologic features, suggesting a unique pathologic mechanism initiated by this specific rare variant. Homology modeling suggests that the substitution alters the structural and dynamic properties of the type IV collagen trimer. Genetic analysis comparing members of the 3 families indicated a distant relationship with a shared haplotype, implying a founder effect. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

[Importance of family examination in juvenile X-linked retinoschisis].

PubMed

Kłosowska-Zawadka, A; Bernardczyk-Meller, J; Gotz-Wieckowska, A; Krawczyński, M

2005-12-01

Congenital (juvenile) retinoschisis belongs to the group of hereditary vitreoretinopathies. This disorder is inherited in an X-linked recessive pattern and its onset usually occurs in 5- to 10-year-old boys. Presenting clinical signs include decreased visual acuity due to maculopathy. The authors present a case of a 17-year-old boy with decreased visual acuity, hypermetropia, and bilateral retinoschisis with maculopathy upon fundus examination. In view of a 50% risk of the disorder occurring in the brothers of the affected male, they underwent full ophthalmological and electrophysiological examinations (until then asymptomatic). In one of them decreased visual acuity, mixed astigmatism, and maculopathy were present, without any changes of the peripheral retina. In the youngest brother decreased visual acuity, hypermetropia, and maculopathy were diagnosed. Genetic counseling and ophthalmological examination of family members at risk facilitated early recognition of the pathological changes in the siblings. Genetic counseling with pedigree analysis and genetic analysis, if possible, should be offered to all affected patients and family members.

Nature and Recurrence of AVPR2 Mutations in X-linked Nephrogenic Diabetes Insipidus

PubMed Central

Bichet, Daniel G.; Birnbaumer, Mariel; Lonergan, Michèle; Arthus, Marie-Françoise; Rosenthal, Walter; Goodyer, Paul; Nivet, Hubert; Benoit, Stéphane; Giampietro, Philip; Simonetti, Simonetta; Fish, Alfred; Whitley, Chester B.; Jaeger, Philippe; Gertner, Joseph; New, Maria; DiBona, Francis J.; Kaplan, Bernard S.; Robertson, Gary L.; Hendy, Geoffrey N.; Fujiwara, T. Mary; Morgan, Kenneth

1994-01-01

X-linked nephrogenic diabetes insipidus (NDI) is a rare disease with defective renal and extrarenal arginine-vasopressin V2 receptor responses due to mutations in the AVPR2 gene in Xq28. We analyzed 31 independent NDI families to determine the nature and recurrence of AVPR2 mutations. Twenty-one new putative disease-causing mutations were identified: 113delCT, 253del35, 255del9, 274insG, V88M, R106C, 402delCT, C112R, Y124X, S126F, W164S, S167L, 684delTA, 804insG, W284X, A285P, W293X, R337X, and three large deletions or gene rearrangements. Five other mutations—R113W, Y128S, R137H, R181C, and R202C—that previously had been reported in other families were detected. There was evidence for recurrent mutation for four mutations (R113W, R137H, S167L, and R337X). Eight de novo mutation events were detected (274insG, R106C, Y128S, 167L [twice], R202C, 684delTA, and R337X). The origins were maternal (one), grandmaternal (one), and grandpaternal (six). In the 31 NDI families and 6 families previously reported by us, there is evidence both for mutation hot spots for nucleotide substitutions and for small deletions and insertions. More than half (58%) of the nucleotide substitutions in 26 families could be a consequence of 5-methylcytosine deamination at a CpG dinucleotide. Most of the small deletions and insertions could be attributed to slipped mispairing during DNA replication. PMID:8037205

[Detection of large deletions in X linked Alport syndrome using competitive multiplex fluorescence polymerase chain reaction].

PubMed

Wang, F; Zhang, Y Q; Ding, J; Yu, L X

2017-10-18

To evaluate the ability of multiplex competitive fluorescence polymerase chain reaction in detection of large deletion and duplication genotypes of X-linked Alport syndrome. Clinical diagnosis of X-linked Alport syndrome was based on either abnormal staining of type IV collagen α5 chain in the epidermal basement membrane alone or with abnormal staining of type IV collagen α5 chain in the glomerular basement membrane and Bowman's capsule/ultrastructural changes in the glomerular basement membrane typical of Alport syndrome. A total of 20 unrelated Chinese patients (13 males and 7 females) clinically diagnosed as X-linked Alport syndrome were included in the study. Their genotypes were unknown. Control subjects included a male patient with other renal disease and two patients who had large deletions in COL4A5 gene detected by multiplex ligation-dependent probe amplification. Genomic DNA was isolated from peripheral blood leukocytes in all the participants. Multiplex competitive fluorescence polymerase chain reaction was used to coamplify 53 exons of COL4A5 gene and four reference genes in a single reaction. When a deletion removed exon 1 of COL4A5 gene was identified, the same method was used to coamplify the first 4 exons of COL4A5 and COL4A6 genes, a promoter shared by COL4A5 and COL4A6 genes, and three reference genes in a single reaction. Any copy number loss suggested by this method was verified by electrophoresis of corresponding polymerase chain reaction amplified products or DNA sequencing to exclude possible DNA variations in the primer regions. Genotypes of two positive controls identified by multiplex competitive fluorescence polymerase chain reaction were consistent with those detected by multiplex ligation-dependent probe amplification. Deletions were identified in 6 of the 20 patients, including two large deletions removing the 5' part of both COL4A5 and COL4A6 genes with the breakpoint located in the second intron of COL4A6, two large deletions

X-linked agammaglobulinemia - first case with Bruton tyrosine kinase mutation from Pakistan.

PubMed

Zaidi, Samreen Kulsom; Qureshi, Sonia; Qamar, Farah Naz

2017-03-01

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency with more than 600 mutations in Bruton tyrosine kinase (Bkt) gene which are responsible for early-onset agammaglobulinemia and repeated infections. Herein we present a case of a 3-year-old boy with history of repeated diarrhoea and an episode of meningoencephalitis with hemiplegia. The workup showed extremely low levels of immunoglobulin with low CD+19 cells. Genetic analysis showed Btk mutation 18 c.1883delCp.T628fs. To the best of our knowledge this is the first report of a case of XLA confirmed by molecular technique from Pakistan.

AB067. X-linked adrenoleukodystrophy: Phenotype and genotype in Vietnamese patients

PubMed Central

Nguyen, Khanh Ngoc; Nguyen, Ha Thu; Can, Ngoc Thi Bich; Bui, Thao Phuong; Nobuyuki, Shimozawa; Vu, Huynh Anh; Do, Mai Thi Thanh; Vu, Dung Chi

2017-01-01

Background X-linked adrenoleukodystrophy (X-ALD) is caused by a defect in the gene ABCD1, which maps to Xq28 and codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily. This disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. Objective is to identify phenotype and genotype in Vietnamese patients with X-ALD. Methods Genomic DNA from 20 Vietnamese patients from 18 unrelated families was extracted using standard procedures from the peripheral blood leukocytes. Mutation analysis of ABCD1 was performed using polymerase chain reaction (PCR) and DNA direct sequencing. Results We identified 17 different mutations of ABCD1 in 20 patients including missense mutations (2/17), deletion (4/17), frameshift mutation (1/17) and splice site mutation (1/17). Of which, six novel mutations including c.1202G>T (p.Arg401Trp); c.1208T>A (p.Met403Lys); IVS8+28-551bp del; c.1668G>C (p.Q556H); c.292_296delTCGGC (p.S98RfsX95); and the extent of deletion included between IVS1+505 and IVS2+1501, containing whole the exon 2 (4243bp), plus insertion of 79bp from BAP31 and 8bp from unknown origin in this deleted region were identified in six unrelated patients. Eleven reported mutations including c.796G>A (p.Gly266Arg); c.1628C>T (p.Pro543Leu); c.1553G>A (p.Arg518Gln); c.1552 C>T (p.Arg518Trp); c.854G>C (p.R285P); c.1825G>A (p.E609K); c.1415_1416delAG (p.Q472RfsX83) and c.46-53del insG, c.1553G>A (p.Arg518Gln), c.1946-1947insA (p.Asp649fsX733), c.1978C>T (p.Arg660Trp) were identified in 14 patients from 12 families. Most of patients (17/20) presented cerebral ALD type with/without adrenal insufficiency and only 3 patients presented Addison type. Conclusions Mutation analysis of ABCD1 gene helped confirmation of diagnosis of X-ALD, genetic counselling and prenatal diagnosis but could not be used to predict the specific phenotype of X-ALD.

Apparent X-linked primary ciliary dyskinesia associated with retinitis pigmentosa and a hearing loss.

PubMed

Krawczyński, Maciej R; Dmeńska, Hanna; Witt, Michał

2004-01-01

Three brothers, one 10-year-old and a pair of 14-year-old dizygotic twins--expressed the classical, early-onset retinitis pigmentosa (RP) with typical ophthalmoscopic findings, night blindness, visual field constricted to 10 degrees and flat ERG response. All three brothers were also diagnosed with primary ciliary dyskinesia (PCD) and had recurrent respiratory infections, chronic sinusitis and bronchiectasis. In all of them, resection of the middle lobe of the right lung was performed. A similar clinical picture of coexisting RP and PCD was noted in the brother of the probands' mother. All probands displayed situs solitus. Consistent with the X-linked mode of RP inheritance, there were also three obligatory female carriers of the disorder in this family: the mother of the affected boys, her mother and a daughter of her brother. In all of them, retinitis pigmentosa "sine pigmento" was found with milder but clinically significant symptoms (mild night blindness, visual field constricted to 30 degrees, and scotopic and photopic ERG responses reduced to 30-60%). No extraocular symptoms were detected in any of the heterozygous female carriers. This family presents an example of two rare phenomena: X-linked dominant retinitis pigmentosa (with milder expression in females) and a rare combination of RP with recurrent respiratory infections due to PCD.

Mutational Survey of the PHEX Gene in Patients with X-linked Hypophosphatemic Rickets

PubMed Central

Ichikawa, Shoji; Traxler, Elizabeth A.; Estwick, Selina A.; Curry, Leah R.; Johnson, Michelle L.; Sorenson, Andrea H.; Imel, Erik A.; Econs, Michael J.

2008-01-01

X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. XLH is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). In this study, we sequenced the PHEX gene in subjects from 26 kindreds who were clinically diagnosed with XLH. Sequencing revealed 18 different mutations, of which thirteen have not been reported previously. In addition to deletions, splice site mutations, and missense and nonsense mutations, a rare point mutation in the 3’-untranslated region (3’-UTR) was identified as a novel cause of XLH. In summary, we identified a wide spectrum of mutations in the PHEX gene. Our data, in accord with those of others, indicate that there is no single predominant PHEX mutation responsible for XLH. PMID:18625346

New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jouet, M.; Kenwick, S.; Moncla, A.

1995-06-01

The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the firstmore » examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function. 39 refs., 5 figs., 3 tabs.« less

Maxillary distraction osteogenesis for treatment of cleft lip and palate in a patient with X-linked agammaglobulinemia.

PubMed

Sato, Yutaka; Mishimagi, Takashi; Katsuki, Yuko; Harada, Kiyoshi

2014-07-01

X-linked agammaglobulinemia (XLA) is a congenital immune deficiency disorder caused by abnormal antibody production. It is a rare disease with an estimated frequency of 1 in 379,000 that has X-linked recessive heredity and develops only in males. The clinical problems include bacterial infection such as otitis media, sinusitis, and bronchitis. In recent years it has become possible to diagnose XLA in the early stage and intravenous immunoglobulin replacement therapy has permitted survival to adulthood. However, there have been no reports of oral surgery in patients with XLA. Here, we describe a case in which immunoglobulin replacement therapy given pre- and postoperatively was used to control infection in oral surgery and maxillary distraction osteogenesis performed for improving occlusion and appearance of a cleft lip and palate in a patient with XLA. Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Low X/Y divergence in four pairs of papaya sex-linked genes.

PubMed

Yu, Qingyi; Hou, Shaobin; Feltus, F Alex; Jones, Meghan R; Murray, Jan E; Veatch, Olivia; Lemke, Cornelia; Saw, Jimmy H; Moore, Richard C; Thimmapuram, Jyothi; Liu, Lei; Moore, Paul H; Alam, Maqsudul; Jiang, Jiming; Paterson, Andrew H; Ming, Ray

2008-01-01

Sex chromosomes in flowering plants, in contrast to those in animals, evolved relatively recently and only a few are heteromorphic. The homomorphic sex chromosomes of papaya show features of incipient sex chromosome evolution. We investigated the features of paired X- and Y-specific bacterial artificial chromosomes (BACs), and estimated the time of divergence in four pairs of sex-linked genes. We report the results of a comparative analysis of long contiguous genomic DNA sequences between the X and hermaphrodite Y (Y(h)) chromosomes. Numerous chromosomal rearrangements were detected in the male-specific region of the Y chromosome (MSY), including inversions, deletions, insertions, duplications and translocations, showing the dynamic evolutionary process on the MSY after recombination ceased. DNA sequence expansion was documented in the two regions of the MSY, demonstrating that the cytologically homomorphic sex chromosomes are heteromorphic at the molecular level. Analysis of sequence divergence between four X and Y(h) gene pairs resulted in a estimated age of divergence of between 0.5 and 2.2 million years, supporting a recent origin of the papaya sex chromosomes. Our findings indicate that sex chromosomes did not evolve at the family level in Caricaceae, and reinforce the theory that sex chromosomes evolve at the species level in some lineages.

X-linked juvenile retinoschisis: Clinical diagnosis, genetic analysis, and molecular mechanisms

PubMed Central

Molday, Robert S.; Kellner, Ulrich; Weber, Bernhard H.F.

2012-01-01

X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization. Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190 disease-causing mutations in the RS1 gene are known with most mutations occurring as non-synonymous changes in the discoidin domain. Cell expression studies have shown that disease-associated missense mutations in the discoidin domain cause severe protein misfolding and retention in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and mutations in regions flanking the discoidin domain cause defective disulphide-linked subunit assembly, all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been generated and shown to display most of the characteristic features found in XLRS patients. Recombinant adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout mice result in long term retinoschisin expression and rescue of retinal structure and function providing a ‘proof of concept’ that gene therapy may be an effective treatment for XLRS. PMID:22245536

[Gene mutation analysis of X-linked hypophosphatemic rickets].

PubMed

Song, Ying; Ma, Hong-Wei; Li, Fang; Hu, Man; Ren, Shuang; Yu, Ya-Fen; Zhao, Gui-Jie

2013-11-01

To investigate the frequency and type of PHEX gene mutations in children with X-linked hypophosphatemic rickets (XLH), the possible presence of mutational hot spots, and the relationship between genotype and clinical phenotype. Clinical data of 10 children with XLH was retrospectively reviewed. The relationship between gene mutation type and severity of XLH was evaluated. PHEX gene mutations were detected in all 10 children with XLH, including 6 cases of missense mutation, 2 cases of splice site mutation, 1 case of frameshift mutation, and 1 case of nonsense mutation. Two new mutations, c.2048T>C and IVS14+1delAG, were found. The type of PHEX gene mutation was not associated with the degree of short stature and leg deformity (P=0.571 and 0.467), and the mutation site was also not associated with the degree of short stature and leg deformity (P=0.400 and 1.000). Missense mutation is the most common type of PHEX gene mutation in children with XLH, and c.2048T>C and IVS14+1delAG are two new PHEX gene mutations. The type and site of PHEX gene mutation are not associated with the severity of XLH.

Suspected X-linked facial dysmorphia and growth retardation in related Labrador retriever puppies.

PubMed

Dierks, C; Hoffmann, H; Heinrich, F; Hellige, M; Hewicker-Trautwein, M; Distl, O

2017-02-01

Seven male Labrador retriever puppies from four different litters were identified with a brachycephalic-like face and skull, associated with low birth weight, severe growth retardation, and reduced abilities to crawl and suckle, which were not compatible with survival. Excessive doming of the cranium, brachygnathia superior and inferior, and an abnormally opened fontanelle were found in all affected puppies by computed tomography and at post-mortem examination. Pedigree analysis supported an X-linked recessive mode of inheritance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Role of the X-linked gene GPR174 in autoimmune Addison's disease.

PubMed

Napier, C; Mitchell, A L; Gan, E; Wilson, I; Pearce, S H S

2015-01-01

Autoimmune endocrinopathies demonstrate a profound gender bias, but the reasons for this remain obscure. The 1000 genes on the X chromosome are likely to be implicated in this inherent susceptibility; various theories, including skewed X chromosome inactivation and fetal microchimerism, have been proposed. GPR174 is an Xq21 putative purinergic receptor that is widely expressed in lymphoid tissues. A single-nucleotide polymorphism, rs3827440, encoding Ser162Pro, has recently been associated with Graves' disease in Chinese and Polish populations, suggesting a role of this X chromosome gene in autoimmune disease. We investigated the role of rs3827440 in a UK cohort of patients with autoimmune Addison's disease (AAD). Samples from 286 AAD cases and 288 healthy controls were genotyped using TaqMan single-nucleotide polymorphism genotyping assays (C_25954273_10) on the Applied Biosystems 7900HT Fast real-time PCR system. Using a dominant (present/absent) model, the serine-encoding T allele of rs3827440 was present in 189 of 286 AAD patients (66%) compared with 132 of 288 unaffected controls (46%) [P = .010, odds ratio 1.80 (5%-95% confidence interval 1.22-2.67)]. An allele dosage model found a significant excess of the T allele in AAD patients compared with controls [P = .03, odds ratio 1.34 (5%-95% confidence interval 1.07-1.67)]. We have demonstrated a significant association of this X chromosome-encoded immunoreceptor with AAD for the first time. This X-linked gene could have a more generalized role in autoimmunity pathogenesis: G protein-coupled receptors are promising drugable targets, and further work to elucidate the functional role of GPR174 is now warranted.

Genetic studies in a patient with X-linked retinoschisis coexisting with developmental delay and sensorineural hearing loss.

PubMed

Sudha, Dhandayuthapani; Patric, Irene Rosita Pia; Ganapathy, Aparna; Agarwal, Smitha; Krishna, Shuba; Neriyanuri, Srividya; Sripriya, Sarangapani; Sen, Parveen; Chidambaram, Subbulakshmi; Arunachalam, Jayamuruga Pandian

2017-01-01

In this study, we present a juvenile retinoschisis patient with developmental delay, sensorineural hearing loss, and reduced axial tone. X-linked juvenile retinoschisis (XLRS) is a retinal dystrophy, most often not associated with systemic anomalies and also not showing any locus heterogeneity. Therefore it was of interest to understand the genetic basis of the condition in this patient. RS1 gene screening for XLRS was performed by Sanger sequencing. Whole genome SNP 6.0 array analysis was carried out to investigate gross chromosomal aberrations that could result in systemic phenotype. In addition, targeted next generation sequencing (NGS) was employed to determine any possible involvement of X-linked syndromic and non-syndromic mental retardation genes. This NGS panel consisted of 550 genes implicated in several other rare inherited diseases. RS1 gene screening revealed a pathogenic hemizygous splice site mutation (c.78+1G>T), inherited from the mother. SNP 6.0 array analysis did not indicate any significant chromosomal aberrations that could be disease-associated. Targeted resequencing did not identify any mutations in the X-linked mental retardation genes. However, variations in three other genes (NSD1, LARGE, and POLG) were detected, which were all inherited from the patient's unaffected father. Taken together, RS1 mutation was found to segregate with retinoschisis phenotype while none of the other identified variations were co-segregating with the systemic defects. Hereby, we infer that the multisystemic defects harbored by the patient are a rare coexistence of XLRS, developmental delay, sensorineural hearing loss, and reduced axial tone reported for the first time in the literature.

Assessment of Spectral-Domain Optical Coherence Tomography Findings in Three Cases of X-Linked Juvenile Retinoschisis in the Same Family.

PubMed

Doğuizi, Sibel; Şekeroğlu, Mehmet Ali; Çolak, Salih; Anayol, Mustafa Alpaslan; Yılmazbaş, Pelin

2017-10-01

X-linked juvenile retinoschisis (XLRS) is an X-linked hereditary retinal dystrophy characterized by splitting of the neurosensory retina. On fundus examination, the macula often has a spoke wheel appearance with foveal cystic lesions, and separation of the retinal layers is typical on spectral-domain optical coherence tomography (SD-OCT). Patients with XLRS can exhibit different clinical courses, stages, and SD-OCT findings, even among members of the same family. SD-OCT is an important imaging method that allows us to achieve more detailed information about XLRS. In this study, we report three patients in the same family who have different clinical features and SD-OCT findings.

Anthropometric characteristics of X-linked hypophosphatemia.

PubMed

Pronicka, Ewa; Popowska, Ewa; Rowińska, Elzbieta; Arasimowicz, Elzbieta; Syczewska, Małgorzata; Jurkiewicz, Dorota; Lebiedowski, Michał

2004-04-15

An anthropometric study was undertaken to assess head proportions of patients with X-linked hypophosphatemia (XLH). Fourteen morphometric parameters of the head were measured and 10 cephalic indices calculated in 82 affected persons (57 females and 25 males) from 55 unrelated families with XLH, and compared with the results obtained in the group of their healthy relatives (37 females and 33 males), as well as with general population control values. Normalized values (SD, z-score) were analyzed statistically. The group of healthy relatives, both males and females, differed significantly from Polish population control values in most of the normalized variables measured, making population control values useless as a control group for the analyzed XLH group. Intrafamilial values of cephalic parameters in healthy relatives of the XLH patients were finally applied for statistical analysis. Generally patients with XLH showed highly statistically significant increase in head length (males 0.95 +/- 1.07 vs. -0.37 +/- 1.02, females 0.57 +/- 1.59 vs. -0.06 +/- 1.15), significant decrease in occipital breadth (males -0.56 +/- 1.27 vs. 0.70 +/- 1.28, females -0.59 +/- 1.7 vs. 0.13 +/- 1.1) and several milder anomalies of craniofacial proportions. Mean cephalic index was significantly lower in XLH patients when compared with the healthy relatives (males -0.909 vs. 0.278 P < 0.0001, females -0.705 vs. 0.381 P = 0.007). The cephalic changes were found both in XLH children and XLH adults and were more pronounced in affected males than in females. There were no differences between offspring born by hypophosphatemic and normophosphatemic mothers. Copyright 2003 Wiley-Liss, Inc.

Test-Retest Intervisit Variability of Functional and Structural Parameters in X-Linked Retinoschisis.

PubMed

Jeffrey, Brett G; Cukras, Catherine A; Vitale, Susan; Turriff, Amy; Bowles, Kristin; Sieving, Paul A

2014-09-01

To examine the variability of four outcome measures that could be used to address safety and efficacy in therapeutic trials with X-linked juvenile retinoschisis. Seven men with confirmed mutations in the RS1 gene were evaluated over four visits spanning 6 months. Assessments included visual acuity, full-field electroretinograms (ERG), microperimetric macular sensitivity, and retinal thickness measured by optical coherence tomography (OCT). Eyes were separated into Better or Worse Eye groups based on acuity at baseline. Repeatability coefficients were calculated for each parameter and jackknife resampling used to derive 95% confidence intervals (CIs). The threshold for statistically significant change in visual acuity ranged from three to eight letters. For ERG a-wave, an amplitude reduction greater than 56% would be considered significant. For other parameters, variabilities were lower in the Worse Eye group, likely a result of floor effects due to collapse of the schisis pockets and/or retinal atrophy. The criteria for significant change (Better/Worse Eye) for three important parameters were: ERG b/a-wave ratio (0.44/0.23), point wise sensitivity (10.4/7.0 dB), and central retinal thickness (31%/18%). The 95% CI range for visual acuity, ERG, retinal sensitivity, and central retinal thickness relative to baseline are described for this cohort of participants with X-linked juvenile retinoschisis (XLRS). A quantitative understanding of the variability of outcome measures is vital to establishing the safety and efficacy limits for therapeutic trials of XLRS patients.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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, themore » 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.« less

Growth, patterning, and weak-link fabrication of superconducting YBa2Cu3O(7-x) thin films

NASA Astrophysics Data System (ADS)

Hilton, G. C.; Harris, E. B.; van Harlingen, D. J.

1988-09-01

Thin films of the high-temperature superconducting ceramic oxides have been grown, and techniques for fabricating weak-link structures have been investigated. Films of YBa2Cu3O(7-x) grown on SrTiO3 by a combination of dc magnetron sputtering and thermal evaporation from the three sources have been patterned into microbridges with widths down to 2 microns. Evidence is found that the bridges behave as arrays of Josephson-coupled superconducting islands. Further weak-link behavior is induced by in situ modification of the coupling by ion milling through the bridge.

A role for heterochromatin protein 1γ at human telomeres

PubMed Central

Canudas, Silvia; Houghtaling, Benjamin R.; Bhanot, Monica; Sasa, Ghadir; Savage, Sharon A.; Bertuch, Alison A.; Smith, Susan

2011-01-01

Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1γ (HP1γ), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1γ localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1γ and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1γ in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC. PMID:21865325

Hematopoietic progenitor cell deficiency in fetuses and children affected by Down's syndrome.

PubMed

Holmes, Denise K; Bates, Nicola; Murray, Mary; Ladusans, E J; Morabito, Antonino; Bolton-Maggs, Paula H B; Johnston, Tracey A; Walkenshaw, Steve; Wynn, Robert F; Bellantuono, Ilaria

2006-12-01

There is an increased risk of myeloid malignancy in individuals with Down's syndrome (DS), which is associated with a mutation in exon 2 of the transcription factor GATA-1. It is recognized that there is accelerated telomere shortening in blood cells of children with DS similar to that in conditions such as Fanconi anemia and dyskeratosis congenita. The latter conditions are associated with stem cell deficiency and clonal change, including acute myeloid leukemia. In this study we address the questions 1) whether the accelerated telomere shortening is associated with progenitor/stem cell deficiency in individuals with DS, predisposing to clonal change and 2) whether the occurrence of reduced numbers of stem/progenitor cells precede the incidence of mutations in exon 2 of GATA-1. Peripheral blood from fetuses (23-35 weeks gestation) and/or bone marrow from children affected by DS and age-matched hematologically healthy controls were analyzed for telomere length, content of stem/progenitor cells, and mutations in exon 2 of GATA-1. We found that hematopoietic stem/progenitor cell deficiency and telomere shortening occurs in individuals with DS in fetal life. Moreover, the presence of a low number of progenitor cells was not associated with mutations in exon 2 of GATA-1. We propose that stem cell deficiency may be a primary predisposing event to DS leukemia development.

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation

PubMed Central

Dietz, Andrew C.; Mehta, Parinda A.; Vlachos, Adrianna; Savage, Sharon A.; Bresters, Dorine; Tolar, Jakub; Boulad, Farid; Dalle, Jean Hugues; Bonfim, Carmem; de la Fuente, Josu; Duncan, Christine N.; Baker, K. Scott; Pulsipher, Michael A.; Lipton, Jeffrey M.; Wagner, John E.; Alter, Blanche P.

2017-01-01

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled “Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease” held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group. PMID:28115275

A Mutation in the Rett Syndrome Gene, MECP2, Causes X-Linked Mental Retardation and Progressive Spasticity in Males

PubMed Central

Meloni, Ilaria; Bruttini, Mirella; Longo, Ilaria; Mari, Francesca; Rizzolio, Flavio; D’Adamo, Patrizia; Denvriendt, Koenraad; Fryns, Jean-Pierre; Toniolo, Daniela; Renieri, Alessandra

2000-01-01

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders. PMID:10986043

Evaluation of pharmacological induction of fatty acid beta-oxidation in X-linked adrenoleukodystrophy.

PubMed

McGuinness, M C; Zhang, H P; Smith, K D

2001-01-01

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder associated with elevated levels of saturated unbranched very-long-chain fatty acids (VLCFA; C > 22:0) in plasma and tissues, and reduced VLCFA beta-oxidation in fibroblasts, white blood cells, and amniocytes from X-ALD patients. The X-ALD gene (ABCD1) at Xq28 encodes the adrenoleukodystrophy protein (ALDP) that is related to the peroxisomal ATP-binding cassette (ABCD) transmembrane half-transporter proteins. The function of ALDP is unknown and its role in VLCFA accumulation unresolved. Previously, our laboratory has shown that sodium 4-phenylbutyrate (4PBA) treatment of X-ALD fibroblasts results in increased peroxisomal VLCFA beta-oxidation activity and increased expression of the X-ALD-related protein, ALDRP, encoded by the ABCD2 gene. In this study, the effect of various pharmacological agents on VLCFA beta-oxidation in ALD mouse fibroblasts is tested. 4PBA, styrylacetate and benzyloxyacetate (structurally related to 4PBA), and trichostatin A (functionally related to 4PBA) increase both VLCFA (peroxisomal) and long-chain fatty acid [LCFA (peroxisomal and mitochondrial)] beta-oxidation. Isobutyrate, zaprinast, hydroxyurea, and 5-azacytidine had no effect on VLCFA or LCFA beta-oxidation. Lovastatin had no effect on fatty acid beta-oxidation under normal tissue culture conditions but did result in an increase in both VLCFA and LCFA beta-oxidation when ALD mouse fibroblasts were cultured in the absence of cholesterol. The effect of trichostatin A on peroxisomal VLCFA beta-oxidation is shown to be independent of an increase in ALDRP expression, suggesting that correction of the biochemical abnormality in X-ALD is not dependent on pharmacological induction of a redundant gene (ABCD2). These studies contribute to a better understanding of the role of ALDP in VLCFA accumulation and may lead to the development of more effective pharmacological therapies. Copyright 2001 Academic Press.

Clinical and Molecular Heterogeneity of RTEL1 Deficiency

PubMed Central

Speckmann, Carsten; Sahoo, Sushree Sangita; Rizzi, Marta; Hirabayashi, Shinsuke; Karow, Axel; Serwas, Nina Kathrin; Hoemberg, Marc; Damatova, Natalja; Schindler, Detlev; Vannier, Jean-Baptiste; Boulton, Simon J.; Pannicke, Ulrich; Göhring, Gudrun; Thomay, Kathrin; Verdu-Amoros, J. J.; Hauch, Holger; Woessmann, Wilhelm; Escherich, Gabriele; Laack, Eckart; Rindle, Liliana; Seidl, Maximilian; Rensing-Ehl, Anne; Lausch, Ekkehart; Jandrasits, Christine; Strahm, Brigitte; Schwarz, Klaus; Ehl, Stephan R.; Niemeyer, Charlotte; Boztug, Kaan; Wlodarski, Marcin W.

2017-01-01

Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy

Clinical and Molecular Heterogeneity of RTEL1 Deficiency.

PubMed

Speckmann, Carsten; Sahoo, Sushree Sangita; Rizzi, Marta; Hirabayashi, Shinsuke; Karow, Axel; Serwas, Nina Kathrin; Hoemberg, Marc; Damatova, Natalja; Schindler, Detlev; Vannier, Jean-Baptiste; Boulton, Simon J; Pannicke, Ulrich; Göhring, Gudrun; Thomay, Kathrin; Verdu-Amoros, J J; Hauch, Holger; Woessmann, Wilhelm; Escherich, Gabriele; Laack, Eckart; Rindle, Liliana; Seidl, Maximilian; Rensing-Ehl, Anne; Lausch, Ekkehart; Jandrasits, Christine; Strahm, Brigitte; Schwarz, Klaus; Ehl, Stephan R; Niemeyer, Charlotte; Boztug, Kaan; Wlodarski, Marcin W

2017-01-01

Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34 + cells failed to expand in vitro , B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether

X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3

PubMed Central

Zhu, Hongwen; Shang, Dandan; Sun, Miao; Choi, Sunju; Liu, Qing; Hao, Jiajie; Figuera, Luis E.; Zhang, Feng; Choy, Kwong Wai; Ao, Yang; Liu, Yang; Zhang, Xiao-Lin; Yue, Fengzhen; Wang, Ming-Rong; Jin, Li; Patel, Pragna I.; Jing, Tao; Zhang, Xue

2011-01-01

X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome combining CGH, scoliosis, and spina bifida and mapped the disease locus to a 5.6 Mb critical region within the interval defined by the previously reported Mexican family. Through the combination of a high-resolution copy-number variation (CNV) scan and targeted genomic sequencing, we identified an interchromosomal insertion at Xq27.1 of a 125,577 bp intragenic fragment of COL23A1 on 5q35.3, with one X breakpoint within and the other very close to a human-specific short palindromic sequence located 82 kb downstream of SOX3. In the Mexican family, we found an interchromosomal insertion at the same Xq27.1 site of a 300,036 bp genomic fragment on 4q31.2, encompassing PRMT10 and TMEM184C and involving parts of ARHGAP10 and EDNRA. Notably, both of the two X breakpoints were within the short palindrome. The two palindrome-mediated insertions fully segregate with the CGH phenotype in each of the families, and the CNV gains of the respective autosomal genomic segments are not present in the public database and were not found in 1274 control individuals. Analysis of control individuals revealed deletions ranging from 173 bp to 9104 bp at the site of the insertions with no phenotypic consequence. Taken together, our results strongly support the pathogenicity of the identified insertions and establish X-linked congenital hypertrichosis syndrome as a genomic disorder. PMID:21636067

Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

PubMed

van de Kamp, J M; Betsalel, O T; Mercimek-Mahmutoglu, S; Abulhoul, L; Grünewald, S; Anselm, I; Azzouz, H; Bratkovic, D; de Brouwer, A; Hamel, B; Kleefstra, T; Yntema, H; Campistol, J; Vilaseca, M A; Cheillan, D; D'Hooghe, M; Diogo, L; Garcia, P; Valongo, C; Fonseca, M; Frints, S; Wilcken, B; von der Haar, S; Meijers-Heijboer, H E; Hofstede, F; Johnson, D; Kant, S G; Lion-Francois, L; Pitelet, G; Longo, N; Maat-Kievit, J A; Monteiro, J P; Munnich, A; Muntau, A C; Nassogne, M C; Osaka, H; Ounap, K; Pinard, J M; Quijano-Roy, S; Poggenburg, I; Poplawski, N; Abdul-Rahman, O; Ribes, A; Arias, A; Yaplito-Lee, J; Schulze, A; Schwartz, C E; Schwenger, S; Soares, G; Sznajer, Y; Valayannopoulos, V; Van Esch, H; Waltz, S; Wamelink, M M C; Pouwels, P J W; Errami, A; van der Knaap, M S; Jakobs, C; Mancini, G M; Salomons, G S

2013-07-01

Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

X-linked gene expression in the Virginia opossum: differences between the paternally derived Gpd and Pgk-A loci

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samollow, P.B.; Ford, A.L.; VandeBerg, J.L.

1987-01-01

Expression of X-linked glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate kinase-A (PGK-A) in the Virginia opossum (Didelphis virginiana) was studied electrophoretically in animals from natural populations and those produced through controlled laboratory crosses. Blood from most of the wild animals exhibited a common single-banded phenotype for both enzymes. Rare variant animals, regardless of sex, exhibited single-banded phenotypes different in mobility from the common mobility class of the respective enzyme. The laboratory crosses confirmed the allelic basis for the common and rare phenotypes. Transmission of PGK-A phenotypes followed the pattern of determinate (nonrandom) inactivation of the paternally derived Pgk-A allele, and transmission ofmore » G6PD also was consistent with this pattern. A survey of tissue-specific expression of G6PD phenotypes of heterozygous females revealed, in almost all tissues, three-banded patterns skewed in favor of the allele that was expressed in blood cells. Three-banded patterns were never observed in males or in putatively homozygous females. These patterns suggest simultaneous, but unequal, expression of the maternally and paternally derived Gpd alleles within individual cells. The absence of such partial expression was noted in a parallel survey of females heterozygous at the Pgd-A locus. Thus, it appears that Gpd and Pgk-A are X-linked in D. virginiana and subject to preferential paternal allele inactivation, but that dosage compensation may not be complete for all paternally derived X-linked genes.« less

Spontaneous closure of macular hole in a patient with x-linked juvenile retinoschisis.

PubMed

Gao, Hua; Province, William D; Peracha, Mohammed O

2010-01-01

To observe macular hole in a patient with juvenile retinoschisis. A 4-year-old boy with X-linked juvenile retinoschisis was examined and followed-up for 2 years. Optical coherence tomography was used to study his maculae. A full-thickness macular hole was detected by clinical examination and optical coherence tomography. Spontaneous closure of the macular hole was noticed and confirmed by optical coherence tomography 2 years later with visual improvement. Macular hole in patients with juvenile retinoschisis should be observed for at least a short period of time before a surgical repair is considered.

Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma.

PubMed

Du, Zhen-Fang; Xu, Chen-Ming; Zhao, Yan; Liu, Wen-Ting; Chen, Xiao-Ling; Chen, Chun-Yue; Fang, Hong; Ke, Hai-Ping; Zhang, Xian-Ning

2012-01-01

Mutations in the KRT6A or KRT16 gene cause pachyonychia congenita type 1 (PC-1), while mutations in KRT16 or KRT6C underlie focal palmoplantar keratoderma (FPPK). A new classification system of PC has been adopted based on the mutated gene. PC rarely presents the symptoms of diffuse plantar keratoderma. Mutation in the tail domain of keratins is rarely reported. PC combined with fissured tongue has never been described. To investigate the genotype-phenotype correlations between clinical features and gene mutational sites in two unrelated southern Chinese PC pedigrees (one family presented with specific fissured tongue, the other with diffuse plantar keratoderma). The whole coding regions of the KRT6A/KRT16/KRT17/KRT6B genes were amplified and directly sequenced to detect the mutation. To confirm the effect of the IVS8-2A>C mutation in KRT6A at the mRNA level, total RNA from the plantar lesion of a patient was extracted and reverse-transcribed to cDNA for sequence analysis. Two novel de novo mutations, a splice acceptor site variant IVS8-2A>C (p.S487FfsX72) in KRT6A and a heterozygous substitution c.AA373_374GG (p.N125G) within exon 1 of KRT16, were found separately in the two PC families. Genotype-phenotype correlations among PC patients with codon-125 mutation in KRT16 were established, while the phenotypes caused by the IVS8-2A>C mutation in KRT6A need further studies to confirm the rare feature of fissured tongue.

An RNA-splicing mutation (G{sup +51VS20}) in the Type II collagen gene (COL2A1) in a family with spondyloepiphyseal dysplasia congenita

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tiller, G.E.; Polumbo, P.A.; Weis, M.A.

1995-02-01

Defects in type II collagen have been demonstrated in a phenotypic continuum of chondrodysplasias that includes achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita (SEDC), Kniest dysplasia, and Stickler syndrome. We have determined that cartilage from a terminated fetus with an inherited form of SEDC contained both normal {alpha}1(II) collagen chains and chains that lacked amino acids 256-273 of the triple-helical domain. PCR amplification of this region of COL2A1, from genomic DNA, yielded products of normal size, while amplification of cDNA yielded a normal sized species and a shorter fragment missing exon 20. Sequence analysis of genomic DNA from the fetus revealedmore » a G{yields}T transversion at position +5 of intron 20; the affected father was also heterozygous for the mutation. Allele-specific PCR and heteroduplex analysis of a VNTR in COL2A1 independently confirmed the unaffected status of a fetus in a subsequent pregnancy. Thermodynamic calculations suggest that the mutation prevents normal splicing of exon 20 by interfering with binding of U{sub 1} small-nuclear RNA to pre-mRNA, thus leading to skipping of exon 20 in transcripts from the mutant allele. Electron micrographs of diseased cartilage showed intracellular inclusion bodies, which were stained by an antibody to {alpha}1(II) procollagen. Our findings support the hypothesis that {alpha}-chain length alterations that preserve the Gly-X-Y repeat motif of the triple helix result in partial intracellular retention of {alpha}1(II) procollagen and produce mild to moderate chondrodysplasia phenotypes. 50 refs., 6 figs., 1 tab.« less

Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, C.; Ainsworth, P.

1994-09-01

Charcot-Marie-Tooth disease is a pathologically and genetically hetergenous group of disorders that cause a progressive neuropathy, defined pathologically by degeneration of the myelin (CMT 1) of the axon (CMT 2) of the peripheral nerves. An X-linked type of the demyelinating form of this disorder (CMT X) has recently been linked to mutations in the connexin 32 (Cx32) gene, which codes for a 284 amino acid gap junction protein found in myelinated peripheral nerve. To date some 7 different mutations in this gene have been identified as being responsible for CMT X. The majority of these predict nonconservative amino acid substitutions,more » while one is a frameshift mutation which predicts a premature stop at codon 21. We report the results of molecular studies on three further local CMT X kindreds. The Cx32 gene was amplified by PCR in three overlapping fragments 300-450 bp in length using leukocyte-derived DNA as template. These were either sequenced directly using a deaza dGTP sequencing protocol, or were cloned and sequenced using a TA vector. In two of the kindreds the affected members carried a point mutation which was predicted to effect a non-conservative amino acid change within the first transmembrane domain. Both of these mutations caused a restriction site alteration (the loss of an Nla III and the creation of a Pvu II, respectively), and the former mutation was observed to segregate with the clinicial phenotype in affected family members. Affected members of the third kindred, which was a very large multigenerational family that had been extensively studied previously, were shown to carry a point mutation predicted to cause a premature truncation of the Cx32 gene product in the intracellular carboxy terminus. This mutation obliterated an Rsa I site which allowed a rapid screen of several other family members.« less

X-linked recessive panhypopituitarism associated with a regional duplication in Xq25-q26.

PubMed Central

Lagerström-Fermér, M; Sundvall, M; Johnsen, E; Warne, G L; Forrest, S M; Zajac, J D; Rickards, A; Ravine, D; Landegren, U; Pettersson, U

1997-01-01

We present a linkage analysis and a clinical update on a previously reported family with X-linked recessive panhypopituitarism, now in its fourth generation. Affected members exhibit variable degrees of hypopituitarism and mental retardation. The markers DXS737 and DXS1187 in the q25-q26 region of the X chromosome showed evidence for linkage with a peak LOD score (Zmax) of 4.12 at zero recombination fraction (theta(max) = 0). An apparent extra copy of the marker DXS102, observed in the region of the disease gene in affected males and heterozygous carrier females, suggests that a segment including this marker is duplicated. The gene causing this disorder appears to code for a dosage-sensitive protein central to development of the pituitary. Images Figure 2 PMID:9106538

DNA Damage and Oxidative Stress in Dyskeratosis Congenita: Analysis of Pathways and Therapeutic Stategies Using CPISPR and iPSC Model Systems

DTIC Science & Technology

2017-06-01

Milestone Achieved: HRPO/ACURO Approval 6 Finished Major Task 2 CRISPR knockout/RNAseq Viral infection/prep 3-6 CRISPR KO virus library prep...finished; RNA-Seq: ~75% Cell manipulation 3-6 CRISPR KO virus infection: 50%; Single cDNA infections: finished Bioinformatics 1 CRISPR KO library...characterization 1-3 Finished Update: production of iPSC clones harboring DC mutations generated by CRISPR : Design 1 Finished Update: production of

DNA Damage and Oxidative Stress in Dyskeratosis Congenita: Analysis of Pathways and Therapeutic Stategies Using CPISPR and iPSC Model Systems

DTIC Science & Technology

2016-06-01

telomeres and characterized by a classical clinical triad of leukoplakia, skin dyspigmentation and nail dystrophy with concomitant marrow failure...DC symptomology, to a degree, corresponds to critically shortened telomeres that limits cellular replicative potential and thus prematurely exhausts...stem cell pools. Our previous findings support a hypothesis whereby shortened telomeres increase DNA damage responses within the cell leading to

X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms.

PubMed

Molday, Robert S; Kellner, Ulrich; Weber, Bernhard H F

2012-05-01

X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization. Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190 disease-causing mutations in the RS1 gene are known with most mutations occurring as non-synonymous changes in the discoidin domain. Cell expression studies have shown that disease-associated missense mutations in the discoidin domain cause severe protein misfolding and retention in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and mutations in regions flanking the discoidin domain cause defective disulphide-linked subunit assembly, all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been generated and shown to display most of the characteristic features found in XLRS patients. Recombinant adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout mice result in long-term retinoschisin expression and rescue of retinal structure and function providing a 'proof of concept' that gene therapy may be an effective treatment for XLRS. Copyright © 2012 Elsevier Ltd. All rights reserved.

Status of Adults With X-Linked Agammaglobulinemia

PubMed Central

Winkelstein, Jerry A.; Conley, Mary Ellen; James, Cynthia; Howard, Vanessa; Boyle, John

2010-01-01

Since many children with X-linked agammaglobulinemia (XLA) can now be expected to reach adulthood, knowledge of the status of adults with XLA would be of importance to the patients, their families, and the physicians caring for these patients. We performed the current study in adults with XLA to examine the impact of XLA on their daily lives and quality of life, their educational and socioeconomic status, their knowledge of the inheritance of their disorder, and their reproductive attitudes. Physicians who had entered adult patients with XLA in a national registry were asked to pass on a survey instrument to their patients. The patients then filled out the survey instrument and returned it directly to the investigators. Adults with XLA were hospitalized more frequently and missed more work and/or school than did the general United States population. However, their quality of life was comparable to that of the general United States population. They achieved a higher level of education and had a higher income than did the general United States population. Their knowledge of the inheritance of their disease was excellent. Sixty percent of them would not exercise any reproductive planning options as a result of their disease. The results of the current study suggest that although the disease impacts the daily lives of adults with XLA, they still become productive members of society and excel in many areas. PMID:18794707

Mapping X-linked ophthalmic diseases. IV. Provisional assignment of the locus for X-linked congenital cataracts and microcornea (the Nance-Horan syndrome) to Xp22.2-p22.3.

PubMed

Lewis, R A; Nussbaum, R L; Stambolian, D

1990-01-01

The Nance-Horan syndrome (NHS) is an infrequent X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies. The regional location of the genetic mutation causing NHS is unknown. The authors applied the modern molecular techniques of analysis of restriction fragment length polymorphisms to five multigenerational kindreds in which NHS segregated. Provisional linkage is established to two DNA markers--DXS143 at Xp22.3-p22.2 and DXS43 at Xp22.2. Regional localization of NHS will provide potential antenatal diagnosis in families at risk for the disease and will enhance understanding of the multifaceted genetic defects.

Chiari malformation, syringomyelia and bulbar palsy in X linked hypophosphataemia

PubMed Central

Watts, Laura; Wordsworth, Paul

2015-01-01

X linked hypophosphataemia (XLH) is a rare condition with numerous musculoskeletal complications. It may mimic other more familiar conditions, such as vitamin D deficiency, ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. We describe two cases with Chiari type 1 malformations and syringomyelia, neither of which is well recognised in XLH. The first presented late with the additional complications of spinal cord compression, pseudofracture, renal stones and gross femoroacetabular impingement requiring hip replacement. The second also had bulbar palsy; the first case to be described in this condition, to the best of our knowledge. We wish to raise awareness of the important neurological complications of syringomyelia, Chiari malformation, spinal cord compression and bulbar palsy when treating these patients. We also wish to draw attention to the utility of family history and genetic testing when making the diagnosis of this rare but potentially treatable condition. PMID:26561226

Chiari malformation, syringomyelia and bulbar palsy in X linked hypophosphataemia.

PubMed

Watts, Laura; Wordsworth, Paul

2015-11-11

X linked hypophosphataemia (XLH) is a rare condition with numerous musculoskeletal complications. It may mimic other more familiar conditions, such as vitamin D deficiency, ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. We describe two cases with Chiari type 1 malformations and syringomyelia, neither of which is well recognised in XLH. The first presented late with the additional complications of spinal cord compression, pseudofracture, renal stones and gross femoroacetabular impingement requiring hip replacement. The second also had bulbar palsy; the first case to be described in this condition, to the best of our knowledge. We wish to raise awareness of the important neurological complications of syringomyelia, Chiari malformation, spinal cord compression and bulbar palsy when treating these patients. We also wish to draw attention to the utility of family history and genetic testing when making the diagnosis of this rare but potentially treatable condition. 2015 BMJ Publishing Group Ltd.

Nephrogenic diabetes insipidus: an X chromosome-linked dominant inheritance pattern with a vasopressin type 2 receptor gene that is structurally normal.

PubMed Central

Friedman, E; Bale, A E; Carson, E; Boson, W L; Nordenskjöld, M; Ritzén, M; Ferreira, P C; Jammal, A; De Marco, L

1994-01-01

Nephrogenic diabetes insipidus is a rare hereditary disorder, most commonly transmitted in an X chromosome-linked recessive manner and characterized by the lack of renal response to the action of antidiuretic hormone [Arg8]vasopressin. The vasopressin type 2 receptor (V2R) has been suggested to be the gene that causes the disease, and its role in disease pathogenesis is supported by mutations within this gene in affected individuals. Using the PCR, denaturing gradient gel electrophoresis, and direct DNA sequencing, we examined the V2R gene in four unrelated kindreds. In addition, linkage analysis with chromosome Xq28 markers was done in one large Brazilian kindred with an apparent unusual X chromosome-linked dominant inheritance pattern. In one family, a mutation in codon 280, causing a Tyr-->Cys substitution in the sixth transmembrane domain of the receptor, was found. In the other three additional families with nephrogenic diabetes insipidus, the V2R-coding region was normal in sequence. In one large Brazilian kindred displaying an unusual X chromosome-linked dominant mode of inheritance, the disease-related gene was localized to the same region of the X chromosome as the V2R, but no mutations were found, thus raising the possibility that this disease is caused by a gene other than V2R. Images PMID:8078903

Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clincal review with six additional families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schrander-Stumpel, C.; Hoeweler, C.; Jones, M.

X-linked hydrocephalus (HSAS) (MIM{sup *}307000), MASA syndrome (MIM {sup *}303350), and complicated spastic paraplegia (SPG1) (MIM {sup *}3129000) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previousmore » reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1. 79 refs., 6 figs., 2 tabs.« less

Hungry bone syndrome and normalisation of renal phosphorus threshold after total parathyroidectomy for tertiary hyperparathyroidism in X-linked hypophosphataemia: a case report.

PubMed

Crowley, Rachel K; Kilbane, Mark; King, Thomas Fj; Morrin, Michelle; O'Keane, Myra; McKenna, Malachi J

2014-03-04

This is the first report of which the authors are aware to describe this c.2166delinsGG mutation in X-linked hypophosphataemia and to describe normalisation of renal threshold for phosphate excretion after parathyroidectomy for tertiary hyperparathyroidism in X-linked hypophosphataemia. We present the case of a 34-year-old Caucasian woman with X-linked hypophosphataemia. She developed tertiary hyperparathyroidism with markedly high bone turnover requiring total parathyroidectomy and had prolonged requirement for intravenous calcium infusion after surgery. She had a novel mutation in her phosphate-regulating gene with homologies to endopeptidases on the X-chromosome and had an unusual degree of dependence on phosphate supplementation. Prior to operative intervention she had a trial of cinacalcet that improved bone turnover markers when used in isolation but which led to a paradoxical rise in parathyroid hormone levels when given with phosphate supplementation. After correction of hungry bone syndrome, the renal phosphorus threshold normalised as a manifestation of hypoparathyroid state despite marked elevation in level of fibroblast growth factor 23. This case illustrates the risk of tertiary hyperparathyroidism as a complication of treatment for hypophosphataemia; it highlights the morbidity associated with hungry bone syndrome and provides novel insight into renal handling of phosphorus.

Sex-linked recessive

MedlinePlus

X-linked recessive diseases most often occur in males. Males have only one X chromosome. A single recessive ... half of the XY gene pair in the male. However, the Y chromosome doesn't contain most ...

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism

PubMed Central

Jamain, Stéphane; Quach, Hélène; Betancur, Catalina; Råstam, Maria; Colineaux, Catherine; Gillberg, I Carina; Söderström, Henrik; Giros, Bruno; Leboyer, Marion; Gillberg, Christopher; Bourgeron, Thomas

2003-01-01

Many studies have supported a genetic aetiology for autism. Here we report mutations in two X-linked genes, neuroligins NLGN3 and NLGN4, in siblings with autism spectrum disorders. These mutations affect cell adhesion molecules localised at the synapse and suggest that a defect of synaptogenesis may predispose to autism. PMID:12669065

Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.

PubMed

Jamain, Stéphane; Quach, Hélène; Betancur, Catalina; Råstam, Maria; Colineaux, Catherine; Gillberg, I Carina; Soderstrom, Henrik; Giros, Bruno; Leboyer, Marion; Gillberg, Christopher; Bourgeron, Thomas

2003-05-01

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.

Generation of induced pluripotent stem cells from a patient with X-linked juvenile retinoschisis.

PubMed

Peng, Chi-Hsien; Huang, Kang-Chieh; Lu, Huai-En; Syu, Shih-Han; Yarmishyn, Aliaksandr A; Lu, Jyh-Feng; Buddhakosai, Waradee; Lin, Tai-Chi; Hsu, Chih-Chien; Hwang, De-Kuang; Shen, Chia-Ning; Chen, Shih-Jen; Chiou, Shih-Hwa

2018-05-01

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal dystrophy manifested as splitting of anatomical layers of retina. In this report, we generated a patient-specific induced pluripotent stem cell (iPSC) line, TVGH-iPSC-013-05, from the peripheral blood mononuclear cells of a male patient with XLRS by using the Sendai-virus delivery system. We believe that XLRS patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease. Copyright © 2018. Published by Elsevier B.V.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 andmore » 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.« less

Misdiagnosis of X-linked retinitis pigmentosa in a choroideremia patient with heavily pigmented fundi.

PubMed

Nanda, A; Salvetti, A P; Martinez-Fernandez de la Camara, C; MacLaren, R E

2018-06-01

Inherited retinal diseases are thought to be the leading cause of sight loss in the working age population. Mutations found in the RPGR and CHM genes cause retinitis pigmentosa (RP) and choroideremia, respectively. In the first instance, an X-linked family history of visual field loss commonly raises the suspicion of one of these two genes. In choroideremia, the classic description of a white fundal reflex secondary to the widespread chorioretinal degeneration was made over a hundred years ago in Caucasians. But, it is not so obvious in heavily pigmented fundi. Hence, the clinical diagnosis of CHM in non-Caucasian patients may be challenging in the first stages of the disease. Here we report a case of a Southeast Asian gentleman who has a family history of X-linked retinal degeneration and was found to have a confirmed in-frame deletion of 12 DNA nucleotides in exon 15 of the RPGR gene. Later in life, however, his fundal appearance showed unusual areas of circular pigment hypertrophy and clumping. He was therefore tested for carrying a disease-causing mutation in the CHM gene and a null mutation was found. Since gene therapy trials are ongoing for both of these conditions, it has now become critically important to establish the correct genetic diagnosis in order to recruit suitable candidates. Moreover, this case demonstrates the necessity to remain vigilant in the interpretation of genetic results which are inconsistent with clinical features.

PROTECTIVE LEVELS OF VARICELLA-ZOSTER ANTIBODY DID NOT EFFECTIVELY PREVENT CHICKENPOX IN AN X-LINKED AGAMMAGLOBULINEMIA PATIENT.

PubMed

Nobre, Fernanda Aimée; Gonzalez, Isabela Garrido da Silva; de Moraes-Pinto, Maria Isabel; Costa-Carvalho, Beatriz Tavares

2015-01-01

We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG) therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.

The missing links of neutron star evolution in the eROSITA all-sky X-ray survey

NASA Astrophysics Data System (ADS)

Pires, A. M.

2017-12-01

The observational manifestation of a neutron star is strongly connected with the properties of its magnetic field. During the star’s lifetime, the field strength and its changes dominate the thermo-rotational evolution and the source phenomenology across the electromagnetic spectrum. Signatures of magnetic field evolution are best traced among elusive groups of X-ray emitting isolated neutron stars (INSs), which are mostly quiet in the radio and γ-ray wavelengths. It is thus important to investigate and survey INSs in X-rays in the hope of discovering peculiar sources and the long-sought missing links that will help us to advance our understanding of neutron star evolution. The Extended Röntgen Survey with an Imaging Telescope Array (eROSITA), the primary instrument on the forthcoming Spectrum-RG mission, will scan the X-ray sky with unprecedented sensitivity and resolution. The survey has thus the unique potential to unveil the X-ray faint end of the neutron star population and probe sources that cannot be assessed by standard pulsar surveys.

Identification of novel missense mutations in the Norrie disease gene associated with one X-linked and four sporadic cases of familial exudative vitreoretinopathy.

PubMed

Shastry, B S; Hejtmancik, J F; Trese, M T

1997-01-01

X-linked Familial Exudative Vitreoretinopathy (XLFEVR) is a hereditary eye disorder that affects both the retina and the vitreous body. It is characterized by an abnormal vascularization of the peripheral retina. It has been previously shown by linkage and candidate gene analysis that XLFEVR and Norrie disease are allelic. In this report we describe four novel mutations (R41K, H42R, K58N, and Y120C) in the Norrie disease gene associated with one X-linked and four sporadic cases of FEVR. One mutation (H42R) was found to be segregating with the disease in three generations (X-linked family), and the others are sporadic. These sequence alterations changed the encoded amino acids in the Norrie disease protein and were not found in 17 unaffected family members or in 36 randomly selected normal individuals. This study provides additional evidence that mutations in the same gene can result in FEVR and Norrie disease. It also demonstrates that it may be beneficial for clinical diagnosis to screen for mutations in the Norrie disease gene in sporadic FEVR cases.

Heterogeneity analysis in 40 X-linked retinitis pigmentosa families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teague, P.W.; Aldred, M.A.; Dempster, M.

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 othermore » 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.« less

Multifocal ERG findings in carriers of X-linked retinoschisis

PubMed Central

Kim, Linda S.; Seiple, William; Szlyk, Janet P.

2006-01-01

Purpose To determine whether retinal dysfunction in obligate carriers of X-linked retinoschisis (XLRS) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram (mfERG). Methods Nine obligate carriers of XLRS (mean age, 46.2 years) were examined for the study. Examination of each carrier included an ocular examination and mfERG testing. For the mfERG, we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40° in diameter. The amplitudes and implicit times in each location for the mfERG were compared with the corresponding values determined for a group of 34 normally-sighted, age-similar control subjects. Results Mapping of 103 local electroretinographic response amplitudes and implicit times within a central 40° area with the mfERG showed regions of reduced mfERG amplitudes and delayed implicit times in two of nine carriers. Conclusions The mfERG demonstrated areas of retinal dysfunction in two carriers of XLRS. When present, retinal dysfunction was evident in the presence of a normal-appearing fundus. Multifocal ERG testing can be useful for identifying some carriers of XLRS. PMID:17180613

A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy.

PubMed

Chen, Z Y; Battinelli, E M; Fielder, A; Bundey, S; Sims, K; Breakefield, X O; Craig, I W

1993-10-01

Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by an abnormality of the peripheral retina. Both autosomal dominant (adFEVR) and X-linked (XLFEVR) forms have been described, but the biochemical defect(s) underlying the symptoms are unknown. Molecular analysis of the Norrie gene locus (NDP) in a four generation FEVR family (shown previously to exhibit linkage to the X-chromosome markers DXS228 and MAOA (Xp11.4-p11.3)) reveals a missense mutation in the highly conserved region of the NDP gene, which caused a neutral amino acid substitution (Leu124Phe), was detected in all of the affected males, but not in the unaffected family members, nor in normal controls. The observations suggest that phenotypes of both XLFEVR and Norrie disease can result from mutations in the same gene.

Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links With Pragmatic Language

PubMed Central

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2014-01-01

This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 28 with typical development (TD), aged 4–15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did not differ from boys with ASD. Dampened vagal tone predicted pragmatic impairment in ASD, and associations emerged between cardiac activity and receptive/expressive vocabulary across groups. Findings support autonomic dysfunction as a mechanism underlying pragmatic impairment in ASD and suggest that biophysiological profiles are shared in ASD and FXS, which has implications for understanding the role of fragile X mental retardation-1 (FMR1, the FXS gene) in the pathophysiology of ASD. PMID:24432860

Effects of oxygen stoichiometry on the scaling behaviors of YBa{sub 2}Cu{sub 3}O{sub x} grain boundary weak-links

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, K.H.; Fu, C.M.; Jeng, W.J.

1994-12-31

The effects of oxygen stoichiometry on the transport properties of the pulsed laser deposited YBa{sub 2}Cu{sub 3}O{sub x} bicrystalline grain boundary weak-link junctions were studied. It is found that not only the cross boundary resistive transition foot structure can be manipulated repeatedly with oxygen annealling processes but the junction behaviors are also altered in accordance. In the fully oxygenated state i.e. with x=7.0 in YBa{sub 2}Cu{sub 3}O{sub x} stoichiometry, the junction critical current exhibits a power of 2 scaling behavior with temperature. In contrast, when annealed in the conditions of oxygen-deficient state (e.g. with x=6.9 in YBa{sub 2}Cu{sub 3}O{sub x}more » stoichiometry) the junction critical current switches to a linear temperature dependence behavior. The results are tentatively attributed to the modification of the structure in the boundary area upon oxygen annealing, which, in turn, will affect the effective dimension of the geometrically constrained weak-link bridges. The detailed discussion on the responsible physical mechanisms as well as the implications of the present results on device applications will be given.« less

The X linked recessive form of XY gonadal dysgenesis with a high incidence of gonadal germ cell tumours: clinical and genetic studies.

PubMed

Mann, J R; Corkery, J J; Fisher, H J; Cameron, A H; Mayerová, A; Wolf, U; Kennaugh, A A; Woolley, V

1983-08-01

Five phenotypic females in one family had the genotype 46,XY and all had gonadal germ cell tumours. Studies of the family pedigree suggest that this form of XY gonadal dysgenesis is inherited in an X linked recessive manner. G banding of elongated metaphase chromosomes from two subjects with XY gonadal dysgenesis and a female carrier showed no aberrations of the X chromosome. The titres of H-Y antigen in three girls with XY gonadal dysgenesis were in the male control range. Thus it appears that, in the X linked form, XY gonadal dysgenesis may be caused by a point deletion or mutation of a gene on the X chromosome, which controls the gonad specific receptor for the H-Y antigen. Studies of Xg blood groups were uninformative about linkage of Xg with the X borne gene causing the XY gonadal dysgenesis. Dermatoglyphic studies in the girls with XY gonadal dysgenesis and female carriers revealed high a-b palmar ridge counts and a tendency for the A mainline to terminate in the thenar area. Both of these features have been described in patients with Turner's syndrome.

STRP linkage studies in a new family with X-linked mental retardation: Tight linkage to DXS458

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lazzarini, A.; Stenroos, E.S.; Lehner, T.

1994-09-01

Isolated or non-specific mental retardation is defined as {open_quote}non-progressive intellectual handicap segregating in an X-linked manner without any consistent somatic or diagnostic features{close_quote}. The Human Gene Mapping Nomenclature Committee sequentially designates each newly reported MRX family, MRX1, MRX2,... etc. when a lod score of +2 is demonstrated between the MR locus and one or more X chromosome markers. A family, designated MRX20, was studied with nine short tandem repeat polymorphism (STRP) markers. Two-point lod scores above 3 were obtained with DXYS1 (Z = 3.02, {theta} = 0), DX3 (Z = 3.22, {theta} = 0), and DXS458 (Z = 3.31, {theta}more » = 0). A multipoint lod score of 3.66 was obtained with a peak between DXS3 and DXS458, 1.1cM distal to DXS3. A one-unit support interval is 16 cM between PGK1 and DXS458. This family represents the ninth of fourteen reported MRX families linked to markers in the region of DXYS1, perhaps reflecting a cluster of genes involved in brain function. The identification of genetic markers linked to the disease-causing gene has allowed gene carrier risk assessment for females in the family. Future research will concentrate on comparing the diversity of haplotypes containing the disease genes in different families, on physical mapping of the region, and on isolation of the MRX 20 gene.« less

Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Braun, A.; Ambach, H.; Kammerer, S.

Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expressions were cerebral childhood ALD, adrenomyecloneuropathy (AMN), and {open_quotes}Addison disease only{close_quotes} (AD) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5{prime} portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-bindingmore » domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis. 19 refs., 6 figs., 3 tabs.« less

Progressive engineering of a homing endonuclease genome editing reagent for the murine X-linked immunodeficiency locus

PubMed Central

Wang, Yupeng; Khan, Iram F.; Boissel, Sandrine; Jarjour, Jordan; Pangallo, Joseph; Thyme, Summer; Baker, David; Scharenberg, Andrew M.; Rawlings, David J.

2014-01-01

LAGLIDADG homing endonucleases (LHEs) are compact endonucleases with 20–22 bp recognition sites, and thus are ideal scaffolds for engineering site-specific DNA cleavage enzymes for genome editing applications. Here, we describe a general approach to LHE engineering that combines rational design with directed evolution, using a yeast surface display high-throughput cleavage selection. This approach was employed to alter the binding and cleavage specificity of the I-Anil LHE to recognize a mutation in the mouse Bruton tyrosine kinase (Btk) gene causative for mouse X-linked immunodeficiency (XID)—a model of human X-linked agammaglobulinemia (XLA). The required re-targeting of I-AniI involved progressive resculpting of the DNA contact interface to accommodate nine base differences from the native cleavage sequence. The enzyme emerging from the progressive engineering process was specific for the XID mutant allele versus the wild-type (WT) allele, and exhibited activity equivalent to WT I-AniI in vitro and in cellulo reporter assays. Fusion of the enzyme to a site-specific DNA binding domain of transcription activator-like effector (TALE) resulted in a further enhancement of gene editing efficiency. These results illustrate the potential of LHE enzymes as specific and efficient tools for therapeutic genome engineering. PMID:24682825

A novel missense mutation of NDP in a Chinese family with X-linked familial exudative vitreoretinopathy.

PubMed

Liu, Hong Yan; Huang, Jia; Wang, Rui Li; Wang, Yue; Guo, Liang Jie; Li, Tao; Wu, Dong; Wang, Hong Dan; Guo, Qian Nan; Dong, Dao Quan

2016-11-01

Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. In this report, we describe a novel missense mutation of the Norrie disease gene (NDP) in a Chinese family with X-linked FEVR. Ophthalmologic evaluation was performed on four male patients and seven unaffected individuals after informed consent was obtained. Venous blood was collected from the 11 members of this family, and genomic DNA was extracted using standard methods. The coding exons 2 and 3 and their corresponding exon-intron junctions of NDP were amplified by polymerase chain reaction and then subjected to direct DNA sequencing. A novel missense mutation (c.310A>C) in exon 3, leading to a lysine-to-glutamine substitution at position 104 (p.Lys104Gln), was identified in all four patients with X-linked FEVR. Three unaffected female individuals (III2, IV3, and IV11) were found to be carriers of the mutation. This mutation was not detected in other unaffected individuals. The mutation c.310A>C (p.Lys104Gln) in exon 3 of NDP is associated with FEVR in the studied family. This result further enriches the mutation spectrum of FEVR. Copyright © 2016. Published by Elsevier Taiwan LLC.

Heat shock protein expression in cerebral X-linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss.

PubMed

Görtz, A L; Peferoen, L A N; Gerritsen, W H; van Noort, J M; Bugiani, M; Amor, S

2018-06-01

X-linked adrenoleukodystrophy (X-ALD) is a genetic white matter disorder in which demyelination occurs due to accumulation of very long-chain fatty acids. Inflammation in the brain white matter is a hallmark of the pathology of cerebral X-ALD, but the underlying pathogenic mechanisms are still largely unknown. In other inflammatory demyelinating disorders, such as multiple sclerosis, the expression of heat shock proteins (HSPs) in combination with interferon-γ (IFN-γ) has been suggested to play a prominent role in the initiation of demyelination and inflammation. We therefore investigated these pathways in X-ALD lesions. By immunohistochemistry, we examined the expression of small HSPs (HSPB1, HSPB5, HSPB6, HSPB8) and higher molecular weight HSPs (HSPA, HSPD1), and the expression of elements of the IFN-γ pathway on autopsy material of five patients with X-ALD. The expression of the larger HSPs, HSPA and HSPD1, as well as small HSPs is increased in X-ALD lesions compared with normal-appearing white matter. Such upregulation can already be detected before demyelination and inflammation occur, and it is predominant in astrocytes. The IFN-γ pathway does not seem to play a leading role in the observed inflammation. The finding that astrocytes show signs of cellular stress before demyelination suggests that they play a major role early in the pathogenesis of cerebral X-ALD, and may therefore be involved in the initiation of inflammation and demyelination. © 2017 British Neuropathological Society.

X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face.

PubMed

Harakalova, Magdalena; van den Boogaard, Marie-Jose; Sinke, Richard; van Lieshout, Stef; van Tuil, Marc C; Duran, Karen; Renkens, Ivo; Terhal, Paulien A; de Kovel, Carolien; Nijman, Ies J; van Haelst, Mieke; Knoers, Nine V A M; van Haaften, Gijs; Kloosterman, Wigard; Hennekam, Raoul C M; Cuppen, Edwin; Ploos van Amstel, Hans Kristian

2012-08-01

We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype. We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated. HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.

X-linked microtubule-associated protein, Mid1, regulates axon development

PubMed Central

Lu, Tingjia; Chen, Renchao; Cox, Timothy C.; Moldrich, Randal X.; Kurniawan, Nyoman; Tan, Guohe; Perry, Jo K.; Ashworth, Alan; Bartlett, Perry F.; Xu, Li; Zhang, Jing; Lu, Bin; Wu, Mingyue; Shen, Qi; Liu, Yuanyuan; Richards, Linda J.; Xiong, Zhiqi

2013-01-01

Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS, Midline-1 (MID1), encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However, how Mid1 functions during neural development is largely unknown. In this study, we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation, resulting in a disruption of callosal axon projections in the contralateral cortex. In addition, a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together, these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS. PMID:24194544

X-linked microtubule-associated protein, Mid1, regulates axon development.

PubMed

Lu, Tingjia; Chen, Renchao; Cox, Timothy C; Moldrich, Randal X; Kurniawan, Nyoman; Tan, Guohe; Perry, Jo K; Ashworth, Alan; Bartlett, Perry F; Xu, Li; Zhang, Jing; Lu, Bin; Wu, Mingyue; Shen, Qi; Liu, Yuanyuan; Richards, Linda J; Xiong, Zhiqi

2013-11-19

Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS, Midline-1 (MID1), encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However, how Mid1 functions during neural development is largely unknown. In this study, we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation, resulting in a disruption of callosal axon projections in the contralateral cortex. In addition, a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together, these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS.

The localization of a gene causing X-linked cleft palate and ankyloglossia (CPX) in an Icelandic kindred is between DXS326 and DXYS1X

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stainer, P.; Forbes, S.A.; Moore, G.

1993-09-01

The locus responsible for X-linked, nonsyndromic cleft palate and/or ankyloglossia (CPX) has previously been mapped to the proximal long arm of the human X chromosome between Xq21.31 and q21.33 in an Icelandic kindred. The authors have extended these studies by analyzing an additional 14 informative markers in the family as well as including several newly investigated family members. Recombination analysis indicates that the CPX locus is more proximal than previously thought, within the interval Xq21.1-q21.31. Two recombinants place DXYS1X as the distal flanking marker, while one recombinant defines DXS326 as the proximal flanking marker, an interval of less than 5more » cM. Each of the flanking markers recombines with the CPX locus, giving 2-point lod scores of Z[sub max] = 4.16 at [theta] = 0.08 (DXS326) and Z[sub max] = 5.80 at [theta] = 0.06 (DXYS1X). 35 refs., 3 figs., 2 tabs.« less

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

PubMed Central

Jensen, Lars R; Chen, Wei; Moser, Bettina; Lipkowitz, Bettina; Schroeder, Christopher; Musante, Luciana; Tzschach, Andreas; Kalscheuer, Vera M; Meloni, Ilaria; Raynaud, Martine; van Esch, Hilde; Chelly, Jamel; de Brouwer, Arjan P M; Hackett, Anna; van der Haar, Sigrun; Henn, Wolfram; Gecz, Jozef; Riess, Olaf; Bonin, Michael; Reinhardt, Richard; Ropers, Hans-Hilger; Kuss, Andreas W

2011-01-01

X-linked intellectual disability (XLID), also known as X-linked mental retardation, is a highly genetically heterogeneous condition for which mutations in >90 different genes have been identified. In this study, we used a custom-made sequencing array based on the Affymetrix 50k platform for mutation screening in 17 known XLID genes in patients from 135 families and found eight single-nucleotide changes that were absent in controls. For four mutations affecting ATRX (p.1761M>T), PQBP1 (p.155R>X) and SLC6A8 (p.390P>L and p.477S>L), we provide evidence for a functional involvement of these changes in the aetiology of intellectual disability. PMID:21267006

Tremor in X-linked recessive spinal and bulbar muscular atrophy (Kennedy's disease).

PubMed

Dias, Francisco A; Munhoz, Renato P; Raskin, Salmo; Werneck, Lineu César; Teive, Hélio A G

2011-01-01

To study tremor in patients with X-linked recessive spinobulbar muscular atrophy or Kennedy's disease. Ten patients (from 7 families) with a genetic diagnosis of Kennedy's disease were screened for the presence of tremor using a standardized clinical protocol and followed up at a neurology outpatient clinic. All index patients were genotyped and showed an expanded allele in the androgen receptor gene. Mean patient age was 37.6 years and mean number of CAG repeats 47 (44-53). Tremor was present in 8 (80%) patients and was predominantly postural hand tremor. Alcohol responsiveness was detected in 7 (88%) patients with tremor, who all responded well to treatment with a β-blocker (propranolol). Tremor is a common feature in patients with Kennedy's disease and has characteristics similar to those of essential tremor.

Refractory Chronic Pleurisy Caused by Helicobacter equorum-Like Bacterium in a Patient with X-Linked Agammaglobulinemia ▿

PubMed Central

Funato, Michinori; Kaneko, Hideo; Ohkusu, Kiyofumi; Sasai, Hideo; Kubota, Kazuo; Ohnishi, Hidenori; Kato, Zenichiro; Fukao, Toshiyuki; Kondo, Naomi

2011-01-01

We describe a 35-year-old man with X-linked agammaglobulinemia who had refractory chronic pleurisy caused by a Helicobacter equorum-like bacterium. Broad-range bacterial PCR targeting the 16S and 23S rRNA genes and in situ hybridization targeting the 16S rRNA gene of H. equorum confirmed the presence of this pathogen in a human for the first time. PMID:21677071

Juvenile X-linked retinoschisis presenting as juxtapapillary retinal fold mimicking combined hamartoma of the retina and retinal pigment epithelium.

PubMed

Pointdujour-Lim, Renelle; Say, Emil Anthony T; Shields, Carol L

2017-04-01

A 21-month-old boy presumptively diagnosed with combined hamartoma of the retina and retinal pigment epithelium was found to have juvenile X-linked retinoschisis with vitreomacular traction and prominent retinal folding. Copyright © 2017 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

PubMed

Goji, Katsumi; Ozaki, Kayo; Sadewa, Ahmad H; Nishio, Hisahide; Matsuo, Masafumi

2006-02-01

Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice.

PubMed

Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; Li, Jian H; Wess, Jürgen; Svelto, Maria

2014-07-01

X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI.

Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice

PubMed Central

Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Barbieri, Claudia; Nicoletti, Maria C; H. Li, Jian; Wess, Jürgen; Svelto, Maria

2014-01-01

X-linked nephrogenic diabetes insipidus (X-NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. Loss of V2R function prevents plasma membrane expression of the AQP2 water channel in the kidney collecting duct cells and impairs the kidney concentration ability. In an attempt to develop strategies to bypass V2R signaling in X-NDI, we evaluated the effects of secretin and fluvastatin, either alone or in combination, on kidney function in a mouse model of X-NDI. The secretin receptor was found to be functionally expressed in the kidney collecting duct cells. Based on this, X-NDI mice were infused with secretin for 14 days but urinary parameters were not altered by the infusion. Interestingly, secretin significantly increased AQP2 levels in the collecting duct but the protein primarily accumulated in the cytosol. Since we previously reported that fluvastatin treatment increased AQP2 plasma membrane expression in wild-type mice, secretin-infused X-NDI mice received a single injection of fluvastatin. Interestingly, urine production by X-NDI mice treated with secretin plus fluvastatin was reduced by nearly 90% and the urine osmolality was doubled. Immunostaining showed that secretin increased intracellular stores of AQP2 and the addition of fluvastatin promoted AQP2 trafficking to the plasma membrane. Taken together, these findings open new perspectives for the pharmacological treatment of X-NDI. PMID:24522493

Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.

PubMed

Li, Qian; Luo, Changying; Luo, Chengjuan; Wang, Jianmin; Li, Benshang; Ding, Lixia; Chen, Jing

2017-08-01

Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 10 8 /kg and 4.3 × 10 6 /kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.

Disrupted lymphocyte homeostasis in hepatitis‐associated acquired aplastic anemia is associated with short telomeres

PubMed Central

Babushok, Daria V.; Grignon, Anne‐Laure; Li, Yimei; Atienza, Jamie; Xie, Hongbo M.; Lam, Ho‐Sun; Hartung, Helge; Bessler, Monica

2016-01-01

Hepatitis‐associated aplastic anemia (HAA) is a variant of acquired aplastic anemia (AA) in which immune‐mediated bone marrow failure (BMF) develops following an acute episode of seronegative hepatitis. Dyskeratosis congenita (DC) is an inherited BMF syndrome characterized by the presence of short telomeres, mucocutaneous abnormalities, and cancer predisposition. While both conditions may cause BMF and hepatic impairment, therapeutic approaches are distinct, making it imperative to establish the correct diagnosis. In clinical practice, lymphocyte telomere lengths (TL) are used as a first‐line screen to rule out inherited telomeropathies before initiating treatment for AA. To evaluate the reliability of TL in the HAA population, we performed a retrospective analysis of TL in 10 consecutively enrolled HAA patients compared to 19 patients with idiopathic AA (IAA). HAA patients had significantly shorter telomeres than IAA patients (P = 0.009), including four patients with TL at or below the 1st percentile for age‐matched controls. HAA patients had no clinical features of DC and did not carry disease‐causing mutations in known genes associated with inherited telomere disorders. Instead, short TLs were significantly correlated with severe lymphopenia and skewed lymphocyte subsets, features characteristic of HAA. Our results indicate the importance of caution in the interpretation of TL measurements in HAA, because, in this patient population, short telomeres have limited specificity. Am. J. Hematol. 91:243–247, 2016. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc. PMID:26615915

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation.

PubMed

Dietz, Andrew C; Mehta, Parinda A; Vlachos, Adrianna; Savage, Sharon A; Bresters, Dorine; Tolar, Jakub; Boulad, Farid; Dalle, Jean Hugues; Bonfim, Carmem; de la Fuente, Josu; Duncan, Christine N; Baker, K Scott; Pulsipher, Michael A; Lipton, Jeffrey M; Wagner, John E; Alter, Blanche P

2017-05-01

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled "Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease" held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group. Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.

Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA

PubMed Central

Schertzer, Michael; Jouravleva, Karina; Perderiset, Mylene; Dingli, Florent; Loew, Damarys; Le Guen, Tangui; Bardoni, Barbara; de Villartay, Jean-Pierre; Revy, Patrick; Londoño-Vallejo, Arturo

2015-01-01

Hoyeraal-Hreidarsson syndrome (HHS) is a severe form of Dyskeratosis congenita characterized by developmental defects, bone marrow failure and immunodeficiency and has been associated with telomere dysfunction. Recently, mutations in Regulator of Telomere ELongation helicase 1 (RTEL1), a helicase first identified in Mus musculus as being responsible for the maintenance of long telomeres, have been identified in several HHS patients. Here we show that RTEL1 is required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex. RTEL1-HHS cells show abnormal subcellular partitioning of pre-U2, defects in the recycling of ribonucleotide proteins (RNP) in the cytoplasm and splicing defects. While most of these phenotypes can be suppressed by re-expressing the wild-type protein in RTEL1-HHS cells, expression of RTEL1 mutated variants in immortalized cells provokes cytoplasmic mislocalizations of pre-U2 and other RNP components, as well as splicing defects, thus phenocopying RTEL1-HHS cellular defects. Strikingly, expression of a cytoplasmic form of RTEL1 is sufficient to correct RNP mislocalizations both in RTEL1–HHS cells and in cells expressing nuclear mutated forms of RTEL1. This work unravels completely unanticipated roles for RTEL1 in RNP trafficking and strongly suggests that defects in RNP biogenesis pathways contribute to the pathology of HHS. PMID:25628358

Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA.

PubMed

Schertzer, Michael; Jouravleva, Karina; Perderiset, Mylene; Dingli, Florent; Loew, Damarys; Le Guen, Tangui; Bardoni, Barbara; de Villartay, Jean-Pierre; Revy, Patrick; Londoño-Vallejo, Arturo

2015-02-18

Hoyeraal-Hreidarsson syndrome (HHS) is a severe form of Dyskeratosis congenita characterized by developmental defects, bone marrow failure and immunodeficiency and has been associated with telomere dysfunction. Recently, mutations in Regulator of Telomere ELongation helicase 1 (RTEL1), a helicase first identified in Mus musculus as being responsible for the maintenance of long telomeres, have been identified in several HHS patients. Here we show that RTEL1 is required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex. RTEL1-HHS cells show abnormal subcellular partitioning of pre-U2, defects in the recycling of ribonucleotide proteins (RNP) in the cytoplasm and splicing defects. While most of these phenotypes can be suppressed by re-expressing the wild-type protein in RTEL1-HHS cells, expression of RTEL1 mutated variants in immortalized cells provokes cytoplasmic mislocalizations of pre-U2 and other RNP components, as well as splicing defects, thus phenocopying RTEL1-HHS cellular defects. Strikingly, expression of a cytoplasmic form of RTEL1 is sufficient to correct RNP mislocalizations both in RTEL1-HHS cells and in cells expressing nuclear mutated forms of RTEL1. This work unravels completely unanticipated roles for RTEL1 in RNP trafficking and strongly suggests that defects in RNP biogenesis pathways contribute to the pathology of HHS. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

PubMed Central

Takai, Hiroyuki; Jenkinson, Emma; Kabir, Shaheen; Babul-Hirji, Riyana; Najm-Tehrani, Nasrin; Chitayat, David A.; Crow, Yanick J.; de Lange, Titia

2016-01-01

Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1CP) in two siblings with CP. POT1CP induced a proliferative arrest that could be bypassed by telomerase. POT1CP was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1CP was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1CP was also defective in the maintenance of the telomeric C strand, causing extended 3′ overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita). PMID:27013236

Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder.

PubMed

Sheikine, Yuri; Woda, Craig B; Lee, Pui Y; Chatila, Talal A; Keles, Sevgi; Charbonnier, Louis-Marie; Schmidt, Birgitta; Rosen, Seymour; Rodig, Nancy M

2015-07-01

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder is an autoimmune disease caused by loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor. These mutations affect the normal function of circulating regulatory T cells. IPEX is characterized by profound immune dysregulation leading to dermatitis, enteropathy, multiple endocrinopathies and failure to thrive. Different forms of renal injury have also been noted in these patients but these have been described to a very limited extent. Three patients with IPEX with characteristic renal findings and mutations in FOXP3, including one novel mutation, are described. Case presentations are followed by a review of the renal manifestations noted in IPEX and the range of therapeutic options for this disorder. We recommend that IPEX be considered in the differential diagnosis of young children who present with signs of immune dysregulation with a concomitant renal biopsy demonstrating immune complex deposition in a membranous-like pattern and/or interstitial nephritis.

Feelings Associated with Being a Carrier and Characteristics of Reproductive Decision Making in Women Known to Be Carriers of X-linked Conditions.

PubMed

Kay, Elizabeth; Kingston, Helen

2002-03-01

Qualitative data were collected from 14 women known to be carriers of an X-linked condition associated with 'serious' disability on feelings about being a carrier and impact on reproductive decisions. Guilt and responsibility were commonly expressed by carriers about issues surrounding pregnancy. Personal experience of the condition influenced their approach to reproductive decisions. Those who had lived with an affected brother were more concrete in their decisions to avoid having an affected child compared to those with less personal experience of the condition. It is concluded that feelings of guilt associated with difficult reproductive decisions are reflected in the strong sense of responsibility attached to being a carrier. Personal experience of the condition has a clear influence on reproductive decisions of X-linked carriers.

Molecular analysis of the XLRS1 gene in 4 females affected with X-linked juvenile retinoschisis.

PubMed

Saleheen, Danish; Ali, Azam; Khanum, Shaheen; Ozair, Mohammad Z; Zaidi, Moazzam; Sethi, Muhammad J; Khan, Nadir; Frossard, Philippe

2008-10-01

X-linked juvenile retinoschisis (XLRS) is the most common cause of juvenile macular degeneration in males. Because of its X-linked mode of transmission, the disease is rare in females. In this article, we describe a mutation screen conducted on a family in which 4 female patients affected with XLRS presented with an unusually severe phenotype. DNA was extracted from peripheral blood, and the XLRS1 gene was amplified on DNA samples of all the available family members. The mutation screen was conducted by performing direct DNA sequencing using an MJ Research PTC-225 Peltier Thermal Cycler. A novel mutation, 588-593ins.C, was identified in exon 6 of the gene. The affected father was found to be heterozygous for the mutation, whereas all the female patients were homozygous for this mutation. The homozygosity of the mutation in the affected females led to severe phenotypes. The defective allele was expressed in infancy in 1 patient, whereas the disease manifested itself at variable ages in the other patients, reflecting a variation in the phenotype. This report describes a novel mutation in a family in which consanguinity has led to XLRS in 4 females. A variation in the phenotype of the disease is consistent with the published literature and suggests the involvement of genetic modifiers or environmental factors in influencing the clinical severity of the disease.

Tremor in X-linked recessive spinal and bulbar muscular atrophy (Kennedy's disease)

PubMed Central

Dias, Francisco A; Munhoz, Renato P; Raskin, Salmo; Werneck, Lineu César; Teive, Hélio A G

2011-01-01

OBJECTIVE: To study tremor in patients with X-linked recessive spinobulbar muscular atrophy or Kennedy's disease. METHODS: Ten patients (from 7 families) with a genetic diagnosis of Kennedy's disease were screened for the presence of tremor using a standardized clinical protocol and followed up at a neurology outpatient clinic. All index patients were genotyped and showed an expanded allele in the androgen receptor gene. RESULTS: Mean patient age was 37.6 years and mean number of CAG repeats 47 (44-53). Tremor was present in 8 (80%) patients and was predominantly postural hand tremor. Alcohol responsiveness was detected in 7 (88%) patients with tremor, who all responded well to treatment with a β-blocker (propranolol). CONCLUSION: Tremor is a common feature in patients with Kennedy's disease and has characteristics similar to those of essential tremor. PMID:21808858

CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome

USDA-ARS?s Scientific Manuscript database

X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restori...

Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.

PubMed

Naves, Luciana A; Daly, Adrian F; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Júnior, Armindo Jreige; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S; Stratakis, Constantine A; Lupski, James R; Beckers, Albert

2016-02-01

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome

PubMed Central

Naves, Luciana A.; Daly, Adrian F.; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Jreige, Armindo; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S.; Stratakis, Constantine A.; Lupski, James R.

2017-01-01

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome. PMID:26607152

A sex-ratio meiotic drive system in Drosophila simulans. II: an X-linked distorter.

PubMed

Tao, Yun; Araripe, Luciana; Kingan, Sarah B; Ke, Yeyan; Xiao, Hailian; Hartl, Daniel L

2007-11-06

The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel's first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.

Local texture and strongly linked conduction in spray-pyrolyzed TlBa2Ca2Cu3O(8+x) deposits

NASA Astrophysics Data System (ADS)

Kroeger, D. M.; Goyal, A.; Specht, E. D.; Wang, Z. L.; Tkaczyk, J. E.; Sutliff, J. A.; Deluca, J. A.

Local texture in polycrystalline TlBa2Ca2 Cu3O(8+x) deposits has been determined from transmission electron microscopy, electron backscatter diffraction patterns and x-ray diffraction. The small-grained deposits had excellent c-axis alignment and contained colonies of grains with similar but not identical a-axis orientations. Most grain boundaries within a colony have small misorientation angles and should not be weak links. It is proposed that long range conduction utilizes a percolative network of small angle grain boundaries at colony intersections.

Gigantism: X-linked acrogigantism and GPR101 mutations.

PubMed

Iacovazzo, Donato; Korbonits, Márta

X-linked acrogigantism (XLAG) is a recently identified condition of early-onset GH excess resulting from the germline or somatic duplication of the GPR101 gene on chromosome Xq26.3. Thirty patients have been formally reported so far. The disease affects mostly females, occurs usually sporadically, and is characterised by early onset and marked overgrowth. Most patients present with concomitant hyperprolactinaemia. Histopathology shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia. XLAG-related pituitary adenomas present peculiar histopathological features that should contribute to raise the suspicion of this rare condition. Treatment is frequently challenging and multi-modal. While females present with germline mutations, the sporadic male patients reported so far were somatic mosaics with variable levels of mosaicism, although no differences in the clinical phenotype were observed between patients with germline or somatic duplication. The GPR101 gene encodes an orphan G protein-coupled receptor normally expressed in the central nervous system, and at particularly high levels in the hypothalamus. While the physiological function and the endogenous ligand of GPR101 are unknown, the high expression of GPR101 in the arcuate nucleus and the occurrence of increased circulating GHRH levels in some patients with XLAG, suggest that increased hypothalamic GHRH secretion could play a role in the pathogenesis of this condition. In this review, we summarise the published evidence on XLAG and GPR101 and discuss the results of recent studies that have investigated the potential role of GPR101 variants in the pathogenesis of pituitary adenomas. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genetics Home Reference: X-linked juvenile retinoschisis

MedlinePlus

... juvenile retinoschisis (XLRS): a review of genotype-phenotype relationships. Semin Ophthalmol. 2013 Sep-Nov;28(5-6): ... for Links Data Files & API Site Map Subscribe Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & ...

Novel Missense Mutation A789V in IQSEC2 Underlies X-Linked Intellectual Disability in the MRX78 Family

PubMed Central

Kalscheuer, Vera M.; James, Victoria M.; Himelright, Miranda L.; Long, Philip; Oegema, Renske; Jensen, Corinna; Bienek, Melanie; Hu, Hao; Haas, Stefan A.; Topf, Maya; Hoogeboom, A. Jeannette M.; Harvey, Kirsten; Walikonis, Randall; Harvey, Robert J.

2016-01-01

Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2A789V was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family. PMID:26793055

A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome.

PubMed

Ezquerra, Mario; Campdelacreu, Jaume; Muñoz, Esteban; Tolosa, Eduardo; Martí, María J

2005-02-01

X-linked dystonia-deafness syndrome (Mohr-Tranebjaerg syndrome) is a rare neurodegenerative disease characterized by hearing loss and dystonia. So far, 7 mutations in the coding region of the DDP1 gene have been described. They consist of frameshift, nonsense, missense mutations or deletions. To investigate the presence of mutations in the DDP1 gene in a family with dystonia-deafness syndrome. Seven members belonging to 2 generations of a family with 2 affected subjects underwent genetic analysis. Mutational screening in the DDP1 gene was made through DNA direct sequencing. We found an intronic mutation in the DDP1 gene. It consists of an A-to-C substitution in the position -23 in reference to the first nucleotide of exon 2 (IVS1-23A>C). The mutation was present in 2 affected men and their respective unaffected mothers, whereas it was absent in the healthy men from this family and in 90 healthy controls. Intronic mutations in the DDP1 gene can also cause X-linked dystonia-deafness syndrome. In our case, the effect of the mutation could be due to a splicing alteration.

A longitudinal study of visual function in carriers of X-linked recessive retinitis pigmentosa.

PubMed

Grover, S; Fishman, G A; Anderson, R J; Lindeman, M

2000-02-01

This study was carried out to evaluate the progression of visual function impairment in carriers of X-linked recessive retinitis pigmentosa. We also assessed the relationship between the retinal findings at presentation and the extent of deterioration. Observational, retrospective, case series. Twenty-seven carriers of X-linked recessive retinitis pigmentosa. Each carrier was clinically categorized into one of four grades (grades 0 through 3) depending on the presence or absence of a tapetal-like retinal reflex and the extent of peripheral pigmentary degeneration. A complete ophthalmologic examination was performed and data for visual acuity, visual field area, and electroretinographic measurements were collected on the most recent visit in both eyes. These were then compared with similar data obtained on their initial visits. A comparison of visual function was carried out between the initial visit and the most recent visit on each carrier. The visual acuity was measured with Snellen's acuity charts. The visual fields to targets V-4-e and II-4-e were planimeterized and used for the analysis. The electroretinographic (ERG) measures used were light-adapted single-flash b-wave amplitudes and 30-Hz red flicker for cone function, dark-adapted maximal b-wave amplitudes, and response to a low intensity blue-flash for rod function. None of the 11 carriers with a tapetal-like reflex only (grade 1) showed any significant change in visual acuity or fields as compared with 3 of 7 (43%) carriers with diffuse peripheral pigmentary findings (grade 3) who showed significant deterioration in visual acuity in at least one eye, and 6 of 7 (86%) who showed a significant decrease in visual field area with at least one target size in at least one eye. By comparison, only 1 of 10 carriers with a grade 1 fundus finding demonstrated a significant decrease in maximal dark-adapted ERG function as compared with 5 of 6 (83%) carriers with grade 3 in response to a single-flash stimulus and

X-linked dominant protoporphyria: The first reported Japanese case.

PubMed

Ninomiya, Yukiko; Kokunai, Yasuhito; Tanizaki, Hideaki; Akasaka, Eijiro; Nakano, Hajime; Moriwaki, Shinichi

2016-04-01

A 12-year-old boy with photosensitivity since 3 years of age presented with small concavities on both cheeks, the nasal root and the dorsal surface of both hands. According to the clinical features, erythropoietic protoporphyria (EPP) was suspected. Urine and blood samples were tested for porphyrin derivatives, which revealed a markedly elevated level of erythrocyte protoporphyrin (EP) and a diagnosis of EPP was made. The patient's mother had no photosensitivity, however, lesions appearing slightly as small scars were found on the dorsum of her right hand; his elder sister and father showed no rash. The EP levels were elevated in samples from his mother and mildly elevated in those from his elder sister and father. To obtain a definitive diagnosis, genetic analyses were performed using samples from all family members, which revealed no mutations in the ferrochelatase-encoding gene (FECH), which is responsible for EPP. Instead, a pathological mutation of the 5-aminolevulinic acid synthase-encoding gene (ALAS2) was identified in samples from the patient, his mother and his elder sister, confirming a definitive diagnosis of X-linked dominant protoporphyria (XLDPP). This is the first Japanese family reported to have XLDPP, demonstrating evidence of the condition in Japan. In addition, because XLDPP is very similar to EPP in its clinical aspects and laboratory findings, a genetic analysis is required for the differential diagnosis. © 2015 Japanese Dermatological Association.

Novel Phenotypic and Genotypic Findings in X-Linked Retinoschisis

PubMed Central

Tsang, Stephen H.; Vaclavik, Veronika; Bird, Alan C.; Robson, Anthony G.; Holder, Graham E.

2009-01-01

Objective To describe atypical phenotypes associated with the retinoschisis (X-linked, juvenile) 1 mutation (RS1). Methods Seven patients with multiple fine white dots at the macula and reduced visual acuity were evaluated. Six patients underwent pattern and full-field electroretinography (ERG). On-off ERG, optical coherence tomography, and fundus autofluorescence imaging were performed in some patients. Mutational screening of RS1 was prompted by the ERG findings. Results Fine white dots resembling drusenlike deposits and sometimes associated with retinal pigment epithelial abnormalities were present in the maculae. An electronegative bright-flash ERG configuration was present in all patients tested, and abnormal pattern ERG findings confirmed macular dysfunction. A parafoveal ring of high-density autofluorescence was present in 3 eyes; 1 patient showed high-density foci concordant with the white dots. Optical coherence tomography did not show foveal schisis in 3 of 4 eyes. All patients carried mutations in RS1, including 1 with a novel 206T→C mutation in exon 4. Conclusions Multiple fine white dots at the macula may be the initial fundus feature in RS1 mutation. Electrophysiologic findings suggest dysfunction after phototransduction and enable focused mutational screening. Autofluorescence imaging results suggest early retinal pigment epithelium involvement; a parafoveal ring of high-density autofluorescence has not previously been described in this disorder. PMID:17296904

Mutation of the XIST gene upregulates expression of X-linked genes but decreases the developmental rates of cloned male porcine embryos.

PubMed

Yang, Yang; Wu, Dan; Liu, Dewu; Shi, Junsong; Zhou, Rong; He, Xiaoyan; Quan, Jianping; Cai, Gengyuan; Zheng, Enqin; Wu, Zhenfang; Li, Zicong

2017-06-01

XIST is an X-linked, non-coding gene responsible for the cis induction of X-chromosome inactivation (XCI). Knockout of the XIST allele on an active X chromosome abolishes erroneous XCI and enhances the in vivo development of cloned mouse embryos by more than 10-fold. This study aimed to investigate whether a similar manipulation would improve cloning efficiency in pigs. A male, porcine kidney cell line containing an EGFP insert in exon 1 of the XIST gene, resulting in a knockout allele (XIST-KO), was generated by homologous recombination using transcription activator-like effector nucleases (TALENs). The expression of X-linked genes in embryos cloned from the XIST-KO kidney cells was significantly higher than in male embryos cloned from wild-type (WT) kidney cells, but remained lower than that of in vivo fertilization-produced counterparts. The XIST-KO cloned embryos also had a significantly lower blastocyst rate and a reduced full-term development rate compared to cloned WT embryos. These data suggested that while mutation of a XIST gene can partially rescue abnormal XCI, it cannot improve the developmental efficiency of cloned male porcine embryos-a deficiency that may be caused by incomplete rescue of abnormal XCI and/or by long-term drug selection of the XIST-KO nuclear donor cells, which might adversely affect the developmental efficiency of embryos created from them. © 2017 Wiley Periodicals, Inc.

First report on an X-linked hypohidrotic ectodermal dysplasia family with X chromosome inversion: Breakpoint mapping reveals the pathogenic mechanism and preimplantation genetics diagnosis achieves an unaffected birth.

PubMed

Wu, Tonghua; Yin, Biao; Zhu, Yuanchang; Li, Guangui; Ye, Lijun; Liang, Desheng; Zeng, Yong

2017-12-01

To investigate the etiology of X-linked hypohidrotic ectodermal dysplasia (XLHED) in a family with an inversion of the X chromosome [inv(X)(p21q13)] and to achieve a healthy birth following preimplantation genetic diagnosis (PGD). Next generation sequencing (NGS) and Sanger sequencing analysis were carried out to define the inversion breakpoint. Multiple displacement amplification, amplification of breakpoint junction fragments, Sanger sequencing of exon 1 of ED1, haplotyping of informative short tandem repeat markers and gender determination were performed for PGD. NGS data of the proband sample revealed that the size of the possible inverted fragment was over 42Mb, spanning from position 26, 814, 206 to position 69, 231, 915 on the X chromosome. The breakpoints were confirmed by Sanger sequencing. A total of 5 blastocyst embryos underwent trophectoderm biopsy. Two embryos were diagnosed as carriers and three were unaffected. Two unaffected blastocysts were transferred and a singleton pregnancy was achieved. Following confirmation by prenatal diagnosis, a healthy baby was delivered. This is the first report of an XLHED family with inv(X). ED1 is disrupted by the X chromosome inversion in this XLHED family and embryos with the X chromosomal abnormality can be accurately identified by means of PGD. Copyright © 2017. Published by Elsevier B.V.

Infantile vitreous hemorrhage as the initial presentation of X-linked juvenile retinoschisis.

PubMed

Lee, Jong Joo; Kim, Jeong Hun; Kim, So Yeon; Park, Sung Sup; Yu, Young Suk

2009-06-01

The authors report two cases of X-linked juvenile retinoschisis (XLRS) manifested as bilateral vitreous hemorrhage as early as in an 1-month-old infant and in a 3-month-old infant. The one-month-old male infant showed massive bilateral vitreous hemorrhage. During vitrectomy, thin membrane representing an inner part of schisis cavity was excised and intraschisis hemorrhage was evacuated. As intraschisis cavities were cleared, the stump of inner layer appeared as the demarcation line between the outer layer of the schisis retina and non-schisis retina. The other three-month-old male infant presenting with esodeviation also showed bilateral vitreous hemorrhage. Typical bilateral retinoschisis involving maculae could be seen through vitreous hemorrhage in both eyes on fundus examination. Spontaneous absorption of hemorrhage was observed on regular follow-up. XLRS could be manifested as massive hemorrhage inside or outside of the schisis cavity early in infancy.

Infantile Vitreous Hemorrhage as the Initial Presentation of X-linked Juvenile Retinoschisis

PubMed Central

Lee, Jong Joo; Kim, Jeong Hun; Kim, So Yeon; Park, Sung Sup

2009-01-01

The authors report two cases of X-linked juvenile retinoschisis (XLRS) manifested as bilateral vitreous hemorrhage as early as in an 1-month-old infant and in a 3-month-old infant. The one-month-old male infant showed massive bilateral vitreous hemorrhage. During vitrectomy, thin membrane representing an inner part of schisis cavity was excised and intraschisis hemorrhage was evacuated. As intraschisis cavities were cleared, the stump of inner layer appeared as the demarcation line between the outer layer of the schisis retina and non-schisis retina. The other three-month-old male infant presenting with esodeviation also showed bilateral vitreous hemorrhage. Typical bilateral retinoschisis involving maculae could be seen through vitreous hemorrhage in both eyes on fundus examination. Spontaneous absorption of hemorrhage was observed on regular follow-up. XLRS could be manifested as massive hemorrhage inside or outside of the schisis cavity early in infancy. PMID:19568363

PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28.

PubMed Central

Lindsay, S.; Splitt, M.; Edney, S.; Berney, T. P.; Knight, S. J.; Davies, K. E.; O'Brien, O.; Gale, M.; Burn, J.

1996-01-01

We report a three-generation family manifesting a previously undescribed X-linked mental retardation syndrome. Four of the six moderately retarded males have had episodes of manic-depressive psychosis. The phenotype also includes pyramidal signs, Parkinsonian features, and macroorchidism, but there are no characteristic dysmorphic facial features. Affected males do not show fragile sites at distal Xq on cytogenetic analysis, nor do they have expansions of the CGG repeats at the FRAXA, FRAXE, or FRAXF loci. Linkage analyses were undertaken, and a maximal LOD score of 3.311 at theta = .0 was observed with the microsatellite marker DXS1123 in Xq28. A recombination was detected in one of the affected males with DXS1691 (Xq28), which gives the proximal boundary of the localization. No distal recombination has been detected at any of the loci tested. Images Figure 2 PMID:8651288

CUL4B ubiquitin ligase in mouse development: a model for human X-linked mental retardation syndrome?

PubMed

Zhao, Yongchao; Sun, Yi

2012-08-01

CUL4B, a member of the cullin-RING ubiquitin ligase family, is frequently mutated in X-linked mental retardation (XLMR) patients. The study by Liu et al. showed that Cul4b plays an essential developmental role in the extra-embryonic tissues, while it is dispensable in the embryo proper during mouse embryogenesis. Viable Cul4b-null mice provide the first animal model to study neuronal and behavioral deficiencies seen in human CUL4B XLMR patients.

Magnetic Resonance Imaging Features as Surrogate Markers of X-Linked Hypophosphatemic Rickets Activity.

PubMed

Lempicki, Marta; Rothenbuhler, Anya; Merzoug, Valérie; Franchi-Abella, Stéphanie; Chaussain, Catherine; Adamsbaum, Catherine; Linglart, Agnès

2017-01-01

X-linked hypophosphatemic rickets (XLH) is the most common form of inheritable rickets. Rickets treatment is monitored by assessing alkaline phosphatase (ALP) levels, clinical features, and radiographs. Our objectives were to describe the magnetic resonance imaging (MRI) features of XLH and to assess correlations with disease activity. Twenty-seven XLH patients (median age 9.2 years) were included in this prospective single-center observational study. XLH activity was assessed using height, leg bowing, dental abscess history, and serum ALP levels. We looked for correlations between MRI features and markers of disease activity. On MRI, the median maximum width of the physis was 5.6 mm (range 4.8-7.8; normal <1.5), being >1.5 mm in all of the patients. The appearance of the zone of provisional calcification was abnormal on 21 MRI images (78%), Harris lines were present on 24 (89%), and bone marrow signal abnormalities were present on 16 (59%). ALP levels correlated with the maximum physeal widening and with the transverse extent of the widening. MRI of the knee provides precise rickets patterns that are correlated with ALP, an established biochemical marker of the disease, avoiding X-ray exposure and providing surrogate quantitative markers of disease activity. © 2017 S. Karger AG, Basel.

X-linked juvenile retinoschisis: mutations at the retinoschisis and Norrie disease gene loci?

PubMed

Hiraoka, M; Rossi, F; Trese, M T; Shastry, B S

2001-01-01

Juvenile retinoschisis (RS) and Norrie disease (ND) are X-linked recessive retinal disorders. Both disorders, in the majority of cases, are monogenic and are caused by mutations in the RS and ND genes, respectively. Here we report the identification of a family in which mutations in both the RS and ND genes are segregating with RS pathology. Although the mutations identified in this report were not functionally characterized with regard to their pathogenicity, it is likely that both of them are involved in RS pathology in the family analyzed. This suggests the complexity and digenic nature of monogenic human disorders in some cases. If this proves to be a widespread problem, it will complicate the strategies used to identify the genes involved in diseases and to develop methods for intervention.

The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females.

PubMed

Bixler, D; Higgins, M; Hartsfield, J

1984-07-01

This report describes two families with the Nance-Horan syndrome, an X-linked trait featuring lenticular cataracts and anomalies of tooth shape and number. Previous reports have described blindness in affected males but posterior sutural cataracts with normal vision as the primary ocular expression in heterozygous females. In one of these two families, the affected female is not only blind in one eye but reportedly had supernumerary central incisors (mesiodens) removed. This constitutes the most severe ocular and dental expression of this gene in heterozygous females yet reported.

Structure/Psychophysical Relationships in X-Linked Retinoschisis.

PubMed

Bennett, Lea D; Wang, Yi-Zhong; Klein, Martin; Pennesi, Mark E; Jayasundera, Thiran; Birch, David G

2016-02-01

To compare structural properties from spectral-domain optical coherence tomography (SDOCT) and psychophysical measures from a subset of patients enrolled in a larger multicenter natural history study of X-linked retinoschisis (XLRS). A subset of males (n = 24) participating in a larger natural history study of XLRS underwent high-resolution SDOCT. Total retina (TR) thickness and outer segment (OS) thickness were measured manually. Shape discrimination hyperacuity (SDH) and contour integration perimetry (CIP) were performed on an iPad with the myVisionTrack application. Sensitivity was measured with fundus-guided perimetry (4-2 threshold testing strategy; 10-2 grid, spot size 3, 68 points). Correlation was determined with Pearson's r correlation. Values are presented as the mean ± SD. Mean macular OS thickness was less in XLRS patients (17.2 ± 8.1 μm) than in controls (37.1 ± 5.7 μm; P < 0.0001) but mean TR thickness was comparable (P = 0.5884). For patients, total sensitivity was lower (13.2 ± 6.6 dB) than for controls (24.2 ± 2.4 dB; P = 0.0008) and had a strong correlation with photoreceptor OS (R(2) = 0.55, P = 0.0001) and a weak correlation with TR thickness (R(2) = 0.22, P = 0.0158). The XLRS subjects had a logMAR best corrected visual acuity (BCVA) of 0.5 ± 0.3 that was associated with OS (R(2) = 0.79, P < 0.0001) but not TR thickness (R(2) = 0.01, P = 0.6166). Shape DH and CIP inner ring correlated with OS (R(2) = 0.33, P = 0.0085 and R(2) = 0.47, P = 0.0001, respectively) but not TR thickness (R(2) = 0.0004, P = 0.93; R(2) = 0.0043, P = 0.75, respectively). When considered from a single visit, OS thickness within the macula is more closely associated with macular function than TR thickness within the macula in patients with XLRS.

Structure/Psychophysical Relationships in X-Linked Retinoschisis

PubMed Central

Bennett, Lea D.; Wang, Yi-Zhong; Klein, Martin; Pennesi, Mark E.; Jayasundera, Thiran; Birch, David G.

2016-01-01

Purpose To compare structural properties from spectral-domain optical coherence tomography (SDOCT) and psychophysical measures from a subset of patients enrolled in a larger multicenter natural history study of X-linked retinoschisis (XLRS). Methods A subset of males (n = 24) participating in a larger natural history study of XLRS underwent high-resolution SDOCT. Total retina (TR) thickness and outer segment (OS) thickness were measured manually. Shape discrimination hyperacuity (SDH) and contour integration perimetry (CIP) were performed on an iPad with the myVisionTrack application. Sensitivity was measured with fundus-guided perimetry (4-2 threshold testing strategy; 10-2 grid, spot size 3, 68 points). Correlation was determined with Pearson's r correlation. Values are presented as the mean ± SD. Results Mean macular OS thickness was less in XLRS patients (17.2 ± 8.1 μm) than in controls (37.1 ± 5.7 μm; P < 0.0001) but mean TR thickness was comparable (P = 0.5884). For patients, total sensitivity was lower (13.2 ± 6.6 dB) than for controls (24.2 ± 2.4 dB; P = 0.0008) and had a strong correlation with photoreceptor OS (R2 = 0.55, P = 0.0001) and a weak correlation with TR thickness (R2 = 0.22, P = 0.0158). The XLRS subjects had a logMAR best corrected visual acuity (BCVA) of 0.5 ± 0.3 that was associated with OS (R2 = 0.79, P < 0.0001) but not TR thickness (R2 = 0.01, P = 0.6166). Shape DH and CIP inner ring correlated with OS (R2 = 0.33, P = 0.0085 and R2 = 0.47, P = 0.0001, respectively) but not TR thickness (R2 = 0.0004, P = 0.93; R2 = 0.0043, P = 0.75, respectively). Conclusions When considered from a single visit, OS thickness within the macula is more closely associated with macular function than TR thickness within the macula in patients with XLRS. PMID:26830370

Visual Function in Carriers of X-linked Retinitis Pigmentosa

PubMed Central

Comander, Jason; Weigel-DiFranco, Carol; Sandberg, Michael A.; Berson, Eliot L.

2015-01-01

Purpose To determine the frequency and severity of visual function loss in female carriers of X-linked retinitis pigmentosa (XLRP). Design Case series. Participants XLRP carriers with cross-sectional data (n = 242) and longitudinal data (n = 34, median follow-up: 16 years, follow-up range: 3–37 years). Half of the carriers were from RPGR- or RP2-genotyped families. Methods Retrospective medical records review. Main Outcome Measures Visual acuities, visual field areas, final dark adaptation thresholds, and full-field ERGs to 0.5 Hz and 30 Hz flashes. Results In genotyped families, 40% of carriers showed a baseline abnormality on at least one of the three psychophysical tests. There was a wide range of function among carriers; for example 3 of 121 (2%) of genotyped carriers were legally blind due to poor visual acuity, some as young as 35 years of age. Visual fields were less affected than visual acuity. In all carriers, the average ERG amplitude to 30 Hz flashes was about 50% of normal, and the average exponential rate of amplitude loss over time was half that of XLRP males (3.7%/year vs 7.4%/year, respectively). Among obligate carriers with affected fathers and/or sons, 53 of 55 (96%) had abnormal baseline ERGs. Some carriers who initially had completely normal fundi in both eyes went on to develop moderately decreased vision, though not legal blindness. Among carriers with RPGR mutations, those with mutations in ORF15, compared to those in exons 1–14, had worse final dark adaptation thresholds and lower 0.5 Hz and 30 Hz ERG amplitudes. Conclusions Most carriers of XLRP had mildly or moderately reduced visual function but rarely became legally blind. In most cases, obligate carriers could be identified by ERG testing. Carriers of RPGR ORF15 mutations tended to have worse visual function than carriers of RPGR exon 1–14 mutations. Since XLRP carrier ERG amplitudes and decay rates over time were on average half of those of affected males, these observations were

Three-dimensional spectral domain optical coherence tomography in X linked foveal retinoschisis

PubMed Central

Saxena, Sandeep; Manisha; Meyer, Carsten H

2013-01-01

Spectral domain optical coherence tomography (SD-OCT) was performed in two cases of bilateral X linked foveal retinoschisis of different age groups. On fundus examination spoke wheel and honeycomb pattern of cysts were observed along with retinal nerve fibre layer (RNFL) defects. On SD-OCT, schisis was observed in the outer plexiform layer. External limiting membrane disruption was observed in the subfoveal area, along with disruption of outer nuclear layer (ONL) and inner–outer segment junction. Elevation of ONL due to tractional pull of central palisade was a novel observation. Retinoschisis extended beyond the optic disc up to the nasal region. Extracted RNFL tomogram presented an unprecedented visualisation of schisis along 360° of the optic disc. Tractional elevation in the foveal area and schisis involving nasal region, not observed upon clinical examination, was highlighted on SD-OCT. This investigative modality is an important adjunct in the assessment of foveal retinoschisis. PMID:23563673

Leaky phenotype of X-linked agammaglobulinaemia in a Japanese family

PubMed Central

Kaneko, H; Kawamoto, N; Asano, T; Mabuchi, Y; Horikoshi, H; Teramoto, T; JIN-RONG; Matsui, E; Kondo, M; Fukao, T; Kasahara, K; Kondo, N

2005-01-01

X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency that is caused by a block in early B-cell differentiation. Whereas early B precursors in the bone marrow are present in substantial numbers, XLA-affected individuals have dramatically reduced numbers of circulating mature B cells, plasma cells and immunoglobulins of all isotypes. We report on a Japanese family with 3 XLA patients, in whom the serum immunoglobulin levels and number of B cells showed a significant difference among them in spite of harbouring the same splice donor site mutation in the BTK gene. We developed concise method for detection of this mutation, which is helpful for discovering the carrier. Patient 2 showed a significant serum immunoglobulin levels of all isotypes, including allergen-specific IgE. Expression of a normal and truncated size BTK gene was detected in patient 2′s peripheral blood mononuclear cells (PBMCs). Expression of BTK protein was also detected in some B cells. These results suggest that the leaky phenotype in patient 2 was caused in part by the expression of a normal BTK gene transcript. The increased frequency of infection with age expanded the number of B cells with normal BTK gene expression and produced the serum immunoglobulin, including IgE. PMID:15932514

Successful treatment with infliximab for inflammatory colitis in a patient with X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

PubMed

Mizukami, Tomoyuki; Obara, Megumi; Nishikomori, Ryuta; Kawai, Tomoki; Tahara, Yoshihiro; Sameshima, Naoki; Marutsuka, Kousuke; Nakase, Hiroshi; Kimura, Nobuhiro; Heike, Toshio; Nunoi, Hiroyuki

2012-02-01

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.

Refined mapping and YAC contig construction of the X-linked cleft palate and ankyloglossia locus (CPX) including the proximal X-Y homology breakpoint within Xq21.3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Forbes, S.A.; Brennan, L.; Richardson, M.

1996-01-01

The gene for X-linked cleft palate (CPX) has previously been mapped in an Icelandic kindred between the unordered proximal markers DXS1002/DXS349/DXS95 and the distal marker DXYS1X, which maps to the proximal end of the X-Y homology region in Xq21.3. Using six sequence-tagged sites (STSs) within the region, a total of 91 yeast artificial chromosome (YAC) clones were isolated and overlapped in a single contig that spans approximately 3.1 Mb between DXS1002 and DXYS1X. The order of microsatellite and STS markers in this was established as DXS1002-DXS1168-DXS349-DXS95-DXS364-DXS1196-DXS472-DXS1217-DXYS1X. A long-range restriction map of this region was created using eight nonchimeric, overlapping YACmore » clones. Analysis of newly positioned polymorphic markers in recombinant individuals from the Icelandic family has enabled us to identify DXS1196 and DXS1217 as the flanking markers for CPX. The maximum physical distance containing the CPX gene has been estimated to be 2.0 Mb, which is spanned by a minimum set of five nonchimeric YAC clones. In addition, YAC end clone and STS analyses have pinpointed the location of the proximal boundary of the X-Y homology region within the map. 40 refs., 2 figs., 2 tabs.« less

Evaluation of the X-Linked High-Grade Myopia Locus (MYP1) with Cone Dysfunction and Color Vision Deficiencies

PubMed Central

Metlapally, Ravikanth; Michaelides, Michel; Bulusu, Anuradha; Li, Yi-Ju; Schwartz, Marianne; Rosenberg, Thomas; Hunt, David M.; Moore, Anthony T.; Züchner, Stephan; Rickman, Catherine Bowes; Young, Terri L.

2014-01-01

Purpose X-linked high myopia with mild cone dysfunction and color vision defects has been mapped to chromosome Xq28 (MYP1 locus). CXorf2/TEX28 is a nested, intercalated gene within the red-green opsin cone pigment gene tandem array on Xq28. The authors investigated whether TEX28 gene alterations were associated with the Xq28-linked myopia phenotype. Genomic DNA from five pedigrees (with high myopia and either protanopia or deuteranopia) that mapped to Xq28 were screened for TEX28 copy number variations (CNVs) and sequence variants. Methods To examine for CNVs, ultra-high resolution array-comparative genomic hybridization (array-CGH) assays were performed comparing the subject genomic DNA with control samples (two pairs from two pedigrees). Opsin or TEX28 gene-targeted quantitative real-time gene expression assays (comparative CT method) were performed to validate the array-CGH findings. All exons of TEX28, including intron/exon boundaries, were amplified and sequenced using standard techniques. Results Array-CGH findings revealed predicted duplications in affected patient samples. Although only three copies of TEX28 were previously reported within the opsin array, quantitative real-time analysis of the TEX28 targeted assay of affected male or carrier female individuals in these pedigrees revealed either fewer (one) or more (four or five) copies than did related and control unaffected individuals. Sequence analysis of TEX28 did not reveal any variants associated with the disease status. Conclusions CNVs have been proposed to play a role in disease inheritance and susceptibility as they affect gene dosage. TEX28 gene CNVs appear to be associated with the MYP1 X-linked myopia phenotypes. PMID:19098318

MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

PubMed Central

Lindert, Uschi; Cabral, Wayne A.; Ausavarat, Surasawadee; Tongkobpetch, Siraprapa; Ludin, Katja; Barnes, Aileen M.; Yeetong, Patra; Weis, Maryann; Krabichler, Birgit; Srichomthong, Chalurmpon; Makareeva, Elena N.; Janecke, Andreas R.; Leikin, Sergey; Röthlisberger, Benno; Rohrbach, Marianne; Kennerknecht, Ingo; Eyre, David R.; Suphapeetiporn, Kanya; Giunta, Cecilia; Marini, Joan C.; Shotelersuk, Vorasuk

2016-01-01

Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development. PMID:27380894

Central motor and sensory pathway involvement in an X-linked Charcot-Marie-Tooth family.

PubMed

Zambelis, T; Panas, M; Kokotis, P; Karadima, G; Kararizou, E; Karandreas, N

2008-06-01

The aim of the present study was to investigate the subclinical involvement of the central nervous system (CNS) in an X-linked Charcot-Marie-Toth (CMTX) family. Seven subjects, all members of one family with a C.462T > G connexin 32 (Cx32) mutation were investigated by Blink reflex, Somatosensory evoked potentials (SEP) and Transcranial magnetic stimulation (TMS). There were five clinically symptomatic for CMT neuropathy (four male and one female) and two asymptomatic (female) subjects. Subclinical CNS involvement was observed in all, symptomatic and asymptomatic subjects. This is the largest CMTX neuropathy family investigated for CNS involvement. Electrophysiological involvement of the CNS in every examined member of this family was observed, raising the question of a more systematic involvement of the CNS in CMTX disease.

Homodyne BPSK-based optical inter-satellite communication links

NASA Astrophysics Data System (ADS)

Lange, Robert; Smutny, Berry

2007-02-01

Summer 2007, Tesat will verify laser communication terminals based on homodyne BPSK (binary phase shift keying) in-orbit. A 5.625 Gbps LEO-LEO laser communication link, established between the German satellite TerraSAR-X and the US satellite NFIRE, shall demonstrate the performance and advantages of laser communication. End of 2006, a further program has been kicked-off to demonstrate the performance of ~2 Gbps LEO-GEO laser communication links. The link is part of a data relais from the German LEO satellite TanDEM-X via a Geo satellite to ground. The LEO-to-GEO laser commmunication link can be extended to further ~2 Gpbs GEO-GEO, and GEO-to-ground links.

Linkage analysis in a Dutch family with X-linked recessive congenital stationary night blindness (XL-CSNB).

PubMed

Berger, W; van Duijnhoven, G; Pinckers, A; Smits, A; Ropers, H H; Cremers, F

1995-01-01

Linkage analysis has been performed in a large Dutch pedigree with X-linked recessive congenital stationary night blindness (CSNB) by utilizing 16 DNA markers from the proximal short arm of the human X chromosome (Xp21.1-11.2). Thirteen polymorphic markers are at least partially informative and have enabled pairwise and multipoint linkage analysis. For three loci, i.e. DXS228, the monoamine oxidase B gene and the Norrie disease gene (NDG), multipoint linkage studies have yielded maximum lod scores of > 3.0 at a recombination fraction of zero. Analysis of recombination events has enabled us to rule out the possibility that the underlying defect in this family is allelic to RP3; the gene defect could also be excluded from the proximal part of the region known to carry RP2. Linkage data are consistent with a possible involvement of the NDG but mutations in the open reading frame of this gene have not been found.

Integra®-Dermal Regeneration Template and Split-Thickness Skin Grafting: A Therapy Approach to Correct Aplasia Cutis Congenita and Epidermolysis Bullosa in Carmi Syndrome.

PubMed

Trah, Julian; Has, Christina; Hausser, Ingrid; Kutzner, Heinz; Reinshagen, Konrad; Königs, Ingo

2018-05-18

The association of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) and aplasia cutis congenita (ACC) was described by El Shafie et al. (J Pediatr Surg 14(4):446-449, 1979) and Carmi et al. (Am J Med Genet 11:319-328, 1982). Most patients die in the first weeks of life, and no curative treatment options are available so far. We describe a patient with JEB-PA and ACC (OMIM # 226730) who was treated for extensive areas of ACC by Integra ® -Dermal Regeneration Template and split-thickness skin grafting (STSG). Clinically, the dermal template changed into well-vascularized neodermis, and after STSG, full take of the transplants was detected. No infections of the huge ACC areas were seen. Further studies must validate this treatment option in severe and acute cases of JEB-PA with ACC. Based on clinical findings, we postulate that placement of Integra ® -Dermal Regeneration Template with STSG could be a new treatment option for patients having JEB-PA with ACC to prevent severe infection, compartment-syndrome-like conditions, and deformities. Based on literature findings, we assume that Integra ® -Dermal Regeneration Template with STSG could even be able to prevent new blistering and thereby be a treatment option in cases of ACC and JEB.

JS-X syndrome: A multiple congenital malformation with vocal cord paralysis, ear deformity, hearing loss, shoulder musculature underdevelopment, and X-linked recessive inheritance.

PubMed

Hoeve, Hans L J; Brooks, Alice S; Smit, Liesbeth S

2015-07-01

We report on a family with a not earlier described multiple congenital malformation. Several male family members suffer from laryngeal obstruction caused by bilateral vocal cord paralysis, outer and middle ear deformity with conductive and sensorineural hearing loss, facial dysmorphisms, and underdeveloped shoulder musculature. The affected female members only have middle ear deformity and hearing loss. The pedigree is suggestive of an X-linked recessive inheritance pattern. SNP-array revealed a deletion and duplication on Xq28 in the affected family members. A possible aetiology is a neurocristopathy with most symptoms expressed in structures derived from branchial arches. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Golden tapetal reflex in male patients with X-linked retinitis pigmentosa. Case report and practical implications.

PubMed

van Osch, L; van Schooneveld, M; Bleekerwagemakers, E M

1990-12-01

The golden tapetal reflex in the ocular fundus is considered pathognomonic of the carrier state in some families with X-linked retinitis pigmentosa (XRP). Reports concerning affected males with this characteristic reflex are scarce. A six-year-old boy with XRP having a tapetal reflex is described. Recently the tapetal reflex has drawn attention in linkage studies. XRP is probably genetically heterogeneous and has at least two genetic forms. The finding of a tapetal reflex in one or more female carriers in a family with XRP may be helpful in differentiating between these two genetic forms.

Mechanically Strong, Polymer Cross-linked Aerogels (X-Aerogels)

NASA Technical Reports Server (NTRS)

Leventis, Nicholas

2006-01-01

Aerogels comprise a class of low-density, high porous solid objects consisting of dimensionally quasi-stable self-supported three-dimensional assemblies of nanoparticles. Aerogels are pursued because of properties above and beyond those of the individual nanoparticles, including low thermal conductivity, low dielectric constant and high acoustic impedance. Possible applications include thermal and vibration insulation, dielectrics for fast electronics, and hosting of functional guests for a wide variety of optical, chemical and electronic applications. Aerogels, however, are extremely fragile materials, hence they have found only limited application in some very specialized environments, for example as Cerenkov radiation detectors in certain types of nuclear reactors, aboard spacecraft as collectors of hypervelocity particles (refer to NASA's Stardust program) and as thermal insulators on planetary vehicles on Mars (refer to Sojourner Rover in 1997 and Spirit and Opportunity in 2004). Along these lines, the X-Aerogel is a new NASA-developed strong lightweight material that has resolved the fragility problem of traditional (native) aerogels. X-Aerogels are made by applying a conformal polymer coating on the surfaces of the skeletal nanoparticles of native aerogels (see Scanning Electron Micrographs). Since the relative amounts of the polymeric crosslinker and the backbone are comparable, X-Aerogels can be viewed either as aerogels modified by the templated accumulation of polymer on the skeletal nanoparticles, or as nanoporous polymers made by remplated casting of polymer on a nanostructured framework. The most striking feature of X-Aerogels is that for a nominal 3-fold increase in density (still a ultralighweight material), the mechanical strength can be up to 300 times higher than the strength of the underlying native aerogel. Thus, X-Aerogels combine a multiple of the specific compressive strength of steel, with the the thermal conductivity of styrofoam. X

DIA1R is an X-linked gene related to Deleted In Autism-1.

PubMed

Aziz, Azhari; Harrop, Sean P; Bishop, Naomi E

2011-01-17

Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation.

X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping.

PubMed

Dressman, Devin; Ahearn, Mary Ellen; Yariz, Kemal O; Basterrecha, Hugo; Martínez, Francisco; Palau, Francesc; Barmada, M Michael; Clark, Robin Dawn; Meindl, Alfons; Wirth, Brunhilde; Hoffman, Eric P; Baumbach-Reardon, Lisa

2007-01-01

X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have previously reported a single family with XL-SMA that mapped to Xp11.3-q11.2. Here we report further clinical description of XL-SMA plus an additional seven unrelated (XL-SMA) families from North America and Europe that show linkage data consistent with the same region. We first investigated linkage to the candidate disease gene region using microsatellite repeat markers. We further saturated the candidate disease gene region using polymorphic microsatellite repeat markers and single nucleotide polymorphisms in an effort to narrow the critical region. Two-point and multipoint linkage analysis was performed using the Allegro software package. Linkage analysis of all XL-SMA families displayed linkage consistent with the original XL-SMA region. The addition of new families and new markers has narrowed the disease gene interval for a XL-SMA locus between SNP FLJ22843 near marker DXS 8080 and SNP ARHGEF9 which is near DXS7132 (Xp11.3-Xq11.1).

Clinical and molecular characterization of females affected by X-linked retinoschisis.

PubMed

Staffieri, Sandra E; Rose, Loreto; Chang, Andrew; De Roach, John N; McLaren, Terri L; Mackey, David A; Hewitt, Alex W; Lamey, Tina M

2015-01-01

X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family. Consanguineous Eastern European-Australian family Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank. Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS. By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous. Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

PubMed Central

Reinstein, Eyal; Frentz, Sophia; Morgan, Tim; García-Miñaúr, Sixto; Leventer, Richard J; McGillivray, George; Pariani, Mitchel; van der Steen, Anthony; Pope, Michael; Holder-Espinasse, Muriel; Scott, Richard; Thompson, Elizabeth M; Robertson, Terry; Coppin, Brian; Siegel, Robert; Bret Zurita, Montserrat; Rodríguez, Jose I; Morales, Carmen; Rodrigues, Yuri; Arcas, Joaquín; Saggar, Anand; Horton, Margaret; Zackai, Elaine; Graham, John M; Rimoin, David L; Robertson, Stephen P

2013-01-01

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance. PMID:23032111

Manifestations of X-linked congenital stationary night blindness in three daughters of an affected male: Demonstration of homozygosity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bech-Hansen, N.T.; Pearce, W.G.

1993-01-01

X-linked congenital stationary night blindness (CSNB1) is a hereditary retinal disorder in which clinical features in affected males usually include myopia, nystagmus, and impaired visual acuity. Electroretinography demonstrates a marked reduction in b-wave amplitude. In the study of a large Mennonite family with CSNB1, three of five sisters in one sibship were found to have manifestations of CSNB1. All the sons of these three sisters were affected. Each of the two nonmanifesting sisters had at least one unaffected son. Analysis of Xp markers in the region Xp21.1-Xp11.22 showed that the two sisters who were unaffected had inherited the same maternalmore » X chromosome (i.e., M2). Two of the daughters who manifested with CSNB had inherited the other maternal X chromosome (M1). The third manifesting sister inherited a recombinant X chromosome with a crossover between TIMP and DXS255, which suggests that the CSNB1 locus lies proximal to TIMP. One of the affected daughters' sons had inherited the maternal M1 X chromosome, a finding consistent with that chromosome carrying a mutant CSNB gene; the other affected sons inherited the grandfather's X chromosome (i.e., P). Molecular analysis of DNA from three sisters with manifestations of CSNB is consistent with their being homozygous at the CSNB1 locus and with their mother being a carrier of CSNB1. 23 refs., 4 figs., 3 tabs.« less

No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level.

PubMed

Wermter, Anne-Kathrin; Kamp-Becker, Inge; Strauch, Konstantin; Schulte-Körne, Gerd; Remschmidt, Helmut

2008-06-05

Several lines of evidence indicate a role of mutations in the two X-linked genes neuroligin 3 (NLGN3) and neuroligin 4 (NLGN4X) in the etiology of autistic spectrum disorders. To analyze whether genetic variants in the NLGN3 and NLGN4X genes occurs in patients with autistic disorders on high functioning level, we performed a mutation screen of both genes using SSCP in 107 probands with Asperger syndrome, high-functioning autism and atypical autism. We identified four polymorphisms (rs2290488, rs7049300, rs3747333, rs3747334) and one novel synonymous variant (A558) in the NLGN4X. The polymorphisms rs7049300, rs3747333, and rs3747334 did not cause any amino acid substitutions in the total of the eight detected carriers. A family-based association study for rs2290488 in 101 trios did not reveal association of this polymorphism with autistic disorders on high functioning level. We conclude that there is no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level in our study group. (c) 2008 Wiley-Liss, Inc.

A Trial of Metformin in Individuals With Fragile X Syndrome

ClinicalTrials.gov

2018-06-05

Fragile X Syndrome; Fragile X Mental Retardation Syndrome; Mental Retardation, X Linked; Genetic Diseases, X-Linked; Trinucleotide Repeat Expansion; Fra(X) Syndrome; Intellectual Disability; FXS; Neurobehavioral Manifestations; Sex Chromosome Disorders

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 ismore » 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.« less

A natural history study of X-linked myotubular myopathy

PubMed Central

Amburgey, Kimberly; Tsuchiya, Etsuko; de Chastonay, Sabine; Glueck, Michael; Alverez, Rachel; Nguyen, Cam-Tu; Rutkowski, Anne; Hornyak, Joseph; Beggs, Alan H.

2017-01-01

Objective: To define the natural history of X-linked myotubular myopathy (MTM). Methods: We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33). Results: We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non–muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays. Conclusions: MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention. PMID:28842446

Hypertension is a characteristic complication of X-linked hypophosphatemia.

PubMed

Nakamura, Yoshie; Takagi, Masaki; Takeda, Ryojun; Miyai, Kentaro; Hasegawa, Yukihiro

2017-03-31

X-linked hypophosphatemia (XLH) is a group of rare disorders caused by defective proximal tubular reabsorption of phosphate. Mutations in the PHEX gene are responsible for the majority of cases. There are very few reports of long-term complications of XLH other than skeletal and dental diseases. The aim of this study was to identify the phenotypic presentation of XLH during adulthood including complications other than skeletal and dental diseases. The clinical and biochemical phenotype of 22 adult patients with a PHEX gene mutation were examined retrospectively from their medical records. 6 patients had hypertension. The average age of hypertension onset was 29.0 years. Secondary hyperparathyroidism preceded the development of hypertension in 5 patients. 1 patient developed tertiary hyperparathyroidism. 15 patients had nephrocalcinosis. 2 patients had chronic renal dysfunction. Patients with hypertension had a significantly lower eGFR (p=0.010) compared to patients without hypertension. No significant difference was found in any other parameters. To examine the genotype-phenotype correlation, 10 adult males were chosen for analysis. No significant genotype-phenotype correlation analysis was revealed in any of the complications. However, there was a possibility that the age at nephrocalcinosis onset was younger in the non-missense mutation group than in the missense mutation group (p=0.063). This study corroborated the view that early-onset hypertension could be one of the characteristic complications seen in XLH patients. Considering the limited number of our patients, further study is necessary to address a potential cause of hypertension. XLH patients require careful lifelong treatment.

En face swept-source optical coherence tomographic analysis of X-linked juvenile retinoschisis.

PubMed

Ono, Shinji; Takahashi, Atsushi; Mase, Tomoko; Nagaoka, Taiji; Yoshida, Akitoshi

2016-07-01

To clarify the area of retinoschisis by X-linked juvenile retinoschisis (XLRS) using swept-source optical coherence tomography (SS-OCT) en face images. We report two cases of XLRS in the same family. The patients presented with bilateral blurred vision. The posterior segment examination showed a spoked-wheel pattern in the macula. SS-OCT cross-sectional images revealed widespread retinal splitting at the level of the inner nuclear layer bilaterally. We diagnosed XLRS. To evaluate the area of retinoschisis, we obtained en face SS-OCT images, which clearly visualized the area of retinoschisis seen as a sunflower-like structure in the macula. We report the findings on en face SS-OCT images from patients with XLRS. The en face images using SS-OCT showed the precise area of retinoschisis compared with the SS-OCT thickness map and are useful for managing patients with XLRS.

Faster-X evolution: Theory and evidence from Drosophila.

PubMed

Charlesworth, Brian; Campos, José L; Jackson, Benjamin C

2018-02-12

A faster rate of adaptive evolution of X-linked genes compared with autosomal genes can be caused by the fixation of recessive or partially recessive advantageous mutations, due to the full expression of X-linked mutations in hemizygous males. Other processes, including recombination rate and mutation rate differences between X chromosomes and autosomes, may also cause faster evolution of X-linked genes. We review population genetics theory concerning the expected relative values of variability and rates of evolution of X-linked and autosomal DNA sequences. The theoretical predictions are compared with data from population genomic studies of several species of Drosophila. We conclude that there is evidence for adaptive faster-X evolution of several classes of functionally significant nucleotides. We also find evidence for potential differences in mutation rates between X-linked and autosomal genes, due to differences in mutational bias towards GC to AT mutations. Many aspects of the data are consistent with the male hemizygosity model, although not all possible confounding factors can be excluded. © 2018 John Wiley & Sons Ltd.

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa.

PubMed

Beltran, William A; Cideciyan, Artur V; Lewin, Alfred S; Iwabe, Simone; Khanna, Hemant; Sumaroka, Alexander; Chiodo, Vince A; Fajardo, Diego S; Román, Alejandro J; Deng, Wen-Tao; Swider, Malgorzata; Alemán, Tomas S; Boye, Sanford L; Genini, Sem; Swaroop, Anand; Hauswirth, William W; Jacobson, Samuel G; Aguirre, Gustavo D

2012-02-07

Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.

Subcortical laminar heterotopia and lissencephaly in two families: a single X linked dominant gene.

PubMed Central

Pinard, J M; Motte, J; Chiron, C; Brian, R; Andermann, E; Dulac, O

1994-01-01

Neuronal migration disorders can now be recognised by MRI. This paper reports two families in which the mothers had subcortical laminar heterotopia and four of their children had either similar heterotopia (two girls) or severe pachygyria or lissencephaly (two boys). Laminar heterotopia was more evident on MRI T2 weighted images. The patients had mild to severe epilepsy and mental retardation depending on the extent of cortical abnormalities. In these families, subcortical laminar heterotopia, pachygyria, and lissencephaly seem to share the same X linked or autosomal dominant gene. No chromosomal abnormalities, especially of chromosome 17, could be identified. For appropriate genetic counselling of the family of a child with lissencephaly or subcortical laminar heterotopia, MRI should be performed in parents or siblings with mental retardation or epilepsy. Images PMID:8057113

Bruton's Tyrosine Kinase: From X-Linked Agammaglobulinemia Toward Targeted Therapy for B-Cell Malignancies

PubMed Central

Ponader, Sabine; Burger, Jan A.

2014-01-01

Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy. PMID:24778403

Osteopontin and the dento-osseous pathobiology of X-linked hypophosphatemia.

PubMed

Boukpessi, Tchilalo; Hoac, Betty; Coyac, Benjamin R; Leger, Thibaut; Garcia, Camille; Wicart, Philippe; Whyte, Michael P; Glorieux, Francis H; Linglart, Agnès; Chaussain, Catherine; McKee, Marc D

2017-02-01

Seven young patients with X-linked hypophosphatemia (XLH, having inactivating PHEX mutations) were discovered to accumulate osteopontin (OPN) at the sites of defective bone mineralization near osteocytes - the so-called hallmark periosteocytic (lacunar) "halos" of XLH. OPN was also localized in the pericanalicular matrix extending beyond the osteocyte lacunae, as well as in the hypomineralized matrix of tooth dentin. OPN, a potent inhibitor of mineralization normally degraded by PHEX, is a member of a family of acidic, phosphorylated, calcium-binding, extracellular matrix proteins known to regulate dental, skeletal, and pathologic mineralization. Associated with the increased amount of OPN (along with inhibitory OPN peptide fragments) in XLH bone matrix, we found an enlarged, hypomineralized, lacuno-canalicular network - a defective pattern of skeletal mineralization that decreases stiffness locally at: i) the cell-matrix interface in the pericellular environment of the mechanosensing osteocyte, and ii) the osteocyte's dendritic network of cell processes extending throughout the bone. Our findings of an excess of inhibitory OPN near osteocytes and their cell processes, and in dentin, spatially correlates with the defective mineralization observed at these sites in the skeleton and teeth of XLH patients. These changes likely contribute to the dento-osseous pathobiology of XLH, and participate in the aberrant bone adaptation and remodeling seen in XLH. Copyright © 2016 Elsevier Inc. All rights reserved.

Faster-X Evolution of Gene Expression in Drosophila

PubMed Central

Meisel, Richard P.; Malone, John H.; Clark, Andrew G.

2012-01-01

DNA sequences on X chromosomes often have a faster rate of evolution when compared to similar loci on the autosomes, and well articulated models provide reasons why the X-linked mode of inheritance may be responsible for the faster evolution of X-linked genes. We analyzed microarray and RNA–seq data collected from females and males of six Drosophila species and found that the expression levels of X-linked genes also diverge faster than autosomal gene expression, similar to the “faster-X” effect often observed in DNA sequence evolution. Faster-X evolution of gene expression was recently described in mammals, but it was limited to the evolutionary lineages shortly following the creation of the therian X chromosome. In contrast, we detect a faster-X effect along both deep lineages and those on the tips of the Drosophila phylogeny. In Drosophila males, the dosage compensation complex (DCC) binds the X chromosome, creating a unique chromatin environment that promotes the hyper-expression of X-linked genes. We find that DCC binding, chromatin environment, and breadth of expression are all predictive of the rate of gene expression evolution. In addition, estimates of the intraspecific genetic polymorphism underlying gene expression variation suggest that X-linked expression levels are not under relaxed selective constraints. We therefore hypothesize that the faster-X evolution of gene expression is the result of the adaptive fixation of beneficial mutations at X-linked loci that change expression level in cis. This adaptive faster-X evolution of gene expression is limited to genes that are narrowly expressed in a single tissue, suggesting that relaxed pleiotropic constraints permit a faster response to selection. Finally, we present a conceptional framework to explain faster-X expression evolution, and we use this framework to examine differences in the faster-X effect between Drosophila and mammals. PMID:23071459

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes.

PubMed

Kalejaiye, Adedoyin; Giri, Neelam; Brewer, Carmen C; Zalewski, Christopher K; King, Kelly A; Adams, Charleen D; Rosenberg, Philip S; Kim, H Jeffrey; Alter, Blanche P

2016-12-01

The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss. Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy. Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS. FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss. © 2016 Wiley Periodicals, Inc.

Missing Cells: Pathophysiology, Diagnosis, and Management of (Pan)Cytopenia in Childhood

PubMed Central

Erlacher, Miriam; Strahm, Brigitte

2015-01-01

Peripheral blood cytopenia in children can be due to a variety of acquired or inherited diseases. Genetic disorders affecting a single hematopoietic lineage are frequently characterized by typical bone marrow findings, such as lack of progenitors or maturation arrest in congenital neutropenia or a lack of megakaryocytes in congenital amegakaryocytic thrombocytopenia, whereas antibody-mediated diseases such as autoimmune neutropenia are associated with a rather unremarkable bone marrow morphology. By contrast, pancytopenia is frequently associated with a hypocellular bone marrow, and the differential diagnosis includes acquired aplastic anemia, myelodysplastic syndrome, inherited bone marrow failure syndromes such as Fanconi anemia and dyskeratosis congenita, and a variety of immunological disorders including hemophagocytic lymphohistiocytosis. Thorough bone marrow analysis is of special importance for the diagnostic work-up of most patients. Cellularity, cellular composition, and dysplastic signs are the cornerstones of the differential diagnosis. Pancytopenia in the presence of a normo- or hypercellular marrow with dysplastic changes may indicate myelodysplastic syndrome. More challenging for the hematologist is the evaluation of the hypocellular bone marrow. Although aplastic anemia and hypocellular refractory cytopenia of childhood (RCC) can reliably be differentiated on a morphological level, the overlapping pathophysiology remains a significant challenge for the choice of the therapeutic strategy. Furthermore, inherited bone marrow failure syndromes are usually associated with the morphological picture of RCC, and the recognition of these entities is essential as they often present a multisystem disease requiring different diagnostic and therapeutic approaches. This paper gives an overview over the different disease entities presenting with (pan)cytopenia, their pathophysiology, characteristic bone marrow findings, and therapeutic approaches. PMID:26217651

Sirtuins in dermatology: applications for future research and therapeutics.

PubMed

Serravallo, Melissa; Jagdeo, Jared; Glick, Sharon A; Siegel, Daniel M; Brody, Neil I

2013-05-01

Sirtuins are a family of seven proteins in humans (SIRT1-SIRT7) that are involved in multiple cellular processes relevant to dermatology. The role of sirtuins in other organ systems is established. However, the importance of these proteins in dermatology is less defined. Recently, sirtuins gained international attention because of their role as "longevity proteins" that may extend and enhance human life. Sirtuins function in the cell via histone deacetylase and/or adenosine diphosphate ribosyltransferase enzymatic activity that target histone and non-histone substrates, including transcription regulators, tumor suppressors, structural proteins, DNA repair proteins, cell signaling proteins, transport proteins, and enzymes. Sirtuins are involved in cellular pathways related to skin structure and function, including aging, ultraviolet-induced photoaging, inflammation, epigenetics, cancer, and a variety of cellular functions including cell cycle, DNA repair and proliferation. This review highlights sirtuin-related cellular pathways, therapeutics and pharmacological targets in atopic dermatitis, bullous dermatoses, collagen vascular disorders, psoriasis, systemic lupus erythematosus, hypertrophic and keloid scars, cutaneous infections, and non-melanoma and melanoma skin cancer. Also discussed is the role of sirtuins in the following genodermatoses: ataxia telangiectasia, Cowden's syndrome, dyskeratosis congenita, Rubenstein-Taybi, Werner syndrome, and xeroderma pigmentosum. The pathophysiology of these inherited diseases is not well understood, and sirtuin-related processes represent potential therapeutic targets for diseases lacking suitable alternative treatments. The goal of this review is to bring attention to the dermatology community, physicians, and scientists, the importance of sirtuins in dermatology and provide a foundation and impetus for future discussion, research and pharmacologic discovery.

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms

PubMed Central

Marsh, Judith C. W.; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria del Pilar F.; Donaires, Flávia S.; Lopes da Silva, João P.; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E.; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G.; McLornan, Donal P.; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S.; Calado, Rodrigo T.; Townsley, Danielle M.

2018-01-01

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3′ telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants. PMID:29344583

Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

PubMed

Marsh, Judith C W; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria Del Pilar F; Donaires, Flávia S; Lopes da Silva, João P; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G; McLornan, Donal P; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S; Calado, Rodrigo T; Townsley, Danielle M; Mufti, Ghulam J

2018-01-09

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

Genetic diagnosis of sex chromosome aberrations in horses based on parentage test by microsatellite DNA and analysis of X- and Y-linked markers.

PubMed

Kakoi, H; Hirota, K; Gawahara, H; Kurosawa, M; Kuwajima, M

2005-03-01

Sex chromosome aberrations are often associated with clinical signs that affect equine health and reproduction. However, abnormal manifestation with sex chromosome aberration usually appears at maturity and potential disorders may be suspected infrequently. A reliable survey at an early stage is therefore required. To detect and characterise sex chromosome aberrations in newborn foals by the parentage test and analysis using X- and Y-linked markers. We conducted a genetic diagnosis combined with a parentage test by microsatellite DNA and analysis of X- and Y-linked genetic markers in newborn light-breed foals (n = 17, 471). The minimum incidence of sex chromosome aberration in horses was estimated in the context of available population data. Eighteen cases with aberrations involving 63,XO, 65,XXY and 65,XXX were found. The XO, XXY (pure 65,XXY and/or mosaics/chimaeras) and XXX were found in 0.15, 0.02 and 0.01% of the population, respectively, based solely on detection of abnormal segregation of a single X chromosome marker, LEX003. Detection at an early age and understanding of the prevalence of sex chromosome aberrations should assist in the diagnosis and managment of horses kept for breeding. Further, the parental origin of the X chromosome of each disorder could be proved by the results of genetic analysis, thereby contributing to cytogenetic characterisation.

X Linkage of AP3A, a Homolog of the Y-Linked MADS-Box Gene AP3Y in Silene latifolia and S. dioica

PubMed Central

Penny, Rebecca H.; Montgomery, Benjamin R.; Delph, Lynda F.

2011-01-01

Background The duplication of autosomal genes onto the Y chromosome may be an important element in the evolution of sexual dimorphism.A previous cytological study reported on a putative example of such a duplication event in a dioecious tribe of Silene (Caryophyllaceae): it was inferred that the Y-linked MADS-box gene AP3Y originated from a duplication of the reportedly autosomal orthologAP3A. However, a recent study, also using cytological methods, indicated that AP3A is X-linked in Silenelatifolia. Methodology/Principal Findings In this study, we hybridized S. latifolia and S. dioicato investigate whether the pattern of X linkage is consistent among distinct populations, occurs in both species, and is robust to genetic methods. We found inheritance patterns indicative of X linkage of AP3A in widely distributed populations of both species. Conclusions/Significance X linkage ofAP3A and Y linkage of AP3Yin both species indicates that the genes' ancestral progenitor resided on the autosomes that gave rise to the sex chromosomesand that neither gene has moved between chromosomes since species divergence.Consequently, our results do not support the contention that inter-chromosomal gene transfer occurred in the evolution of SlAP3Y from SlAP3A. PMID:21533056

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ott, J.; Terwilliger, J.D.; Bhattacharya, S.

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 halfwaymore » 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.« less

Mapping of a possible X-linked form of familial developmental dysphasia (FDD) in a single large pedigree

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dunne, P.W.; Doody, R.S.; Epstein, H.F.

Children diagnosed with developmental dysphasia develop speech very late without exhibiting sensory or motor dysfunction, and when they do begin to speak their grammar is abnormal. A large three-generation British pedigree was recently identified in which 16 out of 30 members were diagnosed as dysphasic. Assuming a dominant mode of inheritance with homogeneous phenotypic expression and complete penetrance among affected members, we showed by simulation analysis that this pedigree has the power to detect linkage to marker loci with an average maximum LOD score of 3.67 at {theta}=0.1. Given the absence of male-to-male transmission and a ratio of female tomore » male affecteds (10/6) in this pedigree within the expected range for an X-linked dominant mode of inheritance, we decided to begin a genome-wide linkage analysis with microsatellite markers on the human X chromosome. Fifteen individuals (10 affected) from three generations were genotyped with 35 polymorphic STS`s (Research Genetics) which were approximately uniformly distributed along the X chromosome. Two-point linkage was assessed using the MLINK and ILINK programs from the LINKAGE package. Markers DXS1223, DXS987, DXS996 and DXS1060 on Xp22 showed consistent linkage to the disease locus with a maximum LOD score of 0.86 at a distance of 22 cM for DXS1060. If further analysis with additional markers and additional family members confirms X-linkage, such a localization would provide support for Lehrke`s hypothesis for X-linkage of major intellectual traits including verbal functioning.« less

Recapitulating X-Linked Juvenile Retinoschisis in Mouse Model by Knock-In Patient-Specific Novel Mutation.

PubMed

Chen, Ding; Xu, Tao; Tu, Mengjun; Xu, Jinlin; Zhou, Chenchen; Cheng, Lulu; Yang, Ruqing; Yang, Tanchu; Zheng, Weiwei; He, Xiubin; Deng, Ruzhi; Ge, Xianglian; Li, Jin; Song, Zongming; Zhao, Junzhao; Gu, Feng

2017-01-01

X-linked juvenile retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding retinoschisin (RS1), which leads to a significant proportion of visual impairment and blindness. To develop personalized genome editing based gene therapy, knock-in animal disease models that have the exact mutation identified in the patients is extremely crucial, and that the way which genome editing in knock-in animals could be easily transferred to the patients. Here we recruited a family diagnosed with XLRS and identified the causative mutation ( RS1 , p.Y65X), then a knock-in mouse model harboring this disease-causative mutation was generated via TALEN (transcription activator-like effector nucleases). We found that the b-wave amplitude of the ERG of the RS1 -KI mice was significantly decreased. Moreover, we observed that the structure of retina in RS1 -KI mice has become disordered, including the disarray of inner nuclear layer and outer nuclear layer, chaos of outer plexiform layer, decreased inner segments of photoreceptor and the loss of outer segments. The novel knock-in mice ( RS1 -KI) harboring patient-specific mutation will be valuable for development of treatment via genome editing mediated gene correction.

A previously unreported, dominantly inherited syndrome of shortness of stature, ear malformations, and hip dislocation: the coxoauricular syndrome--autosomal or X-linked male-lethal.

PubMed

Duca, D; Pană, I; Ciovirnache, M; Simionesu, L; Ispas, I; Maxililian, C

1981-01-01

We reported an apparently previously undescribed syndrome, designated the coxoauricular syndrome, in a mother and her 3 daughters, all of whom shared in variable manner shortness of stature, minor vertebral and pelvic changes, dislocated hip(s), and microtia with corresponding hearing loss. The oldest daughter had coincidental Ullrich-Turner syndrome with 46, Xdel(X)(q 13) chromosome constitution. Inheritance of the trait in this family is dominant, either autosomal or X-linked, with hemizygote lethality.

X-Linked Hypohidrotic Ectodermal Dysplasia: New Features and a Novel EDA Gene Mutation.

PubMed

Savasta, Salvatore; Carlone, Giorgia; Castagnoli, Riccardo; Chiappe, Francesca; Bassanese, Francesco; Piras, Roberta; Salpietro, Vincenzo; Brazzelli, Valeria; Verrotti, Alberto; Marseglia, Gian L

2017-01-01

We described a 5-year-old male with hypodontia, hypohidrosis, and facial dysmorphisms characterized by a depressed nasal bridge, maxillary hypoplasia, and protuberant lips. Chromosomal analysis revealed a normal 46,XY male karyotype. Due to the presence of clinical features of hypohidrotic ectodermal dysplasia (HED), the EDA gene, located at Xq12q13.1, of the patient and his family was sequenced. Analysis of the proband's sequence revealed a missense mutation (T to A transversion) in hemizygosity state at nucleotide position 158 in exon 1 of the EDA gene, which changes codon 53 from leucine to histidine, while heterozygosity at this position was detected in the slightly affected mother; moreover, this mutation was not found in the publically available Human Gene Mutation Database. To date, our findings indicate that a novel mutation in EDA is associated with X-linked HED, adding it to the repertoire of EDA mutations. © 2017 S. Karger AG, Basel.

Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers.

PubMed

Aguilar, Claire; Lenoir, Christelle; Lambert, Nathalie; Bègue, Bernadette; Brousse, Nicole; Canioni, Danielle; Berrebi, Dominique; Roy, Maryline; Gérart, Stéphane; Chapel, Helen; Schwerd, Tobias; Siproudhis, Laurent; Schäppi, Michela; Al-Ahmari, Ali; Mori, Masaaki; Yamaide, Akiko; Galicier, Lionel; Neven, Bénédicte; Routes, John; Uhlig, Holm H; Koletzko, Sibylle; Patel, Smita; Kanegane, Hirokazu; Picard, Capucine; Fischer, Alain; Bensussan, Nadine Cerf; Ruemmele, Frank; Hugot, Jean-Pierre; Latour, Sylvain

2014-11-01

Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients

Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tranebjaerg, L.; Schwartz, C.; Huggins, K.

1994-07-15

In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localizedmore » to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.« less

X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 DNA marker loci.

PubMed

Thomas, N S; Williams, H; Cole, G; Roberts, K; Clarke, A; Liechti-Gallati, S; Braga, S; Gerber, A; Meier, C; Moser, H

1990-05-01

We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.00), with DXS15 (Z = 3.737, theta = 0.00), with DXS52 (Z = 2.709, theta = 0.00), and with F8C (Z = 1.020, theta = 0.00). In the absence of any observable recombination, we are unable to sublocalise the XLMTM locus further within the Xq28 region. This evidence for an Xq28 localisation may allow us to carry out useful genetic counselling within such families.

A natural history study of X-linked myotubular myopathy.

PubMed

Amburgey, Kimberly; Tsuchiya, Etsuko; de Chastonay, Sabine; Glueck, Michael; Alverez, Rachel; Nguyen, Cam-Tu; Rutkowski, Anne; Hornyak, Joseph; Beggs, Alan H; Dowling, James J

2017-09-26

To define the natural history of X-linked myotubular myopathy (MTM). We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33). We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non-muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays. MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria.

PubMed

Guindo, Aldiouma; Fairhurst, Rick M; Doumbo, Ogobara K; Wellems, Thomas E; Diallo, Dapa A

2007-03-01

Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A- form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. We conducted large case-control studies of the A- form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. The A- form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these

X-Linked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria

PubMed Central

Doumbo, Ogobara K; Wellems, Thomas E; Diallo, Dapa A

2007-01-01

Background Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A− form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. Methods and Findings We conducted large case-control studies of the A− form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. Conclusions The A− form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is

Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.

PubMed

Blasi, Francesca; Bacchelli, Elena; Pesaresi, Giulia; Carone, Simona; Bailey, Anthony J; Maestrini, Elena

2006-04-05

Neuroligin abnormalities have been recently implicated in the aetiology of autism spectrum disorders (ASD), given the finding of point mutations in the two X-linked genes NLGN3 and NLGN4X and the important role of neuroligins in synaptogenesis. To enquire on the relevance and frequency of neuroligin mutations in ASD, we performed a mutation screening of NLGN3 and NLGN4X in a sample of 124 autism probands from the International Molecular Genetic Study of Autism Consortium (IMGSAC). We identified a new non-synonymous variant in NLGN3 (Thr632Ala), which is likely to be a rare polymorphism. Our data indicate that coding mutations in these genes are very rarely associated to ASD. Copyright 2006 Wiley-Liss, Inc.

Contrasting X-Linked and Autosomal Diversity across 14 Human Populations

PubMed Central

Arbiza, Leonardo; Gottipati, Srikanth; Siepel, Adam; Keinan, Alon

2014-01-01

Contrasting the genetic diversity of the human X chromosome (X) and autosomes has facilitated understanding historical differences between males and females and the influence of natural selection. Previous studies based on smaller data sets have left questions regarding how empirical patterns extend to additional populations and which forces can explain them. Here, we address these questions by analyzing the ratio of X-to-autosomal (X/A) nucleotide diversity with the complete genomes of 569 females from 14 populations. Results show that X/A diversity is similar within each continental group but notably lower in European (EUR) and East Asian (ASN) populations than in African (AFR) populations. X/A diversity increases in all populations with increasing distance from genes, highlighting the stronger impact of diversity-reducing selection on X than on the autosomes. However, relative X/A diversity (between two populations) is invariant with distance from genes, suggesting that selection does not drive the relative reduction in X/A diversity in non-Africans (0.842 ± 0.012 for EUR-to-AFR and 0.820 ± 0.032 for ASN-to-AFR comparisons). Finally, an array of models with varying population bottlenecks, expansions, and migration from the latest studies of human demographic history account for about half of the observed reduction in relative X/A diversity from the expected value of 1. They predict values between 0.91 and 0.94 for EUR-to-AFR comparisons and between 0.91 and 0.92 for ASN-to-AFR comparisons. Further reductions can be predicted by more extreme demographic events in excess of those captured by the latest studies but, in the absence of these, also by historical sex-biased demographic events or other processes. PMID:24836452

Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features.

PubMed

Kuroda, Yukiko; Ohashi, Ikuko; Naruto, Takuya; Ida, Kazumi; Enomoto, Yumi; Saito, Toshiyuki; Nagai, Jun-Ichi; Wada, Takahito; Kurosawa, Kenji

2015-06-01

Next-generation sequencing has enabled the screening for a causative mutation in X-linked intellectual disability (XLID). We identified KIAA2022 mutations in two unrelated male patients by targeted sequencing. We selected 13 Japanese male patients with severe intellectual disability (ID), including four sibling patients and nine sporadic patients. Two of thirteen had a KIAA2022 mutation. Patient 1 was a 3-year-old boy. He had severe ID with autistic behavior and hypotonia. Patient 2 was a 5-year-old boy. He also had severe ID with autistic behavior, hypotonia, central hypothyroidism, and steroid-dependent nephrotic syndrome. Both patients revealed consistent distinctive features, including upswept hair, narrow forehead, downslanting eyebrows, wide palpebral fissures, long nose, hypoplastic alae nasi, open mouth, and large ears. De novo KIAA2022 mutations (p.Q705X in Patient 1, p.R322X in Patient 2) were detected by targeted sequencing and confirmed by Sanger sequencing. KIAA2022 mutations and alterations have been reported in only four families with nonsyndromic ID and epilepsy. KIAA2022 is highly expressed in the fetal and adult brain and plays a crucial role in neuronal development. These additional patients support the evidence that KIAA2022 is a causative gene for XLID. © 2015 Wiley Periodicals, Inc.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.

PubMed

Frints, Suzanna G M; Ozanturk, Aysegul; Rodríguez Criado, Germán; Grasshoff, Ute; de Hoon, Bas; Field, Michael; Manouvrier-Hanu, Sylvie; E Hickey, Scott; Kammoun, Molka; Gripp, Karen W; Bauer, Claudia; Schroeder, Christopher; Toutain, Annick; Mihalic Mosher, Theresa; Kelly, Benjamin J; White, Peter; Dufke, Andreas; Rentmeester, Eveline; Moon, Sungjin; Koboldt, Daniel C; van Roozendaal, Kees E P; Hu, Hao; Haas, Stefan A; Ropers, Hans-Hilger; Murray, Lucinda; Haan, Eric; Shaw, Marie; Carroll, Renee; Friend, Kathryn; Liebelt, Jan; Hobson, Lynne; De Rademaeker, Marjan; Geraedts, Joep; Fryns, Jean-Pierre; Vermeesch, Joris; Raynaud, Martine; Riess, Olaf; Gribnau, Joost; Katsanis, Nicholas; Devriendt, Koen; Bauer, Peter; Gecz, Jozef; Golzio, Christelle; Gontan, Cristina; Kalscheuer, Vera M

2018-05-04

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

Gene correction of induced pluripotent stem cells derived from a murine model of X-linked chronic granulomatous disorder.

PubMed

Mukherjee, Sayandip; Thrasher, Adrian J

2014-01-01

Gene therapy presents an attractive alternative to allogeneic haematopoietic stem cell transplantation (HSCT) for treating patients suffering from primary immunodeficiency disorder (PID). The conceptual advantage of gene correcting a patient's autologous HSCs lies in minimizing or completely avoiding immunological complications arising from allogeneic transplantation while conferring the same benefits of immune reconstitution upon long-term engraftment. Clinical trials targeting X-linked chronic granulomatous disorder (X-CGD) have shown promising results in this context. However, long-term clinical benefits in these patients have been limited by issues of poor engraftment of gene-transduced cells coupled with transgene silencing and vector induced clonal proliferation. Novel vectors incorporating safety features such as self-inactivating (SIN) mutations in the long terminal repeats (LTRs) along with synthetic promoters driving lineage-restricted sustainable expression of the gp91phox transgene are expected to resolve the current pitfalls and require rigorous preclinical testing. In this chapter, we have outlined a protocol in which X-CGD mouse model derived induced pluripotent stem cells (iPSCs) have been utilized to develop a platform for investigating the efficacy and safety profiles of novel vectors prior to clinical evaluation.

An X-linked three allele model of hand preference and hand posture for writing.

PubMed

McKeever, Walter F

2004-04-01

This paper describes a genetic model of hand preferences for writing and for handwriting posture (HWP). The challenge of devising an X-linked model for these aspects of human handedness was posed by the results of a large family handedness study (McKeever, 2000) that showed evidence of such linkage. Because X-linkage for handedness has been widely regarded as untenable, the prospects for developing such a model were not initially encouraging, but ultimately a viable model did suggest itself. Family studies of handedness and leading theories of handedness are briefly described, as is some of the research on HWP motivated by the theory of Levy and Nagylaki (1972). It is argued that there is evidence that HWP reflects a biological dictate and not just individual "choices" or "adaptations" to writing in a left-to-right direction with the left hand. The model proposes that inverted handwriting posture is not necessarily highly related to speech and language lateralities of sinistrals, but that it reveals an interhemispheric mediation of writing. It is hypothesised that it reflects a specialisation of the left angular gyrus (with some possible extension into the supramarginal gyrus) for the storage of movement and timing sequences of cursive writing, and right hemisphere motor programming of the motor output of writing. It is also argued that no family handedness study conducted to date is adequate for testing the predictions of extant handedness theories, and the often wide variations between the results of family handedness studies are noted. It is suggested that fMRI studies could definitively test the HWP hypotheses of the model and that the hypothesis of X-linkage could be tested definitively should studies of the human genome identify a gene for handedness.

Extraordinary Sequence Divergence at Tsga8, an X-linked Gene Involved in Mouse Spermiogenesis

PubMed Central

Good, Jeffrey M.; Vanderpool, Dan; Smith, Kimberly L.; Nachman, Michael W.

2011-01-01

The X chromosome plays an important role in both adaptive evolution and speciation. We used a molecular evolutionary screen of X-linked genes potentially involved in reproductive isolation in mice to identify putative targets of recurrent positive selection. We then sequenced five very rapidly evolving genes within and between several closely related species of mice in the genus Mus. All five genes were involved in male reproduction and four of the genes showed evidence of recurrent positive selection. The most remarkable evolutionary patterns were found at Testis-specific gene a8 (Tsga8), a spermatogenesis-specific gene expressed during postmeiotic chromatin condensation and nuclear transformation. Tsga8 was characterized by extremely high levels of insertion–deletion variation of an alanine-rich repetitive motif in natural populations of Mus domesticus and M. musculus, differing in length from the reference mouse genome by up to 89 amino acids (27% of the total protein length). This population-level variation was coupled with striking divergence in protein sequence and length between closely related mouse species. Although no clear orthologs had previously been described for Tsga8 in other mammalian species, we have identified a highly divergent hypothetical gene on the rat X chromosome that shares clear orthology with the 5′ and 3′ ends of Tsga8. Further inspection of this ortholog verified that it is expressed in rat testis and shares remarkable similarity with mouse Tsga8 across several general features of the protein sequence despite no conservation of nucleotide sequence across over 60% of the rat-coding domain. Overall, Tsga8 appears to be one of the most rapidly evolving genes to have been described in rodents. We discuss the potential evolutionary causes and functional implications of this extraordinary divergence and the possible contribution of Tsga8 and the other four genes we examined to reproductive isolation in mice. PMID:21186189

Identification of a mutation in the MTM1 gene, associated with X-linked myotubular myopathy, in a Greek family

PubMed Central

Fidani, L; Karagianni, P; Tsakalidis, C; Mitsiako, G; Hatziioannidis, I; Biancalana, V; Nikolaidis, N

2011-01-01

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually characterized by severe hypotonia and respiratory insufficiency at birth, in affected, male infants. The disease is causally associated with mutations in the MTM1 gene, coding for phosphatase myotubularin. We report a severe case of XLMTM with a novel mutation, at a donor splicing site (c.1467+1G) previously associated with severe phenotype. The mutation was also identified in the patient's mother, providing an opportunity for sound genetic counseling. PMID:22435031

Identification of a mutation in the MTM1 gene, associated with X-linked myotubular myopathy, in a Greek family.

PubMed

Fidani, L; Karagianni, P; Tsakalidis, C; Mitsiako, G; Hatziioannidis, I; Biancalana, V; Nikolaidis, N

2011-07-01

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually characterized by severe hypotonia and respiratory insufficiency at birth, in affected, male infants. The disease is causally associated with mutations in the MTM1 gene, coding for phosphatase myotubularin. We report a severe case of XLMTM with a novel mutation, at a donor splicing site (c.1467+1G) previously associated with severe phenotype. The mutation was also identified in the patient's mother, providing an opportunity for sound genetic counseling.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 syndromemore » 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.« less

Icebox, a recessive X-linked mutation in Drosophila causing low sexual receptivity.

PubMed

Kerr, C; Ringo, J; Dowse, H; Johnson, E

1997-11-01

The X-linked recessive mutation icebox (ibx; 1-23, 7F1) of Drosophila melanogaster lowers the sexual receptivity of females. The probability of mating with mature wild-type males is reduced in ibx homozygotes, and the frequency of rejection behavior (rate per minute) towards courting males is increased. ibx fails to complement In(1)RA35, which is a lethal allele of Neuroglian (Nrg, which encodes a transmembrane protein found in embryonic tissues including the nervous system) due to a breakpoint in that gene; however, both l(1)B4 and l(1)VA142, other lethal mutations of Nrg, do complement ibx. 12-h ibx embryos exhibit a normal pattern of staining for the Neuroglian-specific antibody, Mab BP104. Males and females mutant for ibx have normal egg-to-adult survival and appear normal in several "general" behavioral traits including olfaction, phototaxis, locomotor activity, and heartbeat. ibx males court normally, and are successful in mating. These characteristics suggest that ibx does not cause sensory or motor defects. Ovarian growth and sperm storage are wild-type in ibx/ibx females. Treatment with the JH analog methoprene increases the receptivity of ibx/ibx females.

Analysis of X chromosome inactivation in autism spectrum disorders

PubMed Central

Gong, Xiaohong; Bacchelli, Elena; Blasi, Francesca; Toma, Claudio; Betancur, Catalina; Chaste, Pauline; Delorme, Richard; Durand, Christelle; Fauchereau, Fabien; Botros, Hany Goubran; Leboyer, Marion; Mouren-Simeoni, Marie-Christine; Nygren, Gudrun; Anckarsäter, Henrik; Rastam, Maria; Gillberg, I Carina; Gillberg, Christopher; Moreno-De-Luca, Daniel; Carone, Simona; Nummela, Ilona; Rossi, Mari; Battaglia, Agatino; Jarvela, Irma; Maestrini, Elena; Bourgeron, Thomas

2008-01-01

Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in the susceptibility to ASD by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes. PMID:18361425

Analysis of X chromosome inactivation in autism spectrum disorders.

PubMed

Gong, Xiaohong; Bacchelli, Elena; Blasi, Francesca; Toma, Claudio; Betancur, Catalina; Chaste, Pauline; Delorme, Richard; Durand, Christelle M; Fauchereau, Fabien; Botros, Hany Goubran; Leboyer, Marion; Mouren-Simeoni, Marie-Christine; Nygren, Gudrun; Anckarsäter, Henrik; Rastam, Maria; Gillberg, I Carina; Gillberg, Christopher; Moreno-De-Luca, Daniel; Carone, Simona; Nummela, Ilona; Rossi, Mari; Battaglia, Agatino; Jarvela, Irma; Maestrini, Elena; Bourgeron, Thomas

2008-09-05

Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (> or = 80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes. 2008 Wiley-Liss, Inc.

Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency.

PubMed

Patterson, Emily J; Wilk, Melissa; Langlo, Christopher S; Kasilian, Melissa; Ring, Michael; Hufnagel, Robert B; Dubis, Adam M; Tee, James J; Kalitzeos, Angelos; Gardner, Jessica C; Ahmed, Zubair M; Sisk, Robert A; Larsen, Michael; Sjoberg, Stacy; Connor, Thomas B; Dubra, Alfredo; Neitz, Jay; Hardcastle, Alison J; Neitz, Maureen; Michaelides, Michel; Carroll, Joseph

2016-07-01

Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus.

Malformations among 289,365 Births Attributed to Mutations with Autosomal Dominant and Recessive and X-Linked Inheritance.

PubMed

Toufaily, M Hassan; Westgate, Marie-Noel; Nasri, Hanah; Holmes, Lewis B

2018-01-01

The number of malformations attributed to mutations with autosomal or X-linked patterns of inheritance has increased steadily since the cataloging began in the 1960s. These diagnoses have been based primarily on the pattern of phenotypic features among close relatives. A malformations surveillance program conducted in consecutive pregnancies can identify both known and "new" hereditary disorders. The Active Malformations Surveillance Program was carried out among 289,365 births over 41 years (1972-2012) at Brigham and Women's Hospital in Boston. The findings recorded by examining pediatricians and all consultants were reviewed by study clinicians to establish the most likely diagnoses. The findings in laboratory testing in the newborn period were reviewed, as well. One hundred ninety-six (0.06%) infants among 289,365 births had a malformation or malformation syndrome that was attributed to Mendelian inheritance. A total of 133 (68%) of the hereditary malformations were attributed to autosomal dominant inheritance, with 94 (71%) attributed to apparent spontaneous mutations. Forty-six (23%) were attributed to mutations with autosomal recessive inheritance, 17 associated with consanguinity. Seventeen (9%) were attributed to X-linked inheritance. Fifteen novel familial phenotypes were identified. The family histories showed that most (53 to 71%) of the affected infants were born, as a surprise, to healthy, unaffected parents. It is important for clinicians to discuss with surprised healthy parents how they can have an infant with an hereditary condition. Future studies, using DNA samples from consecutive populations of infants with malformations and whole genome sequencing, will identify many more mutations in loci associated with mendelizing phenotypes. Birth Defects Research 110:92-97, 2018.© 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

A Link-Level Simulator of the cdma2000 Reverse-Link Physical Layer

PubMed Central

Gharavi, H.; Chin, F.; Ban, K.; Wyatt-Millington, R.

2003-01-01

The cdma2000 system is an evolutionary enhancement of the IS-95 standards which support 3G services defined by the International Telecommunications Union (ITU). cdma2000 comes in two phases: 1XRTT and 3XRTT (1X and 3X indicates the number of 1.25 MHz wide radio carrier channels used and RTT stands for Radio Transmission Technology). The cdma2000 1XRTT, which operates within a 1.25 MHz bandwidth, can be utilized in existing IS-95 CDMA channels as it uses the same bandwidth, while 3XRTT requires the commitment of 5 MHz bandwidth to support higher data rates. This paper describes a software model implementation of the cdma2000 reverse link and its application for evaluating the effect of rake receiver design parameters on the system performance under various multipath fading conditions. The cdma2000 models were developed at the National Institute of Standards and Technology (NIST), using SPW (Signal Processing Worksystem) commercial software tools. The model has been developed in a generic manner that includes all the reverse link six radio configurations and their corresponding data rates, according to cdma2000 specifications. After briefly reviewing the traffic channel characteristics of the cdma2000 reverse link (subscriber to base station), the paper discusses the rake receiver implementation including an ideal rake receiver. It then evaluates the performance of each receiver for a Spreading Rate 3 (3XRTT) operation, which is considered as a true “3G” cdma2000 technology. These evaluations are based on the vehicular IMT-2000 (International Mobile Telecommunication 2000) channel model using the link budget defined in cdma2000 specifications for the reverse link. PMID:27413613

X-Linked Retinoschisis in Juveniles: Follow-Up by Optical Coherence Tomography.

PubMed

Hu, Qin-Rui; Huang, Lv-Zhen; Chen, Xiao-Li; Xia, Hui-Ka; Li, Tian-Qi; Li, Xiao-Xin

2017-01-01

Purpose. To explore the structural progression of X-linked retinoschisis (XLRS) in patients by using spectral-domain optical coherence tomography (SD-OCT). Design. Retrospective, observational study. Methods. Patients who were diagnosed with XLRS by genetic testing underwent comprehensive ophthalmological examinations from December 2014 to October 2016. Each eye was measured by SD-OCT using the same clinical protocol. A correlation between best-corrected visual acuity (VA) and SD-OCT measurements was observed. Results. Six patients demonstrated retinoschisis (12 eyes) and typical foveal cyst-like cavities (10 eyes) on SD-OCT images with a mean logMAR VA of 0.48. The median age was 7.5 years at the initial visit. Their foveal retinal thickness (516.9  μ m) and choroid thickness (351.4  μ m) decreased at a rate of 38.1 and 7.5  μ m, respectively, at the 10.5-month follow-up visit; however, there were no significant differences ( P = 0.622 and P = 0.406, resp.). There was no significant correlation between VA, the foveal retinal thickness, and subfoveal choroid thickness. Conclusions. SD-OCT images for XLRS patients during the juvenile period revealed no significant changes in the fundus structure, including the foveal retinal thickness and choroid thickness within one-year follow-up. There was a lack of correlation between VA, foveal retinal thickness, and subfoveal choroid thickness.

X-Linked Retinoschisis in Juveniles: Follow-Up by Optical Coherence Tomography

PubMed Central

Hu, Qin-rui; Huang, Lv-zhen; Xia, Hui-ka; Li, Tian-qi

2017-01-01

Purpose. To explore the structural progression of X-linked retinoschisis (XLRS) in patients by using spectral-domain optical coherence tomography (SD-OCT). Design. Retrospective, observational study. Methods. Patients who were diagnosed with XLRS by genetic testing underwent comprehensive ophthalmological examinations from December 2014 to October 2016. Each eye was measured by SD-OCT using the same clinical protocol. A correlation between best-corrected visual acuity (VA) and SD-OCT measurements was observed. Results. Six patients demonstrated retinoschisis (12 eyes) and typical foveal cyst-like cavities (10 eyes) on SD-OCT images with a mean logMAR VA of 0.48. The median age was 7.5 years at the initial visit. Their foveal retinal thickness (516.9 μm) and choroid thickness (351.4 μm) decreased at a rate of 38.1 and 7.5 μm, respectively, at the 10.5-month follow-up visit; however, there were no significant differences (P = 0.622 and P = 0.406, resp.). There was no significant correlation between VA, the foveal retinal thickness, and subfoveal choroid thickness. Conclusions. SD-OCT images for XLRS patients during the juvenile period revealed no significant changes in the fundus structure, including the foveal retinal thickness and choroid thickness within one-year follow-up. There was a lack of correlation between VA, foveal retinal thickness, and subfoveal choroid thickness. PMID:28286756

X-linked borderline mental retardation with prominent behavioral disturbance: Phenotype, genetic localization, and evidence for disturbed monoamine metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brunner, H.G.; Nelen, M.R.; Zandvoort, P. van

The authors have identified a large Dutch kindred with a new form of X-linked nondysmorphic mild mental retardation. All affected males in this family show very characteristic abnormal behavior, in particular aggressive and sometimes violent behavior. Other types of impulsive behavior include arson, attempted rape, and exhibitionism. Attempted suicide has been reported in a single case. The locus for this disorder could be assigned to the Xp11-21 interval between DXS7 and DXS77 by linkage analysis using markers spanning the X chromosome. A maximal multipoint lod score of 3.69 was obtained at the monoamine oxidase type A (MAOA) monoamine metabolism. Thesemore » data are compatible with a primary defect in the structural gene for MAOA and/or monoamine oxidase type B (MAOB). Normal platelet MAOB activity suggests that the unusual behavior pattern in this family may be caused by isolated MAOA deficiency. 34 refs., 4 figs., 4 tabs.« less

Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease.

PubMed

De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi; Li, Linhong; Wu, Xiaolin; Su, Ling; Raley, Castle; Theobald, Narda; Choi, Uimook; Song, Alexander H; Chan, Andy; Pearl, Jocelynn R; Paschon, David E; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Shivak, David A; Zarember, Kol A; Peshwa, Madhusudan V; Gregory, Philip D; Urnov, Fyodor D; Malech, Harry L

2016-04-01

Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

Identification of novel mutations in the XLRS1 gene in Chinese patients with X-linked juvenile retinoschisis.

PubMed

Zeng, Meizhen; Yi, Changxian; Guo, Xiangming; Jia, Xiaoyun; Deng, Yan; Wang, Juan; Shen, Huangxuan

2007-01-01

X-linked juvenile retinoschisis (XLRS) is a major cause of macular degeneration in young men. In this study we analyzed all six exons of the XLRS1 gene in four sporadic XLRS patients and in an affected family in China who were recently diagnosed. We found there are five different mutations with four containing missense point mutations and one having a frame-shift deletion. Among these mutations both c.644A>T and c.520delC are novel and have not been previously reported. Moreover all the second-generation offsprings and most of the third-generation ones in the affected family were found to carry the mutations bearing X chromosome. The discovery of novel mutations in the XLRS1 gene would increase the available information about the spectrum of genetic abnormalities causing XLRS. Although the limited data failed to reveal a correlation between mutations and disease phenotypes our identification of novel mutations in the XLRS1 gene will facilitate early and correct diagnosis and genetic counseling regarding the prognosis of XLRS disease.

Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.

PubMed

Bertani, Ilaria; Rusconi, Laura; Bolognese, Fabrizio; Forlani, Greta; Conca, Barbara; De Monte, Lucia; Badaracco, Gianfranco; Landsberger, Nicoletta; Kilstrup-Nielsen, Charlotte

2006-10-20

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.

Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia

PubMed Central

McKee, Marc D.; Hoac, Betty; Addison, William N.; Barros, Nilana M.T.; Millán, José Luis; Chaussain, Catherine

2013-01-01

As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth – where calcium phosphate crystals are deposited and grow within an extracellular matrix – is essential to dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition such that teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibres (Sharpey's fibres) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins (SIBLINGs), and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here with clinical examples given, namely tissue-nonspecific alkaline phosphatase (TNAP) and phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH), respectively, where levels of local and systemic circulating mineralization determinants are perturbed. In XLH, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating SIBLING proteins such as matrix extracellular phosphoglycoprotein (MEPE) and osteopontin (OPN), and the phosphorylated peptides proteolytically released from them such as the acidic serine- and aspartate-rich motif (ASARM) peptide, may accumulate locally to impair mineralization in this disease. PMID:23931057

Case report of an atypical early onset X-linked retinoschisis in monozygotic twins.

PubMed

Murro, Vittoria; Caputo, Roberto; Bacci, Giacomo Maria; Sodi, Andrea; Mucciolo, Dario Pasquale; Bargiacchi, Sara; Giglio, Sabrina Rita; Virgili, Gianni; Rizzo, Stanislao

2017-02-24

X-linked Retinoschisis (XLRS) is one of the most common macular degenerations in young males, with a worldwide prevalence ranging from 1:5000 to 1:20000. Clinical diagnosis of XLRS can be challenging due to the highly variable phenotypic presentation and limited correlation has been identified between mutation type and disease severity or progression. We report the atypical early onset of XLRS in 3-month-old monozygotic twins. Fundus examination was characterized by severe bullous retinal schisis with pre-retinal and intraretinal haemorrhages. Molecular genetic analysis of the RS1 was performed and the c.288G > A (p. Trp96Ter) mutation was detected in both patients. Early onset XLRS is associated with a more progressive form of the disease, characterized by large bullous peripheral schisis involving the posterior pole, vascular abnormalities and haemorrhages. The availability of specific technology permitted detailed imaging of the clinical picture of unusual cases of XLRS. The possible relevance of modifying genes should be taken into consideration for the future development of XLRS gene therapy.

MRG-1, an autosome-associated protein, silences X-linked genes and protects germline immortality in Caenorhabditis elegans

PubMed Central

Takasaki, Teruaki; Liu, Zheng; Habara, Yasuaki; Nishiwaki, Kiyoji; Nakayama, Jun-ichi; Inoue, Kunio; Sakamoto, Hiroshi; Strome, Susan

2008-01-01

MRG15, a mammalian protein related to the mortality factor MORF4, is required for cell proliferation and embryo survival. Our genetic analysis has revealed that the Caenorhabditis elegans ortholog MRG-1 serves similar roles. Maternal MRG-1 promotes embryo survival and is required for proliferation and immortality of the primordial germ cells (PGCs). As expected of a chromodomain protein, MRG-1 associates with chromatin. Unexpectedly, it is concentrated on the autosomes and not detectable on the X chromosomes. This association is not dependent on the autosome-enriched protein MES-4. Focusing on possible roles of MRG-1 in regulating gene expression, we determined that MRG-1 is required to maintain repression in the maternal germ line of transgenes on extrachromosomal arrays, and of several X-linked genes previously shown to depend on MES-4 for repression. MRG-1 is not required for PGCs to acquire transcriptional competence or for the turn-on of expression of several PGC-expressed genes (pgl-1, glh-1, glh-4 and nos-1). By contrast to this result in PGCs, MRG-1 is required for ectopic expression of those germline genes in somatic cells lacking the NuRD complex component MEP-1. We discuss how an autosome-enriched protein might repress genes on the X chromosome, promote PGC proliferation and survival, and influence the germ versus soma distinction. PMID:17215300

Relapsing remitting multiple sclerosis in x-linked charcot-marie-tooth disease with central nervous system involvement.

PubMed

Koutsis, Georgios; Karadima, Georgia; Floroskoufi, Paraskewi; Raftopoulou, Maria; Panas, Marios

2015-01-01

We report a patient with relapsing remitting multiple sclerosis (MS) and X-linked Charcot-Marie-Tooth disease (CMTX), carrying a GJB1 mutation affecting connexin-32 (c.191G>A, p. Cys64Tyr) which was recently reported by our group. This is the third case report of a patient with CMTX developing MS, but it is unique in the fact that other family members carrying the same mutation were found to have asymptomatic central nervous system (CNS) involvement (diffuse white matter hyperintensity on brain MRI and extensor plantars). Although this may be a chance association, the increasing number of cases with CMTX and MS, especially with mutations involving the CNS, may imply some causative effect and provide insights into MS pathogenesis.

Relapsing Remitting Multiple Sclerosis in X-Linked Charcot-Marie-Tooth Disease with Central Nervous System Involvement

PubMed Central

Karadima, Georgia; Floroskoufi, Paraskewi; Raftopoulou, Maria; Panas, Marios

2015-01-01

We report a patient with relapsing remitting multiple sclerosis (MS) and X-linked Charcot-Marie-Tooth disease (CMTX), carrying a GJB1 mutation affecting connexin-32 (c.191G>A, p. Cys64Tyr) which was recently reported by our group. This is the third case report of a patient with CMTX developing MS, but it is unique in the fact that other family members carrying the same mutation were found to have asymptomatic central nervous system (CNS) involvement (diffuse white matter hyperintensity on brain MRI and extensor plantars). Although this may be a chance association, the increasing number of cases with CMTX and MS, especially with mutations involving the CNS, may imply some causative effect and provide insights into MS pathogenesis. PMID:25883816

X-linked hypophosphatemic rickets and sagittal craniosynostosis: three patients requiring operative cranial expansion: case series and literature review.

PubMed

Jaszczuk, Phillip; Rogers, Gary F; Guzman, Raphael; Proctor, Mark R

2016-05-01

A defect in a phosphate-regulating gene leads to the most common form of rickets: X-linked hypophosphatemic rickets (XLH) or vitamin D-resistant rickets (VDDR). XLH has been associated with craniosynostosis, the sagittal suture being the most commonly involved. We present three patients with rickets and symptomatic sagittal suture craniosynostosis all of whom presented late (>2 years of age). Two had a severe phenotype and papilledema, while the third presented with an osseous bulging near the anterior fontanel and experienced chronic headaches. All underwent successful cranial vault expansion. Rachitic patients with scaphocephaly should be screened for craniosynostosis.

Variable White Matter Atrophy and Intellectual Development in a Family With X-linked Creatine Transporter Deficiency Despite Genotypic Homogeneity.

PubMed

Heussinger, Nicole; Saake, Marc; Mennecke, Angelika; Dörr, Helmuth-Günther; Trollmann, Regina

2017-02-01

The X-linked creatine transporter deficiency (CRTD) caused by an SLC6A8 mutation represents the second most common cause of X-linked intellectual disability. The clinical phenotype ranges from mild to severe intellectual disability, epilepsy, short stature, poor language skills, and autism spectrum disorders. The objective of this study was to investigate phenotypic variability in the context of genotype, cerebral creatine concentration, and volumetric analysis in a family with CRTD. The clinical phenotype and manifestations of epilepsy were assessed in a Caucasian family with CRTD. DNA sequencing and creatine metabolism analysis confirmed the diagnosis. Cerebral magnetic resonance imaging (cMRI) with voxel-based morphometry and magnetic resonance spectroscopy was performed in all family members. An SLC6A8 missense mutation (c.1169C>T; p.Pro390Leu, exon 8) was detected in four of five individuals. Both male siblings were hemizygous, the mother and the affected sister heterozygous for the mutation. Structural cMRI was normal, whereas voxel-based morphometry analysis showed reduced white matter volume below the first percentile of the reference population of 290 subjects in the more severely affected boy compared with family members and controls. Normalized creatine concentration differed significantly between the individuals (P < 0.005). There is a broad phenotypic variability in CRTD even in family members with the same mutation. Differences in mental development could be related to atrophy of the subcortical white matter. Copyright © 2016 Elsevier Inc. All rights reserved.

X-linked CHARGE-like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations.

PubMed

Pauws, E; Peskett, E; Boissin, C; Hoshino, A; Mengrelis, K; Carta, E; Abruzzo, M A; Lees, M; Moore, G E; Erickson, R P; Stanier, P

2013-04-01

X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the Tbx22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

cDNA cloning of the murine PEX gene implicated in X-linked hypophosphatemia and evidence for expression in bone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, L.; Desbarats, M.; Viel, J.

1996-08-15

The recently identified human PEX g ene apparently encodes for a neutral endopeptidase that is mutated in patients with X-linked hypophosphatemia. The 3{prime} and 5{prime} ends of the coding region of PEX have not been cloned, nor has the tissue expression of the gene been identified. Here we report the isolation and characterization of the complete open reading frame of the mouse Pex gene and the demonstration of its expression in bone. Mouse Pex cDNA is predicted to encode a protein of 749 amino acids with 95% identity to the available human PEX sequence and significant homology to members ofmore » the membrane-bound metalloendopeptidase family. Northern blot analysis revealed a 6.6-kb transcript in bone and in cultured osteoblasts from normal mice that was not detectable in samples from the Hyp mouse, the murine homolog of human X-linked hypophosphatemia. Pex transcripts were, however, detectable in Hyp bone by RT-PCR amplification. Of particular interest, a cDNA clone from rat incisor shows 93% sequence identity to the 5{prime} end of Pex cDNA, suggesting that Pex may be expressed in another calcified tissue, the tooth. The association of impaired mineralization of bone and teeth and disturbed renal phosphate reabsorption with altered expression of Pex suggests that the Pex gene product may play a critical role in these processes. 47 refs., 2 figs., 1 tab.« less

R213W mutation in the retinoschisis 1 gene causes X-linked juvenile retinoschisis in a large Chinese family.

PubMed

Xu, Jun; Gu, Hong; Ma, Kai; Liu, Xipu; Snellingen, Torkel; Sun, Erdan; Wang, Ningli; Liu, Ningpu

2010-08-12

We identified a large Chinese family with X-linked juvenile retinoschisis. The purpose of this study was to report the clinical findings of the family and to identify the genetic mutation by screening the retinoschisis 1 (RS1) gene. Family history was collected and all family members underwent routine ophthalmic examination. Venous blood was collected from family members and genomic DNA was extracted. The exons of RS1 were screened by PCR followed by direct sequencing and/or restriction enzyme digestion. The pedigree of interest was a four-generation family with 52 family members, including seven affected individuals. The proband was a 5-year-old boy showing highly elevated bullous retinoschisis with moderate vitreous hemorrhage in both eyes. Vitrectomy was performed in the left eye of the proband. Five affected males showed large peripheral retinoschisis in both eyes, either involving the macula or combined with foveal stellate cystic change. One of the affected family members showed only a foveal stellate cystic change in both eyes without periphery retinoschisis. Visual acuity of affected individuals ranged from hand motion to 0.4. The R213W mutation in exon 6 of RS1 was identified in all affected individuals, predicting an amino acid substitution of arginine to tryptophan at codon 213. Our data show that the R213W mutation in RS1 causes various severities of retinoschisis in a large Chinese family, providing further evidence for X-linked juvenile retinoschisis phenotypic variability.

R213W mutation in the retinoschisis 1 gene causes X-linked juvenile retinoschisis in a large Chinese family

PubMed Central

Xu, Jun; Gu, Hong; Ma, Kai; Liu, Xipu; Snellingen, Torkel; Sun, Erdan; Wang, Ningli

2010-01-01

Purpose We identified a large Chinese family with X-linked juvenile retinoschisis. The purpose of this study was to report the clinical findings of the family and to identify the genetic mutation by screening the retinoschisis 1 (RS1) gene. Methods Family history was collected and all family members underwent routine ophthalmic examination. Venous blood was collected from family members and genomic DNA was extracted. The exons of RS1 were screened by PCR followed by direct sequencing and/or restriction enzyme digestion. Results The pedigree of interest was a four-generation family with 52 family members, including seven affected individuals. The proband was a 5-year-old boy showing highly elevated bullous retinoschisis with moderate vitreous hemorrhage in both eyes. Vitrectomy was performed in the left eye of the proband. Five affected males showed large peripheral retinoschisis in both eyes, either involving the macula or combined with foveal stellate cystic change. One of the affected family members showed only a foveal stellate cystic change in both eyes without periphery retinoschisis. Visual acuity of affected individuals ranged from hand motion to 0.4. The R213W mutation in exon 6 of RS1 was identified in all affected individuals, predicting an amino acid substitution of arginine to tryptophan at codon 213. Conclusions Our data show that the R213W mutation in RS1 causes various severities of retinoschisis in a large Chinese family, providing further evidence for X-linked juvenile retinoschisis phenotypic variability. PMID:20806044

5.6 Gbps optical intersatellite communication link

NASA Astrophysics Data System (ADS)

Smutny, Berry; Kaempfner, Hartmut; Muehlnikel, Gerd; Sterr, Uwe; Wandernoth, Bernhard; Heine, Frank; Hildebrand, Ulrich; Dallmann, Daniel; Reinhardt, Martin; Freier, Axel; Lange, Robert; Boehmer, Knut; Feldhaus, Thomas; Mueller, Juergen; Weichert, Andreas; Greulich, Peter; Seel, Stefan; Meyer, Rolf; Czichy, Reinhard

2009-02-01

A 5.6 Gbps optical communication link has been verified in-orbit. The intersatellite link uses homodyne BPSK (binary phase shift keying) and allows to transmit data with a duplex data rate of 5.6 Gbps and a bit error rate better than 10-9 between two LEO satellites, NFIRE (U.S.) and TerraSAR-X, Germany). We report on the terminal design and the link performance during the measurement campaign. As an outlook we report on the flight units adapted to LEO-to-GEO intersatellite links that TESAT currently builds and on plans to study GEO-to-ground links.

Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

PubMed Central

Patterson, Emily J.; Wilk, Melissa; Langlo, Christopher S.; Kasilian, Melissa; Ring, Michael; Hufnagel, Robert B.; Dubis, Adam M.; Tee, James J.; Kalitzeos, Angelos; Gardner, Jessica C.; Ahmed, Zubair M.; Sisk, Robert A.; Larsen, Michael; Sjoberg, Stacy; Connor, Thomas B.; Dubra, Alfredo; Neitz, Jay; Hardcastle, Alison J.; Neitz, Maureen; Michaelides, Michel; Carroll, Joseph

2016-01-01

Purpose Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. Methods We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. Results There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Conclusions Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus. PMID:27447086

Novel mutations of the RS1 gene in a cohort of Chinese families with X-linked retinoschisis

PubMed Central

Chen, Jieqiong; Xu, Ke; Zhang, Xiaohui; Pan, Zhe; Dong, Bing

2014-01-01

Purpose X-linked retinoschisis is a retinal dystrophy caused by mutations in the RS1 gene in Xp22.1. These mutations lead to schisis (splitting) of the neural retina and subsequent reduction in visual acuity in affected men (OMIM # 312700). The aim of this study was to identify the RS1 gene mutations in a cohort of Chinese patients with X-linked retinoschisis, and to describe the associated phenotypes. Methods Patients and unaffected individuals from 16 unrelated families underwent detailed ophthalmic examinations. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. All exons including the exon-intron boundaries of the RS1 gene, were amplified by PCR and the products were analyzed by direct sequencing. Long-range PCR followed by DNA sequencing was used to define the breakpoints of the large deletion. Results Sixteen male individuals from 16 families were diagnosed with retinoschisis by clinical examination. The median age at review was 13.2 years (range: 5–34 years); the median best-corrected visual acuity upon review was 0.26 (range 0.02–1.0). Foveal schisis was found in 82.8% of the eyes (24/29) while peripheral schisis was present in 27.5% of the eyes (8/29). Sequencing of the RS1 gene identified 16 mutations, nine of which were novel. The mutations included eight missense mutations, all located in exons 4–6 (50.0%), two nonsense mutations (12.5%), four small deletions or insertions (25.0%), one splice site mutation (6.25%), and one large genomic deletion that included exon1 (6.25%). Conclusions The mutations found in our study broaden the spectrum of RS1 mutations. The identification of the specific mutation in each pedigree will allow future determination of female carrier status for genetic counseling purposes. PMID:24505212

Further linkage evidence for localization of mutational sites for nonsyndromic types of X-linked mental retardation at pericentromeric region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robledo, R.; Melis, P.; Siniscalco, M.

We used several microsatellite markers scattered along the X chromosome to search for linkage relationships in a large Sardinian pedigree segregating for nonspecific X-linked mental retardation (MRX). Markers DXS573 and AR, located at chromosomal subregions Xp11.4-p11.22 and Xq11.2-q12, respectively, were found to segregate in full concordance with the disease, leading to a LOD score of 4.21 at zero recombination value. Recombination with the disease was found with markers MAOB and DXS454 located at Xp11.4-p11.3 and Xq21.1-q22, respectively; accordingly, markers distal to Xp11.4 and Xq22 also segregated independently of the disease. These findings provide strong linkage evidence in favor of themore » localization of one MRX mutational site in the pericentromeric region of the human X chromosome, justifying the assignment of a new symbol (MRX26) to our pedigree. Finally, on the basis of the recombinational events observed in the Xq21-q22 region, we have been able to refine the assignment of marker DXS456 to Xq21.33-q22. 26 refs., 3 figs., 1 tab.« less

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP).

PubMed

Rowe, P S; Oudet, C L; Francis, F; Sinding, C; Pannetier, S; Econs, M J; Strom, T M; Meitinger, T; Garabedian, M; David, A; Macher, M A; Questiaux, E; Popowska, E; Pronicka, E; Read, A P; Mokrzycki, A; Glorieux, F H; Drezner, M K; Hanauer, A; Lehrach, H; Goulding, J N; O'Riordan, J L

1997-04-01

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.

Vertebral Osteomyelitis and Acinetobacter Spp. Paravertebral Soft Tissue Infection in a 4-Year-Old Boy With X-Linked Chronic Granulomatous Disease.

PubMed

Vignesh, Pandiarajan; Bhattad, Sagar; Shandilya, Jitendra-Kumar; Vyas, Sameer; Garg, Rashi; Rawat, Amit

2016-09-01

Vertebral osteomyelitis is known to occur in chronic granulomatous disease, a phagocytic disorder and the etiology is usually a fungus. Indolent spread of fungal infection from lungs to adjacent ribs and vertebra often results in persistent pneumonia and vertebral deformities. We report a 4-year-old boy with chronic cough and kyphosis, who had a fungal vertebral osteomyelitis and Acinetobacter spp. paravertebral soft tissue infection related to X-linked chronic granulomatous disease.