Sample records for autosomal dominant brachydactyly

  1. Autosomal dominant vitreoretinochoroidopathy (ADVIRC).

    PubMed Central

    Blair, N P; Goldberg, M F; Fishman, G A; Salzano, T

    1984-01-01

    We report the second family recognised to have autosomal dominant vitreoretinochoroidopathy. The clinical features were (1) autosomal dominant inheritance; (2) peripheral, coarse pigmentary degeneration of the fundus for 360 degrees, with a relatively discrete posterior border in the equatorial region (this finding may be pathognomonic); (3) superficial punctate yellowish-white opacities in the retina; (4) various vascular abnormalities; (5) breakdown of the blood-retinal barrier; (6) retinal neovascularisation; (7) vitreous abnormalities; and (8) choroidal atrophy. Visual reduction was mainly due to macular oedema or vitreous haemorrhage. Images PMID:6689931

  2. Genetics Home Reference: Autosomal dominant partial epilepsy with auditory features

    MedlinePLUS

    ... OMIM Genetic disorder catalog Conditions > Autosomal dominant partial epilepsy with auditory features (often shortened to ADPEAF ) On ... July 2008 What is ADPEAF? Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an uncommon form ...

  3. Autosomal dominant osteopetrosis and maxillomandibular osteomyelitis.

    PubMed

    Junquera, Luis; Rodríguez-Recio, Cristian; Villarreal, Pedro; García-Consuegra, Luis

    2005-01-01

    Osteopetroses represent a heterogeneous group of rare, hereditary bony dysplasias. They range from a devastating neurometabolic disease (including severe malignant infantile osteopetrosis) to 2 more benign conditions principally affecting adults: autosomal dominant osteopetrosis (ADO) type I and type II. The present study describes the maxillofacial manifestations associated with the 2 subgroups of ADO. In this paper, we present the oldest patient described in the literature with ADO type I (76 years old). We also document the first ADO type II patient described in the literature with synchronic osteomyelitis of the mandible and the maxilla. PMID:15991096

  4. Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases

    Microsoft Academic Search

    Peter C Harris; Vicente E Torres

    2006-01-01

    Autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease are the best known of a large family of inherited diseases characterized by the development of renal cysts of tubular epithelial cell origin. Autosomal dominant and recessive polycystic kidney diseases have overlapping but distinct pathogeneses. Identification of the causative mutated genes and elucidation of the function of their encoded

  5. Genetics Home Reference: Autosomal dominant congenital stationary night blindness

    MedlinePLUS

    ... the brain, leading to a lack of visual perception in low light. Read more about the GNAT1 , ... blindness? autosomal ; autosomal dominant ; cell ; congenital ; gene ; inherited ; perception ; photoreceptor ; prevalence ; protein ; receptor ; retina ; rods ; subunit ; tissue ...

  6. Autosomal dominant sacral agenesis: Currarino syndrome

    PubMed Central

    Lynch, S. A.; Wang, Y.; Strachan, T; Burn, J.; Lindsay, S.

    2000-01-01

    Autosomal dominant sacral agenesis is characterised by a partial agenesis of the sacrum typically involving sacral vertebrae S2-S5 only. Associated features include anorectal malformation, a presacral mass, and urogenital malformation. Together, these features have been defined as the Currarino syndrome. Recently, HLXB9 has been identified as the major causative gene in Currarino syndrome allowing identification of asymptomatic heterozygotes. In this review, we have performed an analysis of medical publications, and our own additional cases, to identify the range of malformations and complications that occur. We have also estimated risks of malformation in heterozygotes by using Weinburg's proband method on families personally known to us in order to provide accurate genetic counselling information.???Keywords: sacral agenesis; presacral mass; anorectal malformation; Currarino triad PMID:10922380

  7. Autosomal dominant dementia with widespread neurofibrillary tangles.

    PubMed

    Reed, L A; Grabowski, T J; Schmidt, M L; Morris, J C; Goate, A; Solodkin, A; Van Hoesen, G W; Schelper, R L; Talbot, C J; Wragg, M A; Trojanowski, J Q

    1997-10-01

    Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity. PMID:9382467

  8. Weill-Marchesani syndrome - possible linkage of the autosomal dominant form to 15q21.1

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Rust, K. [Oregon Health Sciences Univ., Portland, OR (United States)] [and others] [Oregon Health Sciences Univ., Portland, OR (United States); and others

    1996-10-02

    Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait. We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals. 28 refs., 3 figs., 2 tabs.

  9. Hypertension in Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Chapman, Arlene B.; Stepniakowski, Konrad; Rahbari-Oskoui, Frederic

    2010-01-01

    Hypertension is common and occurs in a majority of autosomal dominant polycystic kidney disease (ADPKD) patients prior to loss of kidney function. Hypertension relates to progressive kidney enlargement, and is a significant independent risk factor for progression to end stage renal disease. The pathogenesis of hypertension in ADPKD is complex and dependent on many factors that influence each other. Pkd1 and Pkd2 expression levels are highest in the major vessels and are present in the cilia of endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin 1 or 2 expression is associated with abnormal vascular structure and function. Pkd1/Pkd2 deficiency results in reduced nitric oxide (NO) levels, altered endothelial response to shear stress with attenuation in vascular relaxation. 10–20% of ADPKD children demonstrate hypertension and the majority of adults are hypertensive before any loss of kidney function. Cardiac abnormalities such as left ventricular hypertrophy and carotid intimal wall thickening are present prior to the development of hypertension in ADPKD. Activation of the renin-angiotensin-aldosterone system occurs in ADPKD due to decreased NO production as well as bilateral cyst expansion and intra-renal ischemia. With increasing cyst size, further activation of the RAAS occurs, blood pressure increases and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to ESRD. Inhibition of the angiotensin aldosterone system is possible with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. However, interventional studies have not yet demonstrated benefit in slowing progression to renal failure in ADPKD. Currently, large multicenter studies are being performed to determine the beneficial effects of RAAS inhibition both early and late in ADPKD. PMID:20219618

  10. EDS IV (acrogeria): new autosomal dominant and recessive types.

    PubMed

    Pope, F M; Nicholls, A C; Jones, P M; Wells, R S; Lawrence, D

    1980-03-01

    Evidence is presented that type IV of the Ehlers-Danlos syndrome (EDS IV) is genetically variable. A benign autosomal dominant form and two autosomal recessive variants are described with clinical and biochemical features that are distinct from classical acrogeria. PMID:7230200

  11. Autosomal dominant inheritance of Brachmann-de Lange syndrome

    SciTech Connect

    Kozma, C. [Georgetown Univ. Medical Center, Washington, DC (United States)] [Georgetown Univ. Medical Center, Washington, DC (United States)

    1996-12-30

    A mother with mild phenotype and her severely affected son, both with classic manifestations of Brachmann-de Lange syndrome (BDLS), are described. This documented mother-to-child transmission supports the hypothesis of autosomal dominant transmission with intrafamilial variability. Known cases of BDLS with autosomal dominant inheritance are reviewed. Although most cases of BDLS are sporadic, a careful evaluation of parents of affected children is important for appropriate genetic counseling. 15 refs., 3 figs., 1 tab.

  12. Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy.

    PubMed Central

    Chalmers, R M; Bird, A C; Harding, A E

    1996-01-01

    The association between hereditary motor and sensory neuropathy (HMSN) and optic atrophy has been termed HMSN type VI. The autosomal dominant inheritance of this syndrome is reported. Three generations were affected with optic atrophy, which differed in some respects from classic dominant optic atrophy, and an asymptomatic, mainly sensory, neuropathy. PMID:8708653

  13. PROGRESSIVE WHITE MATTER ABNORMALITIES IN AUTOSOMAL-DOMINANT

    E-print Network

    Thompson, Paul

    P4-154 PROGRESSIVE WHITE MATTER ABNORMALITIES IN AUTOSOMAL-DOMINANT ALZHEIMER'S DISEASE: RESULTS for Alzheimer's Disease Research, Los Angeles, California, United States; 5University of California, Los Angeles States; 12Neuroscience Research Australia, Newcastle, Australia; 13The National Hospital for Neurology

  14. Locus heterogeneity in autosomal dominant congenital external ophthalmoplegia (CFEOM)

    Microsoft Academic Search

    G C Black; R Perveen; E Hatchwell; A Reck; J Clayton-Smith

    1998-01-01

    Congenital external ophthalmoplegia (CFEOM) is an uncommon autosomal dominant condition that has previously been mapped to the pericentromeric region of chromosome 12 in seven families with no evidence of locus heterogeneity. We report three families with typical CFEOM. One family does not map to this region of chromosome 12 or to other chromosomal locations implicated in disorders of lid or

  15. Does ?-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?

    PubMed Central

    Bauer, Ralf; Hudson, Judith; Müller, Harald D; Sommer, Clemens; Dekomien, Gabriele; Bourke, John; Routledge, Daniel; Bushby, Kate; Klepper, Jörg; Straub, Volker

    2009-01-01

    In this study we clinically and genetically characterize a consanguineous family with a homozygous novel missense mutation in the ?-sarcoglycan gene and a second ?-sarcoglycan mutation that has previously been reported to cause severe autosomal-dominant dilated cardiomyopathy. We identified a novel missense mutation in exon 6 (p.A131P) of the ?-sarcoglycan gene, which in a homozygous state leads to the clinical picture of a limb girdle muscular dystrophy. In four heterozygous carriers for the mutation, aged 3–64 years, a second sequence variant in exon 6 (p.S151A) of the ?-sarcoglycan gene was detected on the other allele. This second missense change had previously been reported to be responsible for fatal autosomal-dominant dilated cardiomyopathy at young age. Comprehensive clinical and cardiac investigation in all of the compound heterozygous family members revealed no signs of cardiomyopathy or limb girdle muscular dystrophy. Our findings demonstrate that, even in the presence of a second disease-causing mutation, the p.S151A mutation in the ?-sarcoglycan gene does not result in cardiomyopathy. This finding questions the pathological relevance of this sequence variant for causing familial autosomal-dominant dilated cardiomyopathy and thereby the role of the ?-sarcoglycan gene in general as a disease-causing gene for autosomal-dominant dilated cardiomyopathy. PMID:19259135

  16. CADASIL (“cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy”)

    Microsoft Academic Search

    H Chabriat; M.-G Bousser

    2004-01-01

    CADASIL is a small artery disease of the brain responsible for migraine with aura, subcortical ischemic strokes, mood disturbances and dementia. The disease is transmitted with an autosomal dominant pattern and usually starts during midadulthood. On MRI, the presence of more or less diffuse signal abnormalities within the white-matter associated with typical lacunar infarcts are suggestive of the disorder. The

  17. Gene therapy in animal models of autosomal dominant retinitis pigmentosa

    PubMed Central

    Rossmiller, Brian; Mao, Haoyu

    2012-01-01

    Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

  18. Autosomal dominant polycystic kidney disease: molecular genetics and molecular pathogenesis

    Microsoft Academic Search

    Michael Koptides; C. Constantinou Deltas

    2000-01-01

    Mutations in three different genes, PKD1, PKD2 and PKD3, can cause a very similar clinical picture of the autosomal dominant form of polycystic kidney disease (ADPKD). Apparently, mutations in the PKD3 gene, which is still unmapped, are very rare, whereas PKD1 defects account for about 85% of cases. Although ADPKD is a frequent monogenic disorder affecting approximately 1:1000 individuals in

  19. Autosomal dominant partial epilepsy with auditory features: Defining the phenotype

    PubMed Central

    Winawer, Melodie R.; Hauser, W. Allen; Pedley, Timothy A.

    2009-01-01

    The authors previously reported linkage to chromosome 10q22-24 for autosomal dominant partial epilepsy with auditory features. This study describes seizure semiology in the original linkage family in further detail. Auditory hallucinations were most common, but other sensory symptoms (visual, olfactory, vertiginous, and cephalic) were also reported. Autonomic, psychic, and motor symptoms were less common. The clinical semiology points to a lateral temporal seizure origin. Auditory hallucinations, the most striking clinical feature, are useful for identifying new families with this synome. PMID:10851389

  20. Autosomal dominant polycystic kidney disease: the last 3 years

    PubMed Central

    Torres, Vicente E.; Harris, Peter C.

    2010-01-01

    Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective therapies. The purpose of this review is to update the core of knowledge in this area with recent publications that have appeared during 2006–2009. PMID:19455193

  1. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

    Microsoft Academic Search

    Randall J Bateman; Paul S Aisen; Bart De Strooper; Nick C Fox; Cynthia A Lemere; John M Ringman; Stephen Salloway; Reisa A Sperling; Manfred Windisch; Chengjie Xiong

    2011-01-01

    ABSTRACT: Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are presented, including

  2. Germline mutation in ATR in autosomal- dominant oropharyngeal cancer syndrome.

    PubMed

    Tanaka, Akio; Weinel, Sarah; Nagy, Nikoletta; O'Driscoll, Mark; Lai-Cheong, Joey E; Kulp-Shorten, Carol L; Knable, Alfred; Carpenter, Gillian; Fisher, Sheila A; Hiragun, Makiko; Yanase, Yuhki; Hide, Michihiro; Callen, Jeffrey; McGrath, John A

    2012-03-01

    ATR (ataxia telangiectasia and Rad3 related) is an essential regulator of genome integrity. It controls and coordinates DNA-replication origin firing, replication-fork stability, cell-cycle checkpoints, and DNA repair. Previously, autosomal-recessive loss-of-function mutations in ATR have been demonstrated in Seckel syndrome, a developmental disorder. Here, however, we report on a different kind of genetic disorder that is due to functionally compromised ATR activity, which translates into an autosomal-dominant inherited disease. The condition affects 24 individuals in a five-generation pedigree and comprises oropharyngeal cancer, skin telangiectases, and mild developmental anomalies of the hair, teeth, and nails. We mapped the disorder to a ?16.8 cM interval in chromosomal region 3q22-24, and by sequencing candidate genes, we found that ATR contained a heterozygous missense mutation (c.6431A>G [p.Gln2144Arg]) that segregated with the disease. The mutation occurs within the FAT (FRAP, ATM, and TRRAP) domain-which can activate p53-of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts. Moreover, loss of heterozygosity for the ATR locus was noted in oropharyngeal-tumor tissue. Collectively, the clinicopathological and molecular findings point to a cancer syndrome and provide evidence implicating a germline mutation in ATR and susceptibility to malignancy in humans. PMID:22341969

  3. Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis

    PubMed Central

    Martignetti, John A.; Tian, Lifeng; Li, Dong; Ramirez, Maria Celeste M.; Camacho-Vanegas, Olga; Camacho, Sandra Catalina; Guo, Yiran; Zand, Dina J.; Bernstein, Audrey M.; Masur, Sandra K.; Kim, Cecilia E.; Otieno, Frederick G.; Hou, Cuiping; Abdel-Magid, Nada; Tweddale, Ben; Metry, Denise; Fournet, Jean-Christophe; Papp, Eniko; McPherson, Elizabeth W.; Zabel, Carrie; Vaksmann, Guy; Morisot, Cyril; Keating, Brendan; Sleiman, Patrick M.; Cleveland, Jeffrey A.; Everman, David B.; Zackai, Elaine; Hakonarson, Hakon

    2013-01-01

    Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment. PMID:23731542

  4. A novel autosomal dominant leukodystrophy with specific MRI pattern.

    PubMed

    Corlobé, A; Taithe, F; Clavelou, P; Pierre, E; Carra-Dallière, C; Ayrignac, X; Mouzat, K; Lumbroso, S; Menjot de Champfleur, N; Koenig, M; Boespflug-Tanguy, O; Labauge, P

    2015-04-01

    Etiologic diagnosis of adulthood leukodystrophy is challenging in neurologic practice. We describe here the clinico-radiological features of a novel autosomal dominant leukodystrophy in a single family. Clinical and MRI features were recorded in a three generation family. Exome sequencing was performed in two affected relatives and one healthy member. Four total relatives (3 women and 1 man, mean age at onset: 45, range 32-59) were followed: 2 for migraine and 2 for cognitive loss. MRI features were homogeneous in the four affected relatives: extensive and symmetrical white matter hyperintensities on T2-weighted images, with a posterior predominance, involvement of the middle cerebellar peduncles, corpus callosum and the posterior limb of the internal capsules. An extensive metabolic screening was negative. In addition, sequencing of pathogenic genes involved in dominant leukodystrophies (NOTCH3, LMNB1, GFAP, CSF1R) was negative. No mutation has been identified yet with exome sequencing. This report is peculiar because of dominant inheritance, adult onset, highly homogeneous white matter hyperintensities on T2-weighted MR images, predominant in the middle cerebellar peduncles and posterior part of internal capsule and absence of mutation of the genes involved in dominant leukodystrophies. PMID:25683759

  5. Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy.

    PubMed

    Miyajima, Tomoko; Kumada, Tomohiro; Saito, Keiko; Fujii, Tatsuya

    2013-02-01

    In 1999, Hirose et al. reported a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with a neuronal nicotinic acetylcholine receptor ?4 subunit mutation (S252L). We followed the siblings of this family, and found that the elder brother had Asperger's disorder without mental retardation (MR) and the younger brother had autistic disorder with profound MR. The clinical epileptic features of the siblings were very similar, and both had deficits in socialization, but their cognitive development differed markedly. It thus seems that epilepsy is the direct phenotype of the S252L mutation, whereas other various factors modulate the cognitive and social development. No patients with ADNFLE have previously been reported to have autism spectrum disorder or profound MR. PMID:22883468

  6. Autosomal Dominant Inherited Cowden's Disease in a Family

    PubMed Central

    2013-01-01

    Cowden's disease, also known as a kind of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome, is an uncommon autosomal dominant inherited complex disorder with various hamartomatous growths of multiple organs involving all three germ cell layers. It usually manifests with polyps throughout the gastrointestinal tract, ranging anywhere from 30% to 85%, and more common extra intestinal findings. Mucocutaneous lesions like facial trichilemmomas, acral keratoses, papillomatous papules and macrocephaly, and malignancies including breast, thyroid and endometrial carcinoma are the hallmark of the disease. Here we report on familial Cowden's diseases case of a 52-year-old male proband with mucocutaneous lesions and mutation on the PTEN gene obtained by extrapolating from gastrointestinal polyposis as a starter and his daughter who developed thyroid cancer. PMID:23423780

  7. MOLECULAR ADVANCES IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

    PubMed Central

    Gallagher, Anna Rachel; Germino, Gregory G.; Somlo, Stefan

    2010-01-01

    Autosomal dominant polycystic disease (ADPKD) is the most common form of inherited kidney disease that results renal failure. The understanding the pathogenesis of ADPKD has advanced significantly since the discovery of the two causative genes, PKD1 or PKD2. Dominantly inherited gene mutations followed by somatic second hit mutations inactivating the normal copy of the respective gene result in renal tubular cyst formation that deforms the kidney and eventually impairs its function. The respective gene products, polycystin-1 and polycystin-2, work together in a common cellular pathway. Polycystin-1, a large receptor molecule, forms a receptor-channel complex with polycystin-2, which is a cation channel belonging to the TRP family. Both polycystin proteins have been localized to the primary cilium, a non-motile microtubule based structure that extends from the apical membrane of tubular cells into the lumen. Here we discuss recent insights in the pathogenesis of ADPKD including the genetics of ADPKD, the properties of the respective polycystin proteins, the role of cilia, and some cell signaling pathways that have been implicated in the pathways related to PKD1 and PKD2. PMID:20219615

  8. Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

    PubMed Central

    Chen, Shoujun; Sun, Mei; Meng, Xianmin; Iozzo, Renato V.; Kao, Winston W.-Y.; Birk, David E.

    2011-01-01

    Autosomal-dominant congenital stromal corneal dystrophy (CSCD) is a human genetic disease characterized by corneal opacities beginning shortly after birth. It is linked to a frameshift mutation in decorin, resulting in a C-terminal truncation lacking 33 amino acids that includes the “ear” repeat, a feature specific for small leucine-rich proteoglycans. Our goals are to elucidate the roles of the mutant decorin in CSCD pathophysiology and to decipher the mechanism whereby mutant decorin affects matrix assembly. A novel animal model that recapitulates human CSCD was generated. This transgenic mouse model targets expression of truncated decorin to keratocytes, thereby mimicking the human frameshift mutation. Mutant mice expressed both wild-type and mutant decorin. Corneal opacities were found throughout, with increased severity toward the posterior stroma. The architecture of the lamellae was disrupted with relatively normal lamellae separated by regions of abnormal fibril organization. Within abnormal zones, the interfibrillar spacing and the fibril diameters were increased. Truncated decorin negatively affected the expression of endogenous decorin, biglycan, lumican, and keratocan and positively affected fibromodulin. Our results provide a mechanistic explanation for the generation of corneal opacities in CSCD. Thus, truncated decorin acts in a dominant-negative manner to interfere dually with matrix assembly and binding to receptor tyrosine kinases, thereby causing abnormal expression of endogenous small leucine-rich proteoglycans leading to structural abnormalities within the cornea and vision loss. PMID:21893019

  9. Caffeine intake by patients with autosomal dominant polycystic kidney disease.

    PubMed

    Vendramini, L C; Nishiura, J L; Baxmann, A C; Heilberg, I P

    2012-09-01

    Because caffeine may induce cyst and kidney enlargement in autosomal dominant polycystic kidney disease (ADPKD), we evaluated caffeine intake and renal volume using renal ultrasound in ADPKD patients. Caffeine intake was estimated by the average of 24-h dietary recalls obtained on 3 nonconsecutive days in 102 ADPKD patients (68 females, 34 males; 39 ± 12 years) and compared to that of 102 healthy volunteers (74 females, 28 males; 38 ± 14 years). The awareness of the need for caffeine restriction was assessed. Clinical and laboratory data were obtained from the medical records of the patients. Mean caffeine intake was significantly lower in ADPKD patients versus controls (86 vs 134 mg/day), and 63% of the ADPKD patients had been previously aware of caffeine restriction. Caffeine intake did not correlate with renal volume in ADPKD patients. There were no significant differences between the renal volumes of patients in the highest and lowest tertiles of caffeine consumption. Finally, age-adjusted multiple linear regression revealed that renal volume was associated with hypertension, chronic kidney disease stage 3 and the time since diagnosis, but not with caffeine intake. The present small cross-sectional study indicated a low level of caffeine consumption by ADPKD patients when compared to healthy volunteers, which was most likely due to prior awareness of the need for caffeine restriction. Within the range of caffeine intake observed by ADPKD patients in this study (0-471 mg/day), the renal volume was not directly associated with caffeine intake. PMID:22801417

  10. Evaluation of Nephrolithiasis in Autosomal Dominant Polycystic Kidney Disease Patients

    PubMed Central

    Nishiura, José L.; Neves, Rodrigo F.C.A.; Eloi, Samara R.M.; Cintra, Susan M.L.F.; Ajzen, Sergio A.; Heilberg, Ita P.

    2009-01-01

    Background and objectives: Nephrolithiasis (LIT) is more prevalent in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. Renal ultrasonography may underdetect renal stones because of difficulties imposed by parenchymal and/or cyst wall calcifications. Design, setting, participants, & measurements: A total of 125 patients with ADPKD underwent ultrasonography and unenhanced computed tomography (CT) scan, routine blood chemistry, and spot and 24-h urine collections. Results: CT scan detected calculi in 32 patients, including 20 whose previous ultrasonography revealed no calculi. The percentage of hypocitraturia was high but not statistically different between patients with ADPKD+LIT or ADPKD. Hyperuricosuria and distal renal tubular acidosis were less prevalent but also did not differ between groups, whereas hyperoxaluria was significantly higher in the former. Hypercalciuria was not detected. Renal volume was significantly higher in patients with ADPKD+LIT versus ADPKD, and a stepwise multivariate logistic regression analysis showed that a renal volume ?500 ml was a significant predictor of LIT in patients with ADPKD and normal renal function, after adjustments for age and hypertension. Conclusions: CT scan was better than ultrasonography to detect LIT in patients with ADPKD. Larger kidneys from patients with ADPKD were more prone to develop stones, irrespective of the presence of metabolic disturbances. PMID:19339428

  11. Why kidneys fail in autosomal dominant polycystic kidney disease.

    PubMed

    Grantham, Jared J; Mulamalla, Sumanth; Swenson-Fields, Katherine I

    2011-10-01

    The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease. PMID:21862990

  12. Evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease.

    PubMed

    Yamashita, Chikara; Tomiyama, Hiroyuki; Funayama, Manabu; Inamizu, Saeko; Ando, Maya; Li, Yuanzhe; Yoshino, Hiroyo; Araki, Takehisa; Ichikawa, Tadashi; Ehara, Yoshiro; Ishikawa, Kinya; Mizusawa, Hidehiro; Hattori, Nobutaka

    2014-07-01

    We evaluated the contributions of various polyglutamine (polyQ) disease genes to Parkinson's disease (PD). We compared the distributions of polyQ repeat lengths in 8 common genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1, and HTT) in 299 unrelated patients with autosomal dominant PD (ADPD) and 329 normal controls. We also analyzed the possibility of genetic interactions between ATXN1 and ATXN2, ATXN2 and ATXN3, and ATXN2 and CACNA1A. Intermediate-length polyQ expansions (>24 Qs) of ATXN2 were found in 7 ADPD patients and no controls (7/299 = 2.34% and 0/329 = 0%, respectively; p = 0.0053 < 0.05/8 after Bonferroni correction). These patients showed typical L-DOPA-responsive PD phenotypes. Conversely, no significant differences in polyQ repeat lengths were found between the ADPD patients and the controls for the other 7 genes. Our results may support the hypothesis that ATXN2 polyQ expansion is a specific predisposing factor for multiple neurodegenerative diseases. PMID:24534762

  13. New treatments for autosomal dominant polycystic kidney disease

    PubMed Central

    Chang, Ming-Yang; Ong, Albert C M

    2013-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and results from mutations in PKD1 or PKD2. Cyst initiation and expansion arise from a combination of abnormal cell proliferation, fluid secretion and extracellular matrix defects and results in kidney enlargement and interstitial fibrosis. Since its first description over 200 years ago, ADPKD has been considered an untreatable condition and its management is limited to blood pressure reduction and symptomatic treatment of disease complications. Results of the recently reported TEMPO 3/4 trial thus represent a paradigm shift in demonstrating for the first time that cystic disease and loss of renal function can be slowed in humans. In this paper, we review the major therapeutic strategies currently being explored in ADPKD including a range of novel approaches in preclinical models. It is anticipated that the clinical management of ADPKD will undergo a revolution in the next decade with the translation of new treatments into routine clinical use. PMID:23594398

  14. Hypertension in autosomal-dominant polycystic kidney disease (ADPKD)

    PubMed Central

    Sans-Atxer, Laia; Torra, Roser; Fernández-Llama, Patricia

    2013-01-01

    Cardiovascular (CV) complications are the major cause of death in autosomal-dominant polycystic kidney disease (ADPKD) patients. Hypertension is common in these patients even before the onset of renal insufficiency. Blood pressure (BP) elevation is a key factor in patient outcome, mainly owing to the high prevalence of target organ damage together with a poor renal prognosis when BP is increased. Many factors have been implicated in the pathogenesis of hypertension, including the renin–angiotensin–aldosterone system (RAAS) stimulation. Polycystin deficiency may also contribute to hypertension because of its potential role in regulating the vascular tone. Early diagnosis and treatment of hypertension improve the CV and renal complications of this population. Ambulatory BP monitoring is recommended for prompt diagnosis of hypertension. CV risk assessment is mandatory. Even though a nonpharmacological approach should not be neglected, RAAS inhibitors are the cornerstone of hypertension treatment. Calcium channel blockers (CCBs) should be avoided unless resistant hypertension is present. The BP should be <140/90 mmHg in all ADPKD patients and a more intensive control (<135/85 mmHg) should be pursued as soon as microalbuminuria or left ventricle hypertrophy is present.

  15. Nephrotic syndrome and autosomal dominant polycystic kidney disease

    PubMed Central

    Visciano, Bianca; Di Pietro, Renata A.; Rossano, Roberta; Mancini, Antonio; Zamboli, Pasquale; Cianciaruso, Bruno; Pisani, Antonio

    2012-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by the development and growth of cysts in the kidneys and other organs. In ADPKD patients, nephrotic range proteinuria is unusual and needs to be investigated further to exclude coexisting glomerular disease. Among the anecdotal case reports of ADPKD associated with nephrotic syndrome, focal segmental glomerulosclerosis occurs most frequently. Methods We report the case of a 26-year-old male with ADPKD and concomitant nephrotic syndrome, in which an ultrasound (US)-guided renal biopsy showed a mesangioproliferative glomerulonephritis. We treated the patient with prednisone 1 mg/kg/day, because of the failure of treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker association. Results After 6 months of steroid treatment, we observed a stability of his GFR and a reduction of proteinuria. Conclusion This case report and other cases of the literature underline the importance of a renal biopsy in patients with ADPKD and nephrotic syndrome in order to make an accurate diagnosis and an appropriate treatment/prevention of renal function deterioration.

  16. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis

    SciTech Connect

    Palmer, S.E. [Univ. of Washington, Seattle, WA (United States)] [Univ. of Washington, Seattle, WA (United States); [Univ. of Texas Health Science Center, San Antonio, TX (United States); Dale, D.C. [Univ. of Washington, Seattle, WA (United States)] [Univ. of Washington, Seattle, WA (United States)

    1996-12-30

    Cyclic hematopoiesis (CH, or cyclic neutropenia) is a rare disease manifested by transient severe neutropenia that recurs approximately every 21 days. The hematologic profile of families with the autosomal dominant form (ADCH) has not been well characterized, and it is unknown if the phenotype is distinct from the more common sporadic congenital or acquired forms of CH. We studied nine ADCH families whose children displayed typical CH blood patterns. Pedigrees confirmed dominant inheritance without evidence of heterogeneity or decreased penetrance; three pedigrees suggested new mutations. Families were Caucasian with exception of one with a Cherokee Native American founder. A wide spectrum of symptom severity, ranging from asymptomatic to life-threatening illness, was observed within families. The phenotype changed with age. Children displayed typical neutrophil cycles with symptoms of mucosal ulceration, lymphadenopathy, and infections. Adults often had fewer and milder symptoms, sometimes accompanied by mild chronic neutropenia without distinct cycles. While CH is commonly described as {open_quotes}benign{close_quotes}, four children in three of the nine families died of Clostridium or E. coli colitis, documenting the need for urgent evaluation of abdominal pain. Misdiagnosis with other neutropenias was common but can be avoided by serial blood counts in index cases. Genetic counseling requires specific histories and complete blood counts in relatives at risk to assess status regardless of symptoms, especially to determine individuals with new mutations. We propose diagnostic criteria for ADCH in affected children and adults. Recombinant human granulocyte colony-stimulating factor treatment resulted in dramatic improvement of neutropenia and morbidity. The differential diagnosis from other forms of familial neutropenia is reviewed. 45 refs., 4 figs., 1 tab.

  17. Autosomal Dominant Hypophosphatemic Rickets\\/Osteomalacia: Clinical Characterization of a Novel Renal Phosphate-Wasting Disorder

    Microsoft Academic Search

    MICHAEL J. ECONS; PAUL T. MCENERY

    2010-01-01

    Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries. Although autosomal dominant transmission of renal phosphate wasting has been described, previous studies included too few affected individuals to adequately characterize the disorder. We performed clinical and biochemical evaluations of individuals from a large kindred with autosomal dominant hypophosphatemic rickets\\/osteomalacia. We identified 23 affected

  18. NATURE MEDICINE ADVANCE ONLINE PUBLICATION 1 Autosomal dominant immune dysregulation syndrome in

    E-print Network

    Will, Sebastian

    syndrome with autoimmunity, granulomatous disease, enteropathy, and malignancy4. The majority of familial CVID cases present an autosomal dominant pattern of inheritance, yet disease pen- etrance may appear, most autosomal dominant mutations caus- ing CVID or increasing the disease risk remain to be identified

  19. A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia

    Microsoft Academic Search

    Marcus Deschauer; Reinhard Kiefer; Emma L. Blakely; Langping He; Stephan Zierz; Douglass M. Turnbull; Robert W. Taylor

    2003-01-01

    Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse

  20. LGI1 microdeletion in autosomal dominant lateral temporal epilepsy

    PubMed Central

    Fanciulli, M.; Santulli, L.; Errichiello, L.; Barozzi, C.; Tomasi, L.; Rigon, L.; Cubeddu, T.; de Falco, A.; Rampazzo, A.; Michelucci, R.; Uzzau, S.; Striano, S.; de Falco, F.A.; Striano, P.

    2012-01-01

    Objectives: To characterize clinically and genetically a family with autosomal dominant lateral temporal epilepsy (ADLTE) negative to LGI1 exon sequencing test. Methods: All participants were personally interviewed and underwent neurologic examination. Most affected subjects underwent EEG and neuroradiologic examinations (CT/MRI). Available family members were genotyped with the HumanOmni1-Quad v1.0 single nucleotide polymorphism (SNP) array beadchip and copy number variations (CNVs) were analyzed in each subject. LGI1 gene dosage was performed by real-time quantitative PCR (qPCR). Results: The family had 8 affected members (2 deceased) over 3 generations. All of them showed GTC seizures, with focal onset in 6 and unknown onset in 2. Four patients had focal seizures with auditory features. EEG showed only minor sharp abnormalities in 3 patients and MRI was unremarkable in all the patients examined. Three family members presented major depression and anxiety symptoms. Routine LGI1 exon sequencing revealed no point mutation. High-density SNP array CNV analysis identified a genomic microdeletion about 81 kb in size encompassing the first 4 exons of LGI1 in all available affected members and in 2 nonaffected carriers, which was confirmed by qPCR analysis. Conclusions: This is the first microdeletion affecting LGI1 identified in ADLTE. Families with ADLTE in which no point mutations are revealed by direct exon sequencing should be screened for possible genomic deletion mutations by CNV analysis or other appropriate methods. Overall, CNV analysis of multiplex families may be useful for identifying microdeletions in novel disease genes. PMID:22496201

  1. Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy.

    PubMed

    Dazzo, Emanuela; Fanciulli, Manuela; Serioli, Elena; Minervini, Giovanni; Pulitano, Patrizia; Binelli, Simona; Di Bonaventura, Carlo; Luisi, Concetta; Pasini, Elena; Striano, Salvatore; Striano, Pasquale; Coppola, Giangennaro; Chiavegato, Angela; Radovic, Slobodanka; Spadotto, Alessandro; Uzzau, Sergio; La Neve, Angela; Giallonardo, Anna Teresa; Mecarelli, Oriano; Tosatto, Silvio C E; Ottman, Ruth; Michelucci, Roberto; Nobile, Carlo

    2015-06-01

    Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain. PMID:26046367

  2. Angiotensin Blockade in Late Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Torres, Vicente E.; Abebe, Kaleab Z.; Chapman, Arlene B.; Schrier, Robert W.; Braun, William E.; Steinman, Theodore I.; Winklhofer, Franz T.; Brosnahan, Godela; Czarnecki, Peter G.; Hogan, Marie C.; Miskulin, Dana C.; Rahbari-Oskoui, Frederic F.; Grantham, Jared J.; Harris, Peter C.; Flessner, Michael F.; Moore, Charity G.; Perrone, Ronald D.

    2014-01-01

    BACKGROUND Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin–angiotensin–aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting–enzyme (ACE) inhibitor or angiotensin II–receptor blocker (ARB). METHODS In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m2 of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years. RESULTS There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril–telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups. CONCLUSIONS Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.) PMID:25399731

  3. Association of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease

    Microsoft Academic Search

    B. Lipschitz; W. E. Berdon; A. R. Defelice; J. Levy

    1993-01-01

    The association of autosomal recessive polycystic kidney disease (ARPKD) with congential hepatic fibrosis (CHF) is well known; a rare occurrence is that of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease (ADPKD). We report a family with ADPKD in which congenital hepatic fibrosis with severe portal hypertension (PHT) presented in a 4-year-old girl; the kidneys were initially normal. Typical

  4. Pseudoxanthoma Elasticum: the End of the Autosomal Dominant Segregation Myth

    Microsoft Academic Search

    Arthur A B Bergen

    2006-01-01

    Pseudoxanthoma elasticum (PXE) is a heritable connective-tissue disorder affecting the eye, skin, and vascular system. Recent publications show that PXE exclusively segregates in an autosomal recessive fashion. However, the lack of an internationally accepted clinical “gold standard” for PXE, our incomplete knowledge of PXE etiology, and the incomplete nature of some molecular, clinical, and environmental studies warrant further investigation.

  5. Vertebral Aspergillosis in a Patient with Autosomal-Dominant Hyper-IgE Syndrome

    PubMed Central

    Ma, Hong; Kuang, Lei; Wang, Bing; Lian, Zhesi

    2014-01-01

    We present a report of an autosomal-dominant hyper-IgE syndrome patient with vertebral aspergillosis. Early diagnosis and antifungal therapy with surgery are crucial for improving the outcome of this aggressive condition. PMID:24197892

  6. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease

    Microsoft Academic Search

    Robert W Schrier; Kimberly K McFann; Ann M Johnson

    2003-01-01

    Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease.BackgroundIt is unknown whether the substantial increase in research, identification of risk factors for renal progression, greater antihypertensive armamentarium including inhibitors of the renin-angiotensin-aldosterone system (RAAS) and enhanced educational information have impacted the progression of autosomal dominant polycystic kidney disease (ADPKD) renal disease.MethodsAn epidemiological study involving 513 ADPKD subjects was

  7. A novel GDAP1 Q218E mutation in autosomal dominant Charcot-Marie-Tooth disease

    Microsoft Academic Search

    Ki Wha Chung; Seung Min Kim; Il Nam Sunwoo; Sun Young Cho; Su Jin Hwang; Joonki Kim; Sung Hee Kang; Kee-Duk Park; Kyoung-Gyu Choi; Il Saing Choi; Byung-Ok Choi

    2008-01-01

    A wide range of phenotypes have been reported in autosomal recessive (AR) Charcot-Marie-Tooth disease (CMT) patients carrying\\u000a mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene, such as axonal, demyelinating, and intermediate forms of AR CMT. There have been very few reports of GDAP1 mutations in autosomal dominant (AD) CMT. Here, we report an AD CMT family with a novel

  8. Mutations of the LMNA gene can mimic autosomal dominant proximal spinal muscular atrophy

    Microsoft Academic Search

    Sabine Rudnik-Schöneborn; Elke Botzenhart; Thomas Eggermann; Jan Senderek; Benedikt G. H. Schoser; Rolf Schröder; Manfred Wehnert; Brunhilde Wirth; Klaus Zerres

    2007-01-01

    The molecular basis of autosomal dominant spinal muscular atrophy (AD-SMA) is largely unknown. Because the phenotypic spectrum\\u000a of diseases caused by LMNA mutations is extremely broad and includes myopathies, neuropathies, and cardiomyopathies designated as class 1 laminopathies,\\u000a we sequenced the LMNA gene in index patients with the clinical picture of proximal SMA, who had a family history suggestive of autosomal

  9. Nephrotic Syndrome and Rapid Renal Failure in Autosomal Dominant Polycystic Kidney Disease

    Microsoft Academic Search

    Gayle Murphy; Antonios H. Tzamaloukas; Margaret B. Listrom; Lawrence J. Gibel; Suzanne Meleg Smith

    1990-01-01

    A 44-year-old man, with autosomal dominant polycystic kidney disease and hypertension under satisfactory control, developed nephrotic syndrome with negative serology. Open renal biopsy revealed focal glomerular sclerosis. Prior to the appearance of heavy proteinuria, serum creatinine was 1.7mg\\/dl. After the nephrotic syndrome had been established, renal function deteriorated rapidly and hemodialysis was started within 2.6 years. In patients with autosomal

  10. Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease

    Microsoft Academic Search

    K. F. Damji; C. J. Gallione; R. R. Allingham; B. Slotterbeck; A. E. Guttmacher; K. A. Pasyk; J. M. Vance; M. A. Pericak-Vance; M. C. Speer; D. A. Marchuk

    1998-01-01

    DNA pooling is an efficient method to rapidly perform genome-wide linkage scans in autosomal recessive diseases in inbred\\u000a populations where affected individuals are likely to be homozygous for alleles near the disease gene locus. We wanted to examine\\u000a whether this approach would detect linkage in autosomal dominant (AD) disorders where affected individuals may share one allele\\u000a identical by descent at

  11. Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5.

    PubMed

    Baulac, Stéphanie

    2014-01-01

    Rare multiplex families with autosomal dominant focal epilepsies have been described with specific age-related and electroclinical syndromes: autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), familial temporal lobe epilepsy (FTLE), and familial focal epilepsy with variable foci (FFEVF). Molecular genetic advances in inherited focal epilepsies have pinpointed their genetic heterogeneity and the fact that they are mediated by different biological pathways: ion channel subunit genes have been linked to ADNFLE (CHRNA4, CHRNA2, CHRNB2, and KCNT1, encoding, respectively, the ?4, ?2, and ?2 subunits of the neuronal nicotinic acetylcholine receptor, and a potassium channel subunit); neuronal secreted protein (LGI1-encoding epitempin) has been linked to autosomal dominant epilepsy with auditory features; and mTORC1-repressor DEPDC5 (DEP domain-containing protein 5) gene has recently been reported in a broad spectrum of inherited focal epilepsies (ADNFLE, FTLE, FFEVF). This chapter focuses on DEPDC5, a newly identified gene. PMID:25194487

  12. Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy

    SciTech Connect

    Rudnik-Schoeneborn, S.; Wirth, B.; Zerres, K. (Univ. of Bonn (Germany))

    1994-07-01

    Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explanation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (= .09[+-].06 for onset at 10-36 mo and .13[+-].07 for onset at >36 mo; and P = .09[+-]0.7 for SMA IIIa and .12[+-].07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. 29 refs., 2 figs., 5 tabs.

  13. A locus for autosomal dominant colobomatous microphthalmia maps to chromosome 15q12-q15.

    PubMed

    Morlé, L; Bozon, M; Zech, J C; Alloisio, N; Raas-Rothschild, A; Philippe, C; Lambert, J C; Godet, J; Plauchu, H; Edery, P

    2000-12-01

    Congenital microphthalmia is a common developmental ocular disorder characterized by shortened axial length. Isolated microphthalmia is clinically and genetically heterogeneous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Here, we studied a five-generation family of Sephardic Jewish origin that included 38 members, of whom 7 have either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. After exclusion of several candidate loci, we performed a genome-scan study and demonstrated linkage to chromosome 15q12-q15. Positive LOD scores were obtained with a maximum at the D15S1007 locus (maximum LOD score 3.77, at recombination fraction 0.00). Haplotype analyses supported the location of the disease-causing gene in a 13.8-cM interval between loci D15S1002 and D15S1040. PMID:11035633

  14. Novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure

    Microsoft Academic Search

    S. Bohlega; G. Van Goethem; A. Al Semari; A. Löfgren; M. Al Hamed; C. Van Broeckhoven; M. Kambouris

    2009-01-01

    A Saudi Arabian family presented with adult onset autosomal dominant progressive external ophthalmoplegia (adPEO) complicated by late onset reversible failure of the CNS, respiratory, hepatic, and endocrine systems. Clinical findings were suggestive of mitochondrial dysfunction and multiple mitochondrial DNA deletions were demonstrated on long range and real time polymerase chain reaction assays but not on Southern blotting. The disorder is

  15. Increases in kidney volume in autosomal dominant polycystic kidney disease can be detected within 6 months

    Microsoft Academic Search

    Andreas D. Kistler; Diane Poster; Fabienne Krauer; Dominik Weishaupt; Shagun Raina; Oliver Senn; Isabelle Binet; Katharina Spanaus; Rudolf P. Wuthrich; Andreas L. Serra

    2009-01-01

    Kidney volume growth is considered the best surrogate marker predicting the decline of renal function in autosomal dominant polycystic kidney disease. To assess the therapeutic benefit of new drugs more rapidly, changes in kidney volume need to be determined over a short time interval. Here we measured renal volume changes by manual segmentation volumetry applied to magnetic resonance imaging scans

  16. Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload

    Microsoft Academic Search

    Anne-Marie Jouanolle; Véronique Douabin-Gicquel; Chantal Halimi; Olivier Loréal; Patricia Fergelot; Thierry Delacour; Anne-Sophie de Lajarte-Thirouard; Bruno Turlin; Jean-Yves Le Gall; Estelle Cadet; Jacques Rochette; Véronique David; Pierre Brissot

    2003-01-01

    We report a family affected with dominant autosomal iron overload related to a new mutation in ferroportin 1, a transmembrane protein involved in the export of iron from duodenal enterocytes and likely from macrophages. The originality of this family is represented by the nature of the mutation consisting in the replacement of glycine 490 with aspartate. Clinicians should be aware

  17. GABAA Receptor 1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy

    E-print Network

    Palmeri, Thomas

    Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors*S Received subunit mutation, A322D (AD), causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJME, in addition to causing a het- erozygous loss of function of 1(AD) subunits, this epilepsy mutation also

  18. Correlation of histopathological features and renal impairment in autosomal dominant Alport syndrome in Bull terriers

    Microsoft Academic Search

    Jennifer C. Hood; John Dowling; John F. Bertram; Richard J. Young; Clive Huxtable; Wayne Robinson; Judy Savige

    Background. Bull terrier hereditary nephritis represents a model for autosomal dominant Alport syndrome, as affected dogs have the characteristically lamellated glomerular basement membrane and demonstrate vertical male-to-male disease transmission. Methods. This study compared the histopathological features in kidneys from affected Bull terrier neonates, puppies, and adult dogs with normal or impaired renal function, with the histopathological appearance of kidneys from

  19. Am. J. Hum. Genet. 68:264268, 2001 Genetic and Physical Mapping of the Locus for Autosomal Dominant

    E-print Network

    Broman, Karl W.

    for Autosomal Dominant Renal Fanconi Syndrome, on Chromosome 15q15.3 U. Lichter-Konecki,1,* K. W. Broman,3 E. B Fanconi syndrome is a genetic model for the study of proximal renal tubular transport pathology. We were of the gene and gene product altered in autosomal dominant renal Fanconi syndrome will allow the study

  20. A new locus for autosomal dominant stargardt-like disease maps to chromosome 4.

    PubMed Central

    Kniazeva, M; Chiang, M F; Morgan, B; Anduze, A L; Zack, D J; Han, M; Zhang, K

    1999-01-01

    Stargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of.00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an approximately 12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4. PMID:10205271

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

    SciTech Connect

    Bunge, S.; Wedemann, H.; Samanns, C.; Horn, M.; Schwinger, E.; Gal, A. (Medizinische Universitaet zu Luebeck (Germany)); David, D. (Laboratorio de Genetica Humana, Lisbon (Portugal)); Terwilliger, D.J.; Ott, J. (Columbia Univ., New York, NY (United States)); Born, L.I. van den (The Netherlands Ophthalmic Research Institute, Amsterdam (Netherlands)) (and others)

    1993-07-01

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

  2. Familial hiatal hernia in a large five generation family confirming true autosomal dominant inheritance

    PubMed Central

    Carre, I; Johnston, B; Thomas, P; Morrison, P

    1999-01-01

    BACKGROUND—Familial hiatal hernia has only rarely been documented.?AIMS—To describe the pattern of inheritance of familial hiatal hernia within an affected family.?SUBJECTS—Thirty eight members of a family pedigree across five generations.?METHODS—All family members were interviewed and investigated by barium meal for evidence of a hiatal hernia.?RESULTS—Twenty three of 38 family members had radiological evidence of a hiatal hernia. No individual with a hiatal hernia was born to unaffected parents. In one case direct male to male transmission was shown.?CONCLUSIONS—Familial inheritance of hiatal hernia does occur. Evidence of direct male to male transmission points to an autosomal dominant mode of inheritance.???Keywords: familial hiatal hernia; Barrett's oesophagus; autosomal dominant genetics PMID:10517898

  3. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

    PubMed Central

    Stojanov, Dragan; Aracki-Trenkic, Aleksandra; Vojinovic, Slobodan; Ljubisavljevic, Srdjan; Benedeto-Stojanov, Daniela; Tasic, Aleksandar; Vujnovic, Sasa

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an autosomal dominant vascular disorder. Diagnosis and follow-up in patients with CADASIL are based mainly on magnetic resonance imaging (MRI). MRI shows white matter hyperintensities (WMHs), lacunar infarcts and cerebral microbleeds (CMBs). WMHs lesions tend to be symmetrical and bilateral, distributed in the periventricular and deep white matter. The anterior temporal lobe and external capsules are predilection sites for WMHs, with higher specificity and sensitivity of anterior temporal lobe involvement compared to an external capsule involvement. Lacunar infarcts are presented by an imaging signal that has intensity of cerebrospinal fluid in all MRI sequences. They are localized within the semioval center, thalamus, basal ganglia and pons. CMBs are depicted as focal areas of signal loss on T2 images which increases in size on the T2*-weighted gradient echo planar images (“blooming effect”). PMID:25725137

  4. Locus heterogeneity in autosomal dominant spinocerebellar ataxia: Evidence for the existence of a fifth locus

    SciTech Connect

    Sarrazin, J.; Rouleau, G.A. [Montreal General Hospital, Quebec (Canada); Andermann, E. [Montreal Neurological Institute and Hospital, Quebec (Canada)] [and others

    1994-09-01

    The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. To date, four loci have been identified: the SCA-1 locus (on chromosome (chr) 6p), the SCA-2 locus (on chr 12q), the SCA-3/MJD locus (on chr 14q), and more recently an SCA-4 locus was described (chr 16q) in a Utah kindred. We have studied one large French Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers which flank the four previously described loci significantly excludes the French Canadian kindred from the SCA-1, SCA-2, SCA-3/MJD and SCA-4 loci. Therefore a fifth, still unmapped, SCA locus remains to be identified.

  5. Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa

    Microsoft Academic Search

    Daniel Mordes; Liya Yuan; Lili Xu; Mariko Kawada; Robert S. Molday; Jane Y. Wu

    2007-01-01

    Several ubiquitously expressed genes encoding pre-mRNA splicing factors have been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8. Molecular mechanisms by which defects in pre-mRNA splicing factors cause photoreceptor degeneration are not clear. To investigate the role of pre-mRNA splicing in photoreceptor gene expression and function, we have begun to search for photoreceptor genes whose pre-mRNA

  6. Novel LGI1 mutation in a family with autosomal dominant partial epilepsy with auditory features.

    PubMed

    Fertig, Evan; Lincoln, Anne; Martinuzzi, Andrea; Mattson, Richard H; Hisama, Fuki M

    2003-05-27

    Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare idiopathic epilepsy syndrome caused by mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene. The authors report that molecular genetic studies in seven affected family members identified a novel F318C substitution that alters a highly conserved residue in a predicted repeat domain of unknown function. This report suggests that this domain may participate in the development of the ADPEAF phenotype. PMID:12771268

  7. [Articular contracture with dwarfism and normal intelligence: a new autosomal dominant familial syndrome].

    PubMed

    Stoll, C; Roth, M P; Levy, J M

    1980-09-01

    A father and his daughter has the same features: short stature, the distal phalanges, the wrists, the elbows, the feet and the knees were flexed. All other joints had abnormal range of motion. Kypho-scoliosis was present in the father only. Father's family was normal. Upon X-rays examination no abnormalities could be seen. This syndrome is inherited as autosomal dominant. PMID:7463030

  8. A Mutation in Autosomal Dominant Myotonia Congenita Affects Pore Properties of the Muscle Chloride Channel

    Microsoft Academic Search

    Christoph Fahlke; Carol L. Beck; Alfred L. George

    1997-01-01

    Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl- channel gene (CLCN1, 7q35). Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the pore properties of a recombinant human muscle Cl- channel (hClC-1) expressed in a mammalian

  9. 1021. Suppression and Replacement Strategies for Rhodopsin-Linked Autosomal Dominant Retinitis Pigmentosa

    Microsoft Academic Search

    Arpad Palfi; Mary O'Reilly; Sophia Millington-Ward; Marius Ader; Naomi Chadderton; Gearoid Tuohy; Anna-Sophia Kiang; Niamh McNally; Marian Humphries; Peter Humphries; Paul F. Kenna; G. Jane Farrar

    2006-01-01

    Retintis pigmentosa (RP) is a term used to describe a group of inherited retinopathies primarily involving photoreceptor cell loss. The clinical and genetic heterogeneity inherent in RP has been highlighted with over 35 disease genes now characterised (http:\\/\\/www.sph.uth.tmc.edu\\/retnet\\/home.htm). One of the first genes to be identified as causative of autosomal dominantly inherited RP (adRP) was the rhodopsin gene (RHO) which

  10. Recurrent Pancreatitis in a Patient with Autosomal-Dominant Polycystic Kidney Disease

    Microsoft Academic Search

    Engin Uçar; Ömer Faruk Yolcu; Seyfettin Köklü; Erkan Parlak; Aysel Ülker

    2006-01-01

    Autosomal-dominant polycystic kidney disease is an inherited disorder characterized by multiple cysts in kidneys and other organs. A 63-year-old man was evaluated for the etiology of recurrent pancreatitis and chronic renal failure. Multiple cysts of kidneys, liver, and pancreas and pancreas divisum was diagnosed. Pancreatitis should be included in the differential diagnosis of abdominal pain in patients with ADPKD. Pancreas

  11. Investigation of eight candidate genes on chromosome 1p36 for autosomal dominant total congenital cataract

    Microsoft Academic Search

    Kathryn P. Burdon; Kathryn Hattersley; Salil A. Lachke; Kate J. Laurie; Richard L. Maas; David A. Mackey; Jamie E. Craig

    2008-01-01

    Purpose: To identify the causative gene for autosomal dominant total congenital cataract in a six-generation Australian family displaying linkage to chromosome 1p36. Methods: Eight candidate genes (HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2) from within the previously defined linkage interval were selected based on expression in lens and their known or putative function. The coding exons were sequenced

  12. Mutation Analysis of Autosomal Dominant Polycystic Kidney Disease Genes in Han Chinese

    Microsoft Academic Search

    Shuzhong Zhang; Changlin Mei; Dianyong Zhang; Bing Dai; Bing Tang; Tianmei Sun; Haidan Zhao; Yukun Zhou; Lin Li; Yumei Wu; Wenjing Wang; Xuefei Shen; Ji Song

    2005-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2. The complexity of these genes, particularly PKD1, has complicated genetic screening, though recent advances have provided new opportunities for amplifying these genes. In the Han Chinese population, no complete mutational analysis has previously been conducted across the entire span of PKD1 and PKD2. Here,

  13. [Prenatal genetic diagnosis of type I autosomal dominant polycystic kidney disease].

    PubMed

    Klaus, Z; Kozáry, M; Czeizel, E

    1997-06-15

    Probanda affected with autosomal dominant polycystic kidney disease (ADPKD) had a molecular genetic analysis which indicated the type I. Of the three pregnancies in the probanda, first two had mutant gene carrier fetuses and these pregnancies were terminated. The fetus of the third pregnancy had no mutant gene and this pregnancy ended in the birth of a healthy boy. The principles of genetic counselling and antenatal care are summarised in ADPKD type I. PMID:9254374

  14. Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology

    Microsoft Academic Search

    Alexander Zimprich; Saskia Biskup; Petra Leitner; Peter Lichtner; Matthew Farrer; Sarah Lincoln; Jennifer Kachergus; Mary Hulihan; Ryan J. Uitti; Donald B. Calne; A. Jon Stoessl; Ronald F. Pfeiffer; Nadja Patenge; Iria Carballo Carbajal; Peter Vieregge; Friedrich Asmus; Bertram Müller-Myhsok; Dennis W. Dickson; Thomas Meitinger; Tim M. Strom; Zbigniew K. Wszolek; Thomas Gasser

    2004-01-01

    We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes

  15. Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy

    Microsoft Academic Search

    Yu-Dong Zhou; Sanghoon Lee; Zhe Jin; Moriah Wright; Stephen E P Smith; Matthew P Anderson

    2009-01-01

    A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing

  16. Nerve conduction studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

    Microsoft Academic Search

    Sa-Yoon Kang; Jung-Hwan Oh; Ji-Hoon Kang; Jay Chol Choi; Jung Seok Lee

    2009-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral\\u000a microangiopathy linked to mutations in the Notch3 gene. The cerebral impairments of CADASIL are well-known, but peripheral\\u000a nervous impairments such as polyneuropathy are less clear. Recently, peripheral neuropathy was proposed as one of the CADASIL\\u000a phenotypes. We investigated peripheral nerve involvement in CADASIL patients. Forty-three CADASIL

  17. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): A patient from Sri Lanka

    Microsoft Academic Search

    K. R. D. De Silva; R. Gamage; Janavi Dunuwille; D. Gunarathna; D. Sirisena; A. Weerasinghe; P. H. Amarasinghe; Akiko Hosomi; Toshiki Mizuno

    2009-01-01

    We report the first patient from Sri Lanka (the third patient from the Indian subcontinent) with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The patient experienced a young onset familial stroke with an 856T>G missense mutation in exon 5 of the NOTCH3 gene resulting in a C260G mutation in the sixth epidermal growth factor-like repeat. We believe

  18. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in a Greek family

    Microsoft Academic Search

    D. Mandellos; G. Limbitaki; A. Papadimitriou; D. Anastasopoulos

    2005-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset inherited\\u000a disease, characterised by recurrent strokes, migraine and cognitive impairment. We present the first Greek family with CADASIL,\\u000a caused by the R153C mutation at exon 4 of the Notch3 gene. A member of this family carrying this mutation was also found to\\u000a be heterozygotic for the MTHFR

  19. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy):an Australian perspective

    Microsoft Academic Search

    T. L. Chuah; K. M. Tan; S. Flanagan; V. Hyland; A. A. Sullivan; R. Henderson; J. MacMillan; C. Lander

    2001-01-01

    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was

  20. Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia

    Microsoft Academic Search

    Maria A Graziewicz; Matthew J Longley; Rachelle J Bienstock; Massimo Zeviani; William C Copeland

    2004-01-01

    Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with mutations in the POLG gene encoding the mitochondrial DNA polymerase (pol ?). Four autosomal dominant mutations that cause PEO encode the amino acid substitutions G923D, R943H, Y955C and A957S in the polymerase domain of pol ?. A homology model of the pol ? catalytic domain in complex with DNA was

  1. Autosomal Dominant Polycystic Kidney Disease: Recent Advances in Pathogenesis and Treatment

    Microsoft Academic Search

    Ming-Yang Chang; Albert C. M. Ong

    2008-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder affecting 1 in 1,000 people in the general population and accounts for up to 10% of all patients on renal replacement therapy. Numerous fluid-filled epithelial cysts arise from different nephron segments as spherical dilatations or small out-pouchings, enlarge progressively and eventually become disconnected from the rest of the renal

  2. A rare novel mutation in TECTA causes autosomal dominant nonsyndromic hearing loss in a Mongolian family

    PubMed Central

    2014-01-01

    Background The genetic basis of autosomal dominant nonsyndromic hearing loss is complex. Genetic factors are responsible for approximately 50% of cases with congenital hearing loss. However, no previous studies have documented the clinical phenotype and genetic basis of autosomal dominant nonsyndromic hearing loss in Mongolians. Methods In this study, we performed exon capture sequencing of a Mongolian family with hereditary hearing loss and identified a novel mutation in TECTA gene, which encodes ? -tectorin, a major component of the inner ear extracellular matrix that contacts the specialized sensory hair cells. Results The novel G???T missense mutation at nucleotide 6016 results in a substitution of amino acid aspartate at 2006 with tyrosine (Asp2006Tyr) in a highly conserved zona pellucida (ZP) domain of ?-tectorin. The mutation is not found in control subjects from the same family with normal hearing and a genotype-phenotype correlation is observed. Conclusion A novel missense mutation c.6016 G?>?T (p.Asp2006Tyr) of TECTA gene is a characteristic TECTA-related mutation which causes autosomal dominant nonsyndromic hearing loss. Our result indicated that mutation in TECTA gene is responsible for the hearing loss in this Mongolian family. PMID:25008054

  3. Brachydactyly type B: clinical description, genetic mapping to chromosome 9q, and evidence for a shared ancestral mutation.

    PubMed Central

    Gong, Y; Chitayat, D; Kerr, B; Chen, T; Babul-Hirji, R; Pal, A; Reiss, M; Warman, M L

    1999-01-01

    Autosomal dominant brachydactyly type B (BDB) is characterized by nail aplasia with rudimentary or absent distal and middle phalanges. We describe two unrelated families with BDB. One family is English; the other family is Canadian but of English ancestry. We assigned the BDB locus in the Canadian family to an 18-cM interval on 9q, using linkage analysis (LOD score 3.5 at recombination fraction [theta] 0, for marker D9S938). Markers across this interval also cosegregated with the BDB phenotype in the English family (LOD score 2.1 at straight theta=0, for marker D9S277). Within this defined interval is a smaller (7.5-cM) region that contains 10 contiguous markers whose disease-associated haplotype is shared by the two families. This latter result suggests a common founder among families of English descent that are affected with BDB. PMID:9973295

  4. Mapping of Both Autosomal Recessive and Dominant Variants of Pseudoxanthoma Elasticum to Chromosome 16p13.1

    Microsoft Academic Search

    Berthold Struk; Kenneth H. Neldner; Valluri S. Rao; Pamela St Jean; Klaus Lindpaintner

    1997-01-01

    Pseudoxanthoma elasticum (PXE) is a classic inherited disorder of the elastic tissue characterized by progressive calcification of elastic fibers with a pathognomonic histological appearance. The clinical manifestations of PXE typically involve the skin, the eye and the cardiovascular system, resulting in skin lesions, decreased vision and vascular disease. Clinically, a more common autosomal recessive and a less common autosomal dominant

  5. TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss.

    PubMed

    Azaiez, Hela; Booth, Kevin T; Bu, Fengxiao; Huygen, Patrick; Shibata, Seiji B; Shearer, A Eliot; Kolbe, Diana; Meyer, Nicole; Black-Ziegelbein, E Ann; Smith, Richard J H

    2014-07-01

    Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal-dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole-exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders. PMID:24729539

  6. Autosomal Dominant Progressive Sensorineural Hearing Loss Due to a Novel Mutation in the KCNQ4 Gene

    PubMed Central

    Arnett, Jameson; Emery, Sarah B.; Kim, Theresa B.; Boerst, Angelique K.; Lee, Kwanghyuk; Leal, Suzanne M.; Lesperance, Marci M.

    2012-01-01

    Objective To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss. Design Prospective molecular genetic research study. Setting Academic genetic research laboratory. Participants Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses. Interventions Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis. Main Outcome Measures Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation. Results Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single-nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34–p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate- binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation. Conclusions Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4. PMID:21242547

  7. Differences in hormonal and renal vascular responses between normotensive patients with autosomal dominant polycystic kidney disease and unaffected family members

    Microsoft Academic Search

    Brendan J Barrett; Robert Foley; Janet Morgan; Donna Hefferton; Patrick Parfrey

    1994-01-01

    Differences in hormonal and renal vascular responses between normotensive patients with autosomal dominant polycystic kidney disease and unaffected family members. We tested the hypothesis that overactivity of the renal and systemic renin-angiotensin system is important to the pathogenesis of hypertension in autosomal dominant polycystic kidney disease (ADPKD). Up to 21 normotensive subjects with ADPKD and creatinine clearance >70 ml\\/min\\/1.73 m2

  8. LGI1 mutations in autosomal dominant partial epilepsy with auditory features

    PubMed Central

    Ottman, R.; Winawer, M.R.; Kalachikov, S.; Barker-Cummings, C.; Gilliam, T.C.; Pedley, T.A.; Hauser, W.A.

    2006-01-01

    Objectives Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations. Methods The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously. Results Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies. Conclusions LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families. PMID:15079011

  9. Altered language processing in autosomal dominant partial epilepsy with auditory features

    PubMed Central

    Ottman, R; Rosenberger, L; Bagic, A; Kamberakis, K; Ritzl, E K.; Wohlschlager, A M.; Shamim, S; Sato, S; Liew, C; Gaillard, W D.; Wiggs, E; Berl, M M.; Reeves-Tyer, P; Baker, E H.; Butman, J A.; Theodore, W H.

    2008-01-01

    Background: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations, frequently associated with mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene. Although affected subjects do not have structural abnormalities detected on routine MRI, a lateral temporal malformation was identified through high resolution MRI in one family. We attempted to replicate this finding and to assess auditory and language processing in ADPEAF using fMRI and magnetoencephalography (MEG). Methods: We studied 17 subjects (10 affected mutation carriers, 3 unaffected carriers, 4 noncarriers) in 7 ADPEAF families, each of which had a different LGI1 mutation. Subjects underwent high-resolution structural MRI, fMRI with an auditory description decision task (ADDT) and a tone discrimination task, and MEG. A control group comprising 26 volunteers was also included. Results: We found no evidence of structural abnormalities in any of the 17 subjects. On fMRI with ADDT, subjects with epilepsy had significantly less activation than controls. On MEG with auditory stimuli, peak 2 auditory evoked field latency was significantly delayed in affected individuals compared to controls. Conclusions: These findings do not support the previous report of a lateral temporal malformation in autosomal dominant partial epilepsy with auditory features (ADPEAF). However, our fMRI and magnetoencephalography data suggest that individuals with ADPEAF have functional impairment in language processing. GLOSSARY ADDT = auditory description decision task; ADPEAF = autosomal dominant partial epilepsy with auditory features; AED = antiepileptic drug; AEF = auditory evoked field; ECD = equivalent current dipole; FLAIR = fluid-attenuated inversion recovery; IGE = idiopathic generalized epilepsy; IIED = identified interictal epileptiform discharges; MEG = magnetoencephalography; MP-RAGE = magnetization prepared rapid gradient echo; SPGR = spoiled gradient echo recalled; SPL = sound-pressure level. PMID:19064878

  10. Seizure semiology in autosomal dominant epilepsy with auditory features, due to novel LGI1 mutations.

    PubMed

    Sadleir, Lynette G; Agher, Dahbia; Chabrol, Elodie; Elkouby, Léa; Leguern, Eric; Paterson, Sarah J; Harty, Rosie; Bellows, Susannah T; Berkovic, Samuel F; Scheffer, Ingrid E; Baulac, Stéphanie

    2013-12-01

    Mutations in LGI1 are found in 50% of families with autosomal dominant epilepsy with auditory features (ADEAF). In ADEAF, family members have predominantly lateral temporal lobe seizures but mesial temporal lobe semiology may also occur. We report here three families with novel LGI1 mutations (p.Ile82Thr, p.Glu225*, c.432-2_436del). Seven affected individuals reported an auditory aura and one a visual aura. A 10-year old boy described a cephalic aura followed by an unpleasant taste and oral automatisms without auditory, visual or psychic features. PMID:24206907

  11. Hereditary hemorrhagic telangiectasia with juvenile polyposis--coincidence or linked autosomal dominant inheritance?

    PubMed

    Ballauff, A; Koletzko, S

    1999-05-01

    Hereditary hemorrhagic telangiectasia (HHT) and familial juvenile polyposis (EJP) are two rare autosomal dominant disorders, Genetic heterogeneity has been shown for HHT and is likely for FJP as well. This paper describes the coexistence of both diseases in a girl and her father in addition to twelve members of five families and two sporadic cases reported in the literature. This implies a new phenotype which may be important in elucidating the underlying genetics in HHT and FJP. Clinical diagnosis of one disease should induce screening for symptoms of the other. PMID:10413846

  12. An autosomal dominant genetically heterogeneous variant of rolandic epilepsy and speech disorder

    PubMed Central

    Kugler, Steven L.; Bali, Bhavna; Lieberman, Philip; Strug, Lisa; Gagnon, Bernadine; Murphy, Peregrine L.; Clarke, Tara; Greenberg, David A.; Pal, Deb K.

    2008-01-01

    SUMMARY We report a three generation pedigree with 11 of 22 affected with a variant form of rolandic epilepsy, speech impairment, oromotor apraxia, and cognitive deficit. The core features comprised nocturnal rolandic seizures, interictal centrotemporal spike waves with early age of onset and late age of offset. The transmission of the phenotype was consistent with autosomal dominant inheritance, with variable expressivity but no evidence of anticipation. We found evidence that the seizure and speech traits may be dissociated. No abnormalities were found by cytogenetic analysis. Linkage analysis excluded loci at 11p, 15q, 16p12, and Xq22 for related phenotypes, suggesting genetic heterogeneity. PMID:18248446

  13. A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss.

    PubMed

    Morlé, L; Bozon, M; Alloisio, N; Latour, P; Vandenberghe, A; Plauchu, H; Collet, L; Edery, P; Godet, J; Lina-Granade, G

    2000-05-01

    Mutations in the GJB2 gene encoding connexin26 (CX26) account for up to 50% of cases of autosomal recessive hearing loss. In contrast, only one GJB2 mutation has been reported to date in an autosomal dominant form of isolated prelingual hearing loss. We report here a novel heterozygous 605G-->T mutation in GJB2 in all affected members of a large family with late childhood onset of autosomal dominant isolated hearing loss. The resulting C202F substitution, which lies in the fourth (M4) transmembrane domain of CX26, may impair connexin oligomerisation. Finally, our study suggests that GJB2 should be screened for heterozygous mutations in patients with autosomal dominant isolated hearing impairment, whatever the severity of the disease. PMID:10807696

  14. The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies.

    PubMed Central

    Wallgren-Pettersson, C; Clarke, A; Samson, F; Fardeau, M; Dubowitz, V; Moser, H; Grimm, T; Barohn, R J; Barth, P G

    1995-01-01

    Clinical differences exist between the three forms of myotubular myopathy. They differ regarding age at onset, severity of the disease, and prognosis, and also regarding some of the clinical characteristics. The autosomal dominant form mostly has a later onset and milder course than the X linked form, and the autosomal recessive form is intermediate in both respects. These differences are, however, quantitative rather than qualitative. Muscle biopsy studies of family members are useful in some cases, and immunohistochemical staining of desmin and vimentin may help distinguish between the X linked and autosomal forms. Determining the mode of inheritance and prognosis in individual families, especially those with a single male patient, still poses a problem. Current molecular genetic results indicate that the gene for the X linked form is located in the proximal Xq28 region. Further molecular genetic studies are needed to examine the existence of genetic heterogeneity in myotubular myopathy and to facilitate diagnosis. Images PMID:8544184

  15. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.

    PubMed

    White, Janson; Mazzeu, Juliana F; Hoischen, Alexander; Jhangiani, Shalini N; Gambin, Tomasz; Alcino, Michele Calijorne; Penney, Samantha; Saraiva, Jorge M; Hove, Hanne; Skovby, Flemming; Kayserili, Hülya; Estrella, Elicia; Vulto-van Silfhout, Anneke T; Steehouwer, Marloes; Muzny, Donna M; Sutton, V Reid; Gibbs, Richard A; Lupski, James R; Brunner, Han G; van Bon, Bregje W M; Carvalho, Claudia M B

    2015-04-01

    Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS. PMID:25817016

  16. Acromicric dysplasia: long term outcome and evidence of autosomal dominant inheritance

    PubMed Central

    Faivre, L; Le Merrer, M; Baumann, C; Polak, M; Chatelain, P; Sulmont, V; Cousin, J; Bost, M; Cordier, M; Zackai, E; Russell, K; Finidori, G; Pouliquen, J; Munnich, A; Maroteaux, P; Cormier-Daire, V

    2001-01-01

    Acromicric dysplasia is a rare bone dysplasia characterised by short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and characteristic x ray abnormalities of the hands. Only a very small number of children with this condition have been reported so far. Here we report on a series of 22 patients including 10 boys and 12 girls with acromicric dysplasia. Length was normal at birth and height fell progressively off the centiles postnatally. The mean adult height was 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs were short and OFC was normal. Intelligence was normal and mild dysmorphic features were noted. Other occasional features included well developed muscles, a hoarse voice, generalised joint limitation in some patients, frequent ear, tracheal, and respiratory complication, and spine abnormalities. Long term follow up showed that facial dysmorphism was less obvious in adults and that carpal tunnel syndrome was frequent in older patients. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x ray abnormalities. No major complications, such as cardiac disease or major orthopaedic problems, occurred in the course of the disease. The condition appeared to be sporadic in 16 cases but the observation of vertical transmission in three families was consistent with an autosomal dominant mode of inheritance.???Keywords: acromicric dysplasia; geleophysic dysplasia; long term outcome; autosomal dominant inheritance PMID:11694546

  17. Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD

    PubMed Central

    Schindler, Suzanne Elizabeth; Fagan, Anne M.

    2015-01-01

    Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-? peptide (A?) leading to early deposition of A? in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF A?42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

  18. Inheritance of human breast cancer: Evidence for autosomal dominant transmission in high-risk families

    SciTech Connect

    Newman, B.; Austin, M.A.; Lee, M.; King, M.C.

    1988-05-01

    Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a population-based series of probands, an autosomal dominant model with a highly penetrant susceptibility allele fully explained disease clustering. From the maximum-likelihood Mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. Inherited susceptibility affected only 4% of families in the sample: multiple cases of this relatively common disease occurred in other families by change. The same genetic models, with higher gene frequency, explained disease clustering in an extended kindred at high risk of breast cancer. Evidence for a highly penetrant, autosomal dominant susceptibility allele for breast cancer in a high-risk family and the general population suggests that high-risk families can serve as models for understanding breast cancer in the population as a whole.

  19. Mutations in INF2 Are a Major Cause of Autosomal Dominant Focal Segmental Glomerulosclerosis

    PubMed Central

    Boyer, Olivia; Benoit, Geneviève; Gribouval, Olivier; Nevo, Fabien; Tête, Marie-Josèphe; Dantal, Jacques; Gilbert-Dussardier, Brigitte; Touchard, Guy; Karras, Alexandre; Presne, Claire; Grunfeld, Jean-Pierre; Legendre, Christophe; Joly, Dominique; Rieu, Philippe; Mohsin, Nabil; Hannedouche, Thierry; Moal, Valérie; Gubler, Marie-Claire; Broutin, Isabelle; Mollet, Géraldine

    2011-01-01

    The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif–containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLC?1, the identification of mutations that may alter the putative INF2–IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS. PMID:21258034

  20. Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts

    PubMed Central

    Ferrera, Denise; Canale, Claudio; Marotta, Roberto; Mazzaro, Nadia; Gritti, Marta; Mazzanti, Michele; Capellari, Sabina; Cortelli, Pietro; Gasparini, Laura

    2014-01-01

    The architecture and structural mechanics of the cell nucleus are defined by the nuclear lamina, which is formed by A- and B-type lamins. Recently, gene duplication and protein overexpression of lamin B1 (LB1) have been reported in pedigrees with autosomal dominant leukodystrophy (ADLD). However, how the overexpression of LB1 affects nuclear mechanics and function and how it may result in pathology remain unexplored. Here, we report that in primary human skin fibroblasts derived from ADLD patients, LB1, but not other lamins, is overexpressed at the nuclear lamina and specifically enhances nuclear stiffness. Transient transfection of LB1 in HEK293 and neuronal N2a cells mimics the mechanical phenotype of ADLD nuclei. Notably, in ADLD fibroblasts, reducing LB1 protein levels by shRNA knockdown restores elasticity values to those indistinguishable from control fibroblasts. Moreover, isolated nuclei from ADLD fibroblasts display a reduced nuclear ion channel open probability on voltage-step application, suggesting that biophysical changes induced by LB1 overexpression may alter nuclear signaling cascades in somatic cells. Overall, the overexpression of LB1 in ADLD cells alters nuclear mechanics and is linked to changes in nuclear signaling, which could help explain the pathogenesis of this disease.—Ferrera, D., Canale, C., Marotta, R., Mazzaro, N., Gritti, M., Mazzanti, M., Capellari, S., Cortelli, P., Gasparini, L. Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts. PMID:24858279

  1. Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts

    PubMed Central

    Nandrot, E; Slingsby, C; Basak, A; Cherif-Chefchaoun..., M; Benazzouz, B; Hajaji, Y; Boutayeb, S; Gribouval, O; Arbogast, L; Berraho, A; Abitbol, M; Hilal, L

    2003-01-01

    Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33–35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction ?=0) was obtained for marker D2S2208 near the ?-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts. PMID:12676897

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

    SciTech Connect

    Goliath, R.; Janssens, P.; Beighton, P. [Univ. of Cape Town (South Africa)] [and others

    1995-10-01

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

  3. Twinkle mutations in two Chinese families with autosomal dominant progressive external ophthalmoplegia.

    PubMed

    Ji, Kunqian; Liu, Kaiming; Lin, Pengfei; Wen, Bing; Luo, Yue-Bei; Zhao, Yuying; Yan, Chuanzhu

    2014-03-01

    Autosomal dominant progressive external ophthalmoplegia (adPEO) is a common adult onset mitochondrial disease caused by mutations in nuclear DNA (nDNA). Twinkle is one of the nuclear genes associated with adPEO. Clinical, histochemical, and molecular genetics findings of 6 patients from two Chinese families with adPEO were reported. Two point mutations (c.1423G>C, p.A475P and c.1061G>C, p.R354P) of Twinkle gene have been found. Multiple mtDNA deletions were also detected in patient's muscle and fibroblasts. This study confirms two mutations in Chinese adPEO families, which were first reported in the Chinese population. PMID:24091712

  4. Autosomal dominant nemaline myopathy caused by a novel alpha-tropomyosin 3 mutation.

    PubMed

    Kiphuth, I C; Krause, S; Huttner, H B; Dekomien, G; Struffert, T; Schröder, R

    2010-04-01

    Nemaline myopathy (NM) is a genetically and clinically heterogenous muscle disorder, which is myopathologically characterized by nemaline bodies. Mutations in six genes have been reported to cause NM: Nebulin (NEB Pelin 1999), alpha-skeletal muscle actin (ACTA1 Nowak 1999), alpha-slow tropomyosin (TPM3 Laing 1995), beta-tropomyosin (TPM2 Donner 2002), slow troponin T (TNNT1 Johnston 2000) and cofilin 2 (CFL2 Agrawal 2007). The majority of cases are due to mutation in NEB and ACTA1. We report on the clinical, myopathological and muscle MRI findings in a German family with autosomal dominant NM due to a novel pathogenic TPM3 mutation (p.Ala156Thr). PMID:20012312

  5. Autosomal dominant lateral temporal epilepsy (ADLTE): absence of chromosomal rearrangements in LGI1 gene.

    PubMed

    Manna, Ida; Mumoli, Laura; Labate, Angelo; Citrigno, Luigi; Ferlazzo, Edoardo; Aguglia, Umberto; Quattrone, Aldo; Gambardella, Antonio

    2014-03-01

    Mutations of leucine-rich, glioma inactivated 1 (LGI1) gene are found in about half of the families with autosomal dominant lateral temporal epilepsy (ADLTE). More recently a LGI1 heterozygous microdeletion was found in a single ADLTE family, suggesting that submicroscopic chromosomal abnormalities should be investigated in cases negative for LGI1 mutations. This study examines whether microdeletions and duplications of the LG1 gene occurred in eight ADLTE families and 20 sporadic patients that were negative for LGI1 mutations. Multiplex ligation-dependent probe amplification (MLPA) was applied to detect potential deletions and duplications of LGI1 gene. In all patients, MLPA analysis did not reveal any pathogenic changes in the LGI1 gene. Chromosomal rearrangements involving the LGI1 gene were not identified in our series of familial or sporadic LTE. These results further illustrate the considerable genetic heterogeneity for ADLTE, despite the relatively homogeneous clinical picture. There are as yet undiscovered mechanisms underlying ADLTE. PMID:24315022

  6. Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

    PubMed Central

    Harris, Peter C.; Torres, Vicente E.

    2014-01-01

    Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments. PMID:24892705

  7. Autosomal dominant type I osteopetrosis is related with iatrogenic fractures in arthroplasty.

    PubMed

    van Hove, Ruud P; de Jong, Tjitte; Nolte, Peter A

    2014-12-01

    Autosomal dominant osteopetrosis (ADO) is a sclerotic bone disorder due to failure of osteoclasts. ADO poses difficulties during arthroplasty because of the increased chance for iatrogenic fractures due to sclerotic bone. ADO is divided into two types based on radiological findings, fracture risk, and osteoclast activity. These differences suggest less brittle bone in patients with ADO I compared to that of patients with ADO II, which suggests a smaller chance of preoperative fractures during cementless arthroplasty in ADO I compared with that in ADO II. A case of cementless total knee arthroplasty in a patient with ADO I is presented. Total hip arthroplasty was performed during follow-up, and known major problems related to ADO II were experienced. Therefore, the differences between ADO I and ADO II may not be clinically relevant for an iatrogenic fracture during arthroplasty in patients with ADO. PMID:25436076

  8. Hereditary thermosensitive neuropathy: an autosomal dominant disorder of the peripheral nervous system.

    PubMed

    Magy, L; Birouk, N; Vallat, J M; Gouider, R; Maisonobe, T; Bouche, P; Lyon-Caen, O; Fontaine, B

    1997-06-01

    We report the clinical and electrophysiologic characteristics of eight patients (four men and four women) with a hereditary neuropathy with probable thermosensitivity (HTN) of autosomal dominant inheritance. Patients presented reversible episodes of ascending muscle weakness, paresthesiae, and areflexia apparently triggered by an elevation of body temperature over 38.5 degrees C. Mean age at onset was 13 +/- 12 (SD; range 6 to 43). Four patients had suffered up to five attacks. EMG and pathologic findings were compatible with a reversible demyelinating neuropathy such as Guillain-Barré syndrome. We excluded loci causing other hereditary demyelinating neuropathies, such as Charcot-Marie-Tooth disease type I (CMT type I) and hereditary neuropathy with liability to pressure palsies (HNPP), by linkage analysis; thus, HTN is not allelic to either CMT type I or to HNPP. PMID:9191787

  9. Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features

    PubMed Central

    Rosanoff, Michael J.; Ottman, Ruth

    2008-01-01

    Background: Assessment of the penetrance of disease-causing mutations is extremely important for developing clinical applications of gene discovery, such as genetic testing and counseling. Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) have been identified in about 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF), but estimates of LGI1 mutation penetrance have ranged widely, from 50 to 85%. The current study aimed to provide a more precise estimate of LGI1 mutation penetrance. Methods: We analyzed data from all 24 previously published ADPEAF families with mutations in LGI1. To estimate penetrance, we used the information from the published pedigree figures to determine the proportion of obligate carriers who were affected. We assessed whether penetrance was associated with the total number of affected individuals in each family, or mutation type (truncating or missense) or location within the gene. We also compared penetrance in males and females, and among different generations within the families. Results: Overall penetrance was 67% (95% CI 55–77%), and did not vary according to mutation type or location within the gene. Penetrance was greater in families with more affected individuals, but this trend was not significant. Penetrance did not differ by gender but increased with advancing generation, probably because of limited information about early generations. Conclusions: Our results suggest that about two-thirds of individuals who inherit a mutation in LGI1 will develop epilepsy. This probably overestimates the true penetrance in the population because it is based on data from families containing multiple affected individuals. GLOSSARY ADPEAF = autosomal dominant partial epilepsy with auditory features; ANOVA = analysis of variance. PMID:18711109

  10. LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy.

    PubMed

    Nobile, Carlo; Michelucci, Roberto; Andreazza, Simonetta; Pasini, Elena; Tosatto, Silvio C E; Striano, Pasquale

    2009-04-01

    Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat (LRR) and C-terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype-phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed. PMID:19191227

  11. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

    PubMed Central

    2012-01-01

    Background Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family. Methods and Results Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified. Conclusions ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum. PMID:22986007

  12. A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease

    PubMed Central

    Nicolaou, Paschalis; Cianchetti, Carlo; Minaidou, Anna; Marrosu, Giovanni; Zamba-Papanicolaou, Eleni; Middleton, Lefkos; Christodoulou, Kyproula

    2013-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33–q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G>A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance. PMID:22781092

  13. A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.

    PubMed

    Nicolaou, Paschalis; Cianchetti, Carlo; Minaidou, Anna; Marrosu, Giovanni; Zamba-Papanicolaou, Eleni; Middleton, Lefkos; Christodoulou, Kyproula

    2013-02-01

    Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G>A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance. PMID:22781092

  14. Localization of genes for autosomal dominant congenital cataracts to chromosomes 2 and 17

    SciTech Connect

    Ayyagari, R.; Scott, M.; Wozencraft, L. [National Eye Institute, Bethesda, MD (United States)] [and others

    1994-09-01

    Linkage analysis was performed in a seven generation family in which 28 of 52 individuals examined had autosomal dominant congenital pulverulent cataracts and a five generation family in which 10 of 17 individuals examined had autosomal dominant congenital zonular cataracts with sutural opacities. Initial analysis with 21 microsatellite markers in 7 candidate gene regions localized the pulverulent cataract locus to the long arm of chromosome 2 near the {beta}B2-crystallin gene. A lod score of 3.6 was obtained with D2S72 ({theta}=0.12), 3.5 with CRYG ({theta}=0.06), 3.4 with ({theta}=0.05), 2.0 with D2S117 ({theta}=0.22) and 6.6 with D2S128 ({theta}=0.05). Multipoint linkage analysis gave Zmax=4.2 at D2S157 with a one lod confidence interval covering 19 cM. The closest flanking markers showing obligate recombinants are D2S157 and D2S173. The zonular cataract locus was mapped to chromosome 2 near the {gamma}-crystallin gene cluster. A maximum lod score of 3.8 was obtained with D17S805 ({theta}=0.0), 2.1 with D17S798 ({theta}=0.60), and 3.7 with NF1 ({theta}=0.0). Multipoint analysis showed Zmax=3.81 at D17S805 with a one lod confidence interval covering 17 cM based on the Genethon map, localizing cataracts between markers D17S799 and D17S800. Further efforts are being directed at refining the localization of these cataract loci and examining the nearby crystallin genes for possible mutations.

  15. Prevalence of Disease-Causing Mutations in Families with Autosomal Dominant Retinitis Pigmentosa

    PubMed Central

    Sullivan, Lori S.; Bowne, Sara J.; Birch, David G.; Hughbanks-Wheaton, Dianna; Heckenlively, John R.; Lewis, Richard Alan; Garcia, Charles A.; Ruiz, Richard S.; Blanton, Susan H.; Northrup, Hope; Gire, Anisa I.; Seaman, Robyn; Duzkale, Hatice; Spellicy, Catherine J.; Zhu, Jingya; Shankar, Suma P.; Daiger, Stephen P.

    2008-01-01

    Purpose To survey families with clinical evidence of autosomal dominant retinitis pigmentosa (adRP) for mutations in genes known to cause adRP. Methods Two hundred adRP families, drawn from a cohort of more than 400 potential families, were selected by analysis of pedigrees. Minimum criteria for inclusion in the adRP cohort included either evidence of at least three generations of affected individuals or two generations with evidence of male-to-male transmission. Probands from each family were screened for mutations in 13 genes known to cause adRP: CA4, CRX, FSCN2, IMPDH1, NRL, PRPF3 (RP18), PRPF8 (RP13), PRPF31 (RP11), RDS, RHO, ROM1, RP1, and RP9. Families without mutations in autosomal genes and in which an X-linked mode of inheritance could not be excluded were tested for mutations in ORF 15 of X-linked RPGR. Potentially pathogenic variants were evaluated based on a variety of genetic and computational criteria, to confirm or exclude pathogenicity. Results A total of 82 distinct, rare (nonpolymorphic) variants were detected among the genes tested. Of these, 57 are clearly pathogenic based on multiple criteria, 10 are probably pathogenic, and 15 are probably benign. In the cohort of 200 families, 94 (47%) have one of the clearly pathogenic variants and 10 (5%) have one of the probably pathogenic variants. One family (0.5%) has digenic RDS-ROM1 mutations. Two families (1%) have a pathogenic RPGR mutation, indicating that families with apparent autosomal transmission of RP may actually have X-linked genetic disease. Thus, 107 families (53.5%) have mutations in known genes, leaving 93 whose underlying cause is still unknown. Conclusions Together, the known adRP genes account for retinal disease in approximately half of the families in this survey, mostly Americans of European origin. Among the adRP genes, IMPDH1, PRPF8, PRPF31, RDS, RHO, and RP1 each accounts for more than 2% of the total; CRX, PRPF3, and RPGR each accounts for roughly 1%. Disease-causing mutations were not found in CA4, FSCN2, NRL, or RP9. Because some mutations are frequent and some regions are more likely to harbor mutations than others, more than two thirds of the detected mutations can be found by screening less than 10% of the total gene sequences. Among the remaining families, mutations may lie in regions of known genes that were not tested, mutations may not be detectable by PCR-based sequencing, or other loci may be involved. PMID:16799052

  16. Molecular genetics of autosomal-dominant demyelinating Charcot-Marie-Tooth disease.

    PubMed

    Houlden, Henry; Reilly, Mary M

    2006-01-01

    Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of disorders and is the most common inherited neuromuscular disorder, with an estimated overall prevalence of 17-40/10,000. Although there has been major advances in the understanding of the genetic basis of CMT in recent years, the most useful classification is still a neurophysiological classification that divides CMT into type 1 (demyelinating; median motor conduction velocity < 38 m/s) and type 2 (axonal; median motor conduction velocity > 38 m/s). An intermediate type is also increasingly being described. Inheritance can be autosomal-dominant (AD), X-linked, or autosomal-recessive (AR). AD CMT1 is the most common type of CMT and was the first form of CMT in which a causative gene was described. This review provides an up-to-date overview of AD CMT1 concentrating on the molecular genetics as the clinical, neurophysiological, and pathological features have been covered elsewhere. Four genes (PMP22, MPZ, LITAF, and EGR2) have been described in the last 15 yr associated with AD CMTI and a further gene (NEFL), originally described as causing AD CMT2 can also cause AD CMT1 (by neurophysiological criteria). Studies have shown many of these genes, when mutated, can cause a wide range of CMT phenotypes from the relatively mild CMT1 to the more severe Dejerine-Sottas disease and congenital hypomyelinating neuropathy, and even in some cases axonal CMT2. This review discusses what is known about these genes and in particular how they cause a peripheral neuropathy, when mutated. PMID:16775366

  17. Mutation Conferring Apical-Targeting Motif on AE1 Exchanger Causes Autosomal Dominant Distal RTA

    PubMed Central

    Fry, Andrew C.; Su, Ya; Yiu, Vivian; Cuthbert, Alan W.; Trachtman, Howard

    2012-01-01

    Mutations in SLC4A1 that mislocalize its product, the chloride/bicarbonate exchanger AE1, away from its normal position on the basolateral membrane of the ?-intercalated cell cause autosomal dominant distal renal tubular acidosis (dRTA). We studied a family exhibiting dominant inheritance and defined a mutation (AE1-M909T) that affects the C terminus of AE1, a region rich in potential targeting motifs that are incompletely characterized. Expression of AE1-M909T in Xenopus oocytes confirmed preservation of its anion exchange function. Wild-type GFP-tagged AE1 localized to the basolateral membrane of polarized MDCK cells, but AE1-M909T localized to both the apical and basolateral membranes. Wild-type AE1 trafficked directly to the basolateral membrane without apical passage, whereas AE1-M909T trafficked to both cell surfaces, implying the gain of an apical-targeting signal. We found that AE1-M909T acquired class 1 PDZ ligand activity that the wild type did not possess. In summary, the AE1-M909T mutation illustrates the role of abnormal targeting in dRTA and provides insight into C-terminal motifs that govern normal trafficking of AE1. PMID:22518001

  18. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial.

    PubMed

    Mills, S M; Mallmann, J; Santacruz, A M; Fuqua, A; Carril, M; Aisen, P S; Althage, M C; Belyew, S; Benzinger, T L; Brooks, W S; Buckles, V D; Cairns, N J; Clifford, D; Danek, A; Fagan, A M; Farlow, M; Fox, N; Ghetti, B; Goate, A M; Heinrichs, D; Hornbeck, R; Jack, C; Jucker, M; Klunk, W E; Marcus, D S; Martins, R N; Masters, C M; Mayeux, R; McDade, E; Morris, J C; Oliver, A; Ringman, J M; Rossor, M N; Salloway, S; Schofield, P R; Snider, J; Snyder, P; Sperling, R A; Stewart, C; Thomas, R G; Xiong, C; Bateman, R J

    2013-10-01

    The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described. PMID:24016464

  19. Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial

    PubMed Central

    Mills, S.M.; Mallmann, J.; Santacruz, A.M.; Fuqua, A.; Carril, M.; Aisen, P.S.; Althage, M.C.; Belyew, S.; Benzinger, T.L.; Brooks, W.S.; Buckles, V.D.; Cairns, N.J.; Clifford, D.; Danek, A.; Fagan, A.M.; Farlow, M.; Fox, N.; Ghetti, B.; Goate, A.M.; Heinrichs, D.; Hornbeck, R.; Jack, C.; Jucker, M.; Klunk, W.E.; Marcus, D.S.; Martins, R.N.; Masters, C.M.; Mayeux, R.; McDade, E.; Morris, J.C.; Oliver, A.; Ringman, J.M.; Rossor, M.N.; Salloway, S.; Schofield, P.R.; Snider, J.; Snyder, P.; Sperling, R.A.; Stewart, C.; Thomas, R.G.; Xiong, C.; Bateman, R.J.

    2013-01-01

    The Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer’s disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer’s disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described. PMID:24016464

  20. Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: A longitudinal study

    Microsoft Academic Search

    Godela M. Fick-Brosnahan; Mark M. Belz; Kim K. McFann; Ann M. Johnson; Robert W. Schrier

    2002-01-01

    In autosomal dominant polycystic kidney disease (ADPKD), renal function remains normal for many years into adult life while cysts form and expand progressively, starting in childhood. The longitudinal relationships between renal volume growth, hypertension, and renal function loss have not been examined in detail. At the University of Colorado (Denver, CO), 229 adult subjects with ADPKD participated in a longitudinal

  1. Reduction of Inner Retinal Thickness in Patients with Autosomal Dominant Optic Atrophy Associated with OPA1 Mutations

    Microsoft Academic Search

    Yasuki Ito; Makoto Nakamura; Tomomi Yamakoshi; Jian Lin; Hiroshi Yatsuya; Hiroko Terasaki

    2007-01-01

    PURPOSE. To determine the morphologic changes in the retina in the macula and around the optic disc in patients with autosomal dominant optic atrophy (ADOA) associated with a mutation in the OPA1 gene. METHODS. Cross-sectional images of the macular area of the retina were obtained by optical coherence tomography (OCT) in patients with ADOA who had a heterozygous mutation in

  2. Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study

    ERIC Educational Resources Information Center

    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-01-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

  3. Autosomal Dominant Pseudohypoaldosteronism Type 1 in an Infant with Salt Wasting Crisis Associated with Urinary Tract Infection and Obstructive Uropathy

    PubMed Central

    Bowden, Sasigarn A.; Cozzi, Corin; Hickey, Scott E.; Thrush, Devon Lamb; Astbury, Caroline; Nuthakki, Sushma

    2013-01-01

    Type 1 pseudohypoaldosteronism (PHA1) is a salt wasting syndrome caused by renal resistance to aldosterone. Primary renal PHA1 or autosomal dominant PHA1 is caused by mutations in mineralocorticoids receptor gene (NR3C2), while secondary PHA1 is frequently associated with urinary tract infection (UTI) and/or urinary tract malformations (UTM). We report a 14-day-old male infant presenting with severe hyperkalemia, hyponatremic dehydration, metabolic acidosis, and markedly elevated serum aldosterone level, initially thought to have secondary PHA1 due to the associated UTI and posterior urethral valves. His serum aldosterone remained elevated at 5 months of age, despite resolution of salt wasting symptoms. Chromosomal microarray analysis revealed a deletion of exons 3–5 in NR3C2 in the patient and his asymptomatic mother who also had elevated serum aldosterone level, confirming that he had primary or autosomal dominant PHA1. Our case raises the possibility that some patients with secondary PHA1 attributed to UTI and/or UTM may instead have primary autosomal dominant PHA1, for which genetic testing should be considered to identify the cause, determine future recurrence risk, and possibly prevent the life-threatening salt wasting in a subsequent family member. Future clinical research is needed to investigate the potential overlapping between secondary PHA1 and primary autosomal dominant PHA1. PMID:24455331

  4. Mitochondrial Oxidative Phosphorylation Compensation May Preserve Vision in Patients with OPA1Linked Autosomal Dominant Optic Atrophy

    Microsoft Academic Search

    Nicole J. van Bergen; Jonathan G. Crowston; Lisa S. Kearns; Sandra E. Staffieri; Alex W. Hewitt; Amy C. Cohn; David A. Mackey; Ian A. Trounce; Janine Santos

    2011-01-01

    Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and

  5. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Two novel mutations in the NOTCH3 gene in Chinese

    Microsoft Academic Search

    Yi-Chung Lee; An-Hang Yang; Hsiu-Chih Liu; Wen-Jang Wong; Yi-Chun Lu; Ming-Hon Chang; Bing-Wen Soong

    2006-01-01

    BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations, usually localized to exons 3 and 4, and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, there has been only limited information about CADASIL in Chinese population.

  6. Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India

    PubMed Central

    Sinha, K; Worth, P; Jha, D; Sinha, S; Stinton, V; Davis, M; Wood, N; Sweeney, M; Bhatia, K

    2004-01-01

    Objective: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India. Methods: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2. Results: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described. Conclusions: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect. PMID:14966163

  7. Further evidence for a locus for autosomal dominant juvenile glaucoma on chromosome 1q and evidence for genetic heterogeneity

    SciTech Connect

    Wiggs, J.; Paglinauan, C.; Stawski, S. [New England Medical Center, Boston, MA (United States)] [and others

    1994-09-01

    Glaucoma is a term used to describe a group of disorders which have in common a characteristic degeneration of the optic nerve associated with typical visual field defects and usually associated with elevated intraocular pressure. Two percent of white Americans and 6-10% of black Americans are affected by the disease. Compelling data indicate that susceptibility to many types of glaucoma is inherited. Hereditary juvenile glaucoma is one form of glaucoma that develops in children and is inherited as an autosomal dominant trait with high penetrance. Using a single large Caucasian pedigree affected with autosomal dominant juvenile glaucoma, Sheffield discovered positive linkage to a group of markers that map to a 30 cM region on the long arm of chromosome 1 (1q21-q31). We have subsequently identified three unrelated Caucasian pedigrees affected with autosomal dominant juvenile glaucoma that also demonstrate linkage to this region on chromosome 1, with the highest combined lod score of 5.12 at theta = .05 for marker D1S218. The identification of critical recombinant individuals in our three pedigrees has allowed us to further localize the disease gene to a 12 cM region between markers D1S242 and D1S431. In addition, we have identified several pedigrees which do not demonstrate linkage to chromosome 1q, including a black family affected with autosomal dominant juvenile glaucoma that is indistinguishable clinically from the disorder affecting the caucasian pedigrees and three pedigrees affected with pigmentary dispersion syndrome, a form of glaucoma that also affects the juvenile population and is also inherited as an autosomal dominant trait. These findings provide evidence for genetic heterogeneity in juvenile glaucoma.

  8. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.

    PubMed

    Kalachikov, Sergey; Evgrafov, Oleg; Ross, Barbara; Winawer, Melodie; Barker-Cummings, Christie; Martinelli Boneschi, Filippo; Choi, Chang; Morozov, Pavel; Das, Kamna; Teplitskaya, Elita; Yu, Andrew; Cayanis, Eftihia; Penchaszadeh, Graciela; Kottmann, Andreas H; Pedley, Timothy A; Hauser, W Allen; Ottman, Ruth; Gilliam, T Conrad

    2002-03-01

    The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies. PMID:11810107

  9. Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy

    PubMed Central

    Zhou, Yu-Dong; Lee, Sanghoon; Jin, Zhe; Wright, Moriah; Smith, Stephen E. P.; Anderson, Matthew P.

    2009-01-01

    A subset of central glutamatergic synapses are coordinatelypruned and matured by unresolved mechanisms during early postnatal life. We report that human epilepsy gene LGI1, mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We introduced full-length genes encoding (1) ADLTE truncated mutant LGI1 (835delC) and (2) excess wild-type LGI1 proteins into transgenic mice. We discovered that the normal postnatal Kv1 channel-dependent down-regulation of presynaptic release probability and Src kinase-related decrease of postsynaptic NR2B/NR2A ratio were arrested by ADLTE mutant LGI1, and contrastingly, were magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial GABAA receptor blockade. Thus, LGI1 represents the first human gene mutated to promote epilepsy through impaired glutamatergic circuit maturation. PMID:19701204

  10. Novel targets for the treatment of autosomal dominant polycystic kidney disease

    PubMed Central

    Belibi, Franck A; Edelstein, Charles L

    2010-01-01

    Importance of the field Autosomal dominant (AD) polycystic kidney disease (PKD) is the most common life-threatening hereditary disorder. There is currently no therapy that slows or prevents cyst formation and kidney enlargement in humans. An increasing number of animal studies have advanced our understanding of molecular and cellular targets of PKD. Areas covered in the review The purpose of this review is to summarize the molecular and cellular targets involved in cystogenesis and to update on the promising therapies that are being developed and tested based on knowledge of these molecular and cellular targets. What the reader will gain Insight into the pathogenesis of PKD and how a better understanding of the pathogenesis of PKD has led to the development of potential therapies to inhibit cyst formation and/or growth and improve kidney function. Take home message The results of animal studies in PKD have led to the development of clinical trials testing potential new therapies to reduce cyst formation and/or growth. A vasopressin V2 receptor antagonist, mTOR inhibitors, blockade of the renin–angiotensin system and statins that reduce cyst formation and improve renal function in animal models of PKD are being tested in interventional studies in humans. PMID:20141351

  11. Trends in the Management and Outcomes of Kidney Transplantation for Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Patel, Madhukar S.; Kandula, Praveen; Wojciechowski, David; Markmann, James F.; Vagefi, Parsia A.

    2014-01-01

    Background. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder leading to end-stage renal failure. The objective of this study was to evaluate a longitudinal experience of kidney transplantation for ADPKD. Methods. A single center retrospective review of patients undergoing kidney transplantation was conducted, with comparisons across two time periods: early (02/2000–04/2007, n = 66) and late (04/2007–08/2012, n = 67). Results. Over the 13.5-year study period, 133 patients underwent transplantation for ADPKD. Overall, no significant difference between the early and late group with regard to intraoperative complications, need for reoperation, readmissions within 30 days, delayed graft function, and mortality was noted. There was a trend towards increase in one-year graft survival (early 93.1% versus late 100%, P = 0.05). In the early group, 67% of recipients had undergone aneurysm screening, compared to 91% of recipients in the late group (P < 0.001). Conclusions. This study demonstrates consistent clinical care with a trend towards improved rates of one-year graft survival. Interestingly, we also note a significantly higher use of cerebral imaging over time, with the majority that were detected requiring surgical intervention which may justify the current practice of nonselective radiological screening until improved screening criteria are developed. PMID:25165573

  12. Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients

    PubMed Central

    Lai, Xianyin; Bacallao, Robert L.; Blazer-Yost, Bonnie L.; Hong, David; Mason, Stephen B.; Witzmann, Frank A.

    2010-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by localized autonomous cellular proliferation, fluid accumulation within the cysts, and intraparenchymal fibrosis of the kidney. Little is known about the cyst fluid's protein composition. We hypothesized that the complex collection of cyst fluid proteins (cyst fluid proteome) plays a major role in cyst formation/maintenance and contains yet unknown diagnostic and mechanistic features that are common to all forms of PKD. We analyzed five kidney cyst fluids from four patients with ADPKD. Tryptic peptides from plasma-protein immunodepleted (ProteoPrep®) and undepleted cyst fluid samples were analyzed by LC-MS/MS. Proteins were identified by SEQUEST™ and validated via the Trans-Proteomic Pipeline; 391 proteins were identified with >90% confidence; 251 of them in undepleted and 362 in immunodepleted samples. Immunodepletion removed >94% of the cyst fluid protein. A surprisingly large and functionally diverse number of proteins common to most cysts were identified. These proteins may be of mechanistic interest and include Ig ?, ?, and fragments; complement components; vitronectin; orosomucoid; prostaglandin D2 synthase; vitamin D-binding protein; clusterin; SERPIN family proteins; hemopexin; and fetuin-A. Additionally, these results suggest that further prefractionation and enhanced chromatographic separation of tryptic peptides is likely to expose an even greater number of relevant proteins. PMID:20411046

  13. A Novel Autosomal Dominant Inclusion Body Myopathy Linked to 7q22.1-31.1

    PubMed Central

    Wang, Min; Li, Xin; Zhang, Feng; Li, Yun; Zhang, Meng; Da, Yuwei; Yu, Jun; Jia, Jianping

    2012-01-01

    We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15–21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1–31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder. PMID:22723986

  14. Molecular diagnosis of autosomal dominant polycystic kidney disease using next-generation sequencing.

    PubMed

    Tan, Adrian Y; Michaeel, Alber; Liu, Genyan; Elemento, Olivier; Blumenfeld, Jon; Donahue, Stephanie; Parker, Tom; Levine, Daniel; Rennert, Hanna

    2014-03-01

    Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2. However, genetic analysis is complicated by six PKD1 pseudogenes, large gene sizes, and allelic heterogeneity. We developed a new clinical assay for PKD gene analysis using paired-end next-generation sequencing (NGS) by multiplexing individually bar-coded long-range PCR libraries and analyzing them in one Illumina MiSeq flow cell. The data analysis pipeline has been optimized and automated with Unix shell scripts to accommodate variant calls. This approach was validated using a cohort of 25 patients with ADPKD previously analyzed by Sanger sequencing. A total of 250 genetic variants were identified by NGS, spanning the entire exonic and adjacent intronic regions of PKD1 and PKD2, including all 16 pathogenic mutations. In addition, we identified three novel mutations in a mutation-negative cohort of 24 patients with ADPKD previously analyzed by Sanger sequencing. This NGS method achieved sensitivity of 99.2% (95% CI, 96.8%-99.9%) and specificity of 99.9% (95% CI, 99.7%-100.0%), with cost and turnaround time reduced by as much as 70%. Prospective NGS analysis of 25 patients with ADPKD demonstrated a detection rate comparable with Sanger standards. In conclusion, the NGS method was superior to Sanger sequencing for detecting PKD gene mutations, achieving high sensitivity and improved gene coverage. These characteristics suggest that NGS would be an appropriate new standard for clinical genetic testing of ADPKD. PMID:24374109

  15. A novel CRYBB2 missense mutation causing congenital autosomal dominant cataract in an Italian family.

    PubMed

    Faletra, Flavio; d'Adamo, Adamo Pio; Pensiero, Stefano; Athanasakis, Emmanouil; Catalano, Dario; Bruno, Irene; Gasparini, Paolo

    2013-01-01

    Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC. PMID:22846113

  16. A Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 11p15.4

    PubMed Central

    Freed, Lisa A.; Acierno Jr., James S.; Dai, Daisy; Leyne, Maire; Marshall, Jane E.; Nesta, Francesca; Levine, Robert A.; Slaugenhaupt, Susan A.

    2003-01-01

    Mitral valve prolapse (MVP) is a common cardiovascular abnormality in the United States, occurring in ?2.4% of the general population. Clinically, patients with MVP exhibit fibromyxomatous changes in one or both of the mitral leaflets that result in superior displacement of the leaflets into the left atrium. Although often clinically benign, MVP can be associated with important accompanying sequelae, including mitral regurgitation, bacterial endocarditis, congestive heart failure, atrial fibrillation, and even sudden death. MVP is genetically heterogeneous and is inherited as an autosomal dominant trait that exhibits both sex- and age-dependant penetrance. In this report, we describe the results of a genome scan and show that a locus for MVP maps to chromosome 11p15.4. Multipoint parametric analysis performed by use of GENEHUNTER gave a maximum LOD score of 3.12 for the chromosomal region immediately surrounding the four-marker haplotype D11S4124-D11S2349-D11S1338-D11S1323, and multipoint nonparametric analysis (NPL) confirms this finding (NPL=38.59; P=.000397). Haplotype analysis across this region defines a 4.3-cM region between the markers D11S1923 and D11S1331 as the location of a new MVP locus, MMVP2, and confirms the genetic heterogeneity of this disorder. The discovery of genes involved in the pathogenesis of this common disease is crucial to understanding the marked variability in disease expression and mortality seen in MVP. PMID:12707861

  17. Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK

    PubMed Central

    Wang, Hong-Ying; Ma, Chi A.; Zhao, Yongge; Fan, Xiying; Zhou, Qing; Edmonds, Pamela; Uzel, Gulbu; Oliveira, Joao Bosco; Orange, Jordan; Jain, Ashish

    2013-01-01

    Mutations in the TNF family of proteins have been associated with inherited forms of immune deficiency. Using an array-based sequencing assay, we identified an autosomal-dominant deficiency in TNF-like weak inducer of apoptosis (TWEAK; TNFSF12) in a kindred with recurrent infection and impaired antibody responses to protein and polysaccharide vaccines. This mutation occurs in the sixth exon of TWEAK and results in the amino acid substitution R145C within the conserved TNF-homology domain of the full-length protein. TWEAK mutant protein formed high molecular weight aggregates under nonreducing conditions, suggesting an increased propensity for intermolecular interactions. As a result, mutant TWEAK associated with B-cell–activating factor (BAFF) protein and down-regulated the BAFF-mediated activation of the noncanonical NF-?B pathway through inhibition of p100 processing to p52, resulting in inhibition of BAFF-dependent B-cell survival and proliferation. As BAFF mediates T-cell–independent isotype switching and B-cell survival, our data implicate TWEAK as a disease-susceptibility gene for a humoral immunodeficiency. PMID:23493554

  18. A recurrent deletion mutation in OPA1 causes autosomal dominant optic atrophy in a Chinese family

    PubMed Central

    Zhang, Liping; Shi, Wei; Song, Liming; Zhang, Xiao; Cheng, Lulu; Wang, Yanfang; Ge, Xianglian; Li, Wei; Zhang, Wei; Min, Qingjie; Jin, Zi-Bing; Qu, Jia; Gu, Feng

    2014-01-01

    Autosomal dominant optic atrophy (ADOA) is the most frequent form of hereditary optic neuropathy and occurs due to the degeneration of the retinal ganglion cells. To identify the genetic defect in a family with putative ADOA, we performed capture next generation sequencing (CNGS) to screen known retinal disease genes. However, six exons failed to be sequenced by CNGS in optic atrophy 1 gene (OPA1). Sequencing of those exons identified a 4?bp deletion mutation (c.2983-1_2985del) in OPA1. Furthermore, we sequenced the transcripts of OPA1 from the patient skin fibroblasts and found there is six-nucleotide deletion (c.2984-c.2989, AGAAAG). Quantitative-PCR and Western blotting showed that OPA1 mRNA and its protein expression have no obvious difference between patient skin fibroblast and control. The analysis of protein structure by molecular modeling suggests that the mutation may change the structure of OPA1 by formation of an alpha helix protruding into an existing pocket. Taken together, we identified an OPA1 mutation in a family with ADOA by filling the missing CNGS data. We also showed that this mutation affects the structural intactness of OPA1. It provides molecular insights for clinical genetic diagnosis and treatment of optic atrophy. PMID:25374051

  19. 50 years to diagnosis: Autosomal dominant tubular aggregate myopathy caused by a novel STIM1 mutation.

    PubMed

    Walter, Maggie C; Rossius, Martina; Zitzelsberger, Manuela; Vorgerd, Matthias; Müller-Felber, Wolfgang; Ertl-Wagner, Birgit; Zhang, Yaxin; Brinkmeier, Heinrich; Senderek, Jan; Schoser, Benedikt

    2015-07-01

    Tubular aggregates in human muscle biopsies have been reported to occur in a variety of acquired and hereditary neuromuscular conditions since 1964. Recently mutations in the gene encoding the main calcium sensor in the sarcoplasmic reticulum, stromal interaction molecule 1 (STIM1), have been identified as a cause of autosomal dominant tubular aggregate myopathy. We studied a German family with tubular aggregate myopathy and defined cellular consequences of altered STIM1 function. Both patients in our family had early progressive myopathy with proximal paresis of arm and leg muscles, scapular winging, ventilatory failure, joint contractures and external ophthalmoplegia. One patient had a well-documented disease course over 50 years. Sequencing of the STIM1 gene revealed a previously unreported missense mutation (c.242G>A; p.Gly81Asp) located in the first calcium binding EF domain. Functional characterization of the new STIM1 mutation by calcium imaging revealed that calcium influx was significantly increased in primary myoblasts of the index patient compared to controls pointing at a severe alteration of intracellular calcium homeostasis. This new family widens the spectrum of STIM1-associated myopathies to a more severe phenotype. PMID:25953320

  20. Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation

    PubMed Central

    Scoazec, Jean Yves; Wielders, Simone J. H.; Trzeciak, Christine; Hackeng, Tilman M.; Négrier, Claude; Hemker, H. Coenraad; Lindhout, Theo; Castoldi, Elisabetta

    2015-01-01

    We describe a family with an autosomal dominant disorder characterized by severe trauma- and surgery-related bleeding. The proband, who experienced life-threatening bleeding during a routine operation, had normal clotting times, but markedly reduced prothrombin consumption. Plasma levels of all coagulation factors and of the main coagulation inhibitors were normal. Thrombin generation at low triggers was severely impaired and mixing experiments suggested the presence of a coagulation inhibitor. Using whole exome sequencing, the underlying genetic defect was identified as the THBD c.1611C>A mutation (p.Cys537Stop), which predicts a truncated form of thrombomodulin that is shed from the vascular endothelium. The patient had decreased expression of endothelium-bound thrombomodulin, but extremely elevated levels of soluble thrombomodulin in plasma, impairing the propagation phase of coagulation via rapid activation of protein C and consequent inactivation of factors Va and VIIIa. The same thrombomodulin mutation has been recently described in an unrelated British family with strikingly similar features. PMID:25564403

  1. Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing

    PubMed Central

    Hopp, Katharina; Sikkink, Robert A.; Sundsbak, Jamie L.; Lee, Yean Kit; Kubly, Vickie; Eckloff, Bruce W.; Ward, Christopher J.; Winearls, Christopher G.; Torres, Vicente E.; Harris, Peter C.

    2012-01-01

    Mutations in two large multi-exon genes, PKD1 and PKD2, cause autosomal dominant polycystic kidney disease (ADPKD). The duplication of PKD1 exons 1–32 as six pseudogenes on chromosome 16, the high level of allelic heterogeneity, and the cost of Sanger sequencing complicate mutation analysis, which can aid diagnostics of ADPKD. We developed and validated a strategy to analyze both the PKD1 and PKD2 genes using next-generation sequencing by pooling long-range PCR amplicons and multiplexing bar-coded libraries. We used this approach to characterize a cohort of 230 patients with ADPKD. This process detected definitely and likely pathogenic variants in 115 (63%) of 183 patients with typical ADPKD. In addition, we identified atypical mutations, a gene conversion, and one missed mutation resulting from allele dropout, and we characterized the pattern of deep intronic variation for both genes. In summary, this strategy involving next-generation sequencing is a model for future genetic characterization of large ADPKD populations. PMID:22383692

  2. Morphological and Functional Features of Hepatic Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Alvaro, Domenico; Onori, Paolo; Alpini, Gianfranco; Franchitto, Antonio; Jefferson, Douglas M.; Torrice, Alessia; Cardinale, Vincenzo; Stefanelli, Fabrizio; Mancino, Maria Grazia; Strazzabosco, Mario; Angelico, Mario; Attili, Adolfo; Gaudio, Eugenio

    2008-01-01

    We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [3H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17?-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17?-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism. PMID:18202196

  3. Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease

    PubMed Central

    Onori, Paolo; Mancinelli, Romina; Franchitto, Antonio; Carpino, Guido; Renzi, Anastasia; Brozzetti, Stefania; Venter, Julie; Francis, Heather; Glaser, Shannon; Jefferson, Douglas M.; Alpini, Gianfranco; Gaudio, Eugenio

    2014-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). Aims To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. Methods Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. Results Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. Conclusion These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD. PMID:23617956

  4. Endothelial Nitric Oxide Synthase Gene Expression Is Associated with Hypertension in Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Kocyigit, Ismail; Taheri, Serpil; Sener, Elif Funda; Unal, Aydin; Eroglu, Eray; Öztürk, Fahir; Korkmaz, Kezban; Zararsiz, Gokmen; Imamoglu, Hakan; Sipahioglu, Murat Hayri; Tokgoz, Bulent; Oymak, Oktay

    2014-01-01

    Background/Aims Early occurrence of hypertension is the prominent feature of autosomal dominant polycystic kidney disease (ADPKD). The role of angiotensin-converting enzyme (ACE) gene polymorphism and endothelial nitric oxide synthase (eNOS) gene polymorphism in the clinical course of ADPKD is not well understood. However, data about the expression of these genes are lacking. Thus, we aimed to investigate the polymorphisms and expressions of both the ACE and eNOS genes that affect hypertension in ADPKD. Methods Whole blood samples were obtained from all participants. ACE and eNOS gene polymorphisms and their expressions were analyzed in 78 ADPKD patients and 30 controls. Gene expressions were assessed by quantitative real-time PCR. Twenty-four-hour blood pressure monitoring was performed for the diagnosis of hypertension in all study participants. Results eNOS expression and the estimated glomerular filtration rate were found to be significantly higher in ADPKD patients without hypertension than in those with hypertension. Each unit of increase in eNOS expression led to a 0.88-fold decrease (95% CI: 0.80-0.96) in the risk of hypertension in multiple logistic regression analysis. Conclusions eNOS gene expression is independently predictive of hypertension in the ADPKD population. This study showed, for the first time, a novel link between eNOS gene expression and hypertension in ADPKD. PMID:25737691

  5. A novel autosomal dominant inclusion body myopathy linked to 7q22.1-31.1.

    PubMed

    Lu, Yan; Li, Xingang; Wang, Min; Li, Xin; Zhang, Feng; Li, Yun; Zhang, Meng; Da, Yuwei; Yu, Jun; Jia, Jianping

    2012-01-01

    We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15-21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1-31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder. PMID:22723986

  6. Linkage of an autosomal dominant clefting syndrome (Van der Woude) to loci on chromosome Iq

    PubMed Central

    Murray, J. C.; Nishimura, D. Y.; Buetow, K. H.; Ardinger, H. H.; Spence, M. A.; Sparkes, R. S.; Falk, R. E.; Falk, P. M.; Gardner, R. J. M.; Harkness, E. M.; Glinski, L. P.; Pauli, R. M.; Nakamura, Y.; Green, P. P.; Schinzel, A.

    1990-01-01

    Van der Woude syndrome (VWS) is an autosomal dominant disorder in which affected individuals have one or more of the following manifestations: cleft lip, cleft palate, hypodontia, or paramedian lower-lip pits. VWS is a well-characterized example of a single-gene abnormality that disturbs normal craniofacial morphogenesis. As a first step in identifying genes involved in human development, we used a candidate-gene-and-region approach to look for a linkage to VWS. Six families with 3 or more generations of affected individuals were studied. Evidence for linkage (? = 0.02, lod score = 9.09) was found between the renin (REN) gene on 1q and VWS. Other linked loci included CR1, D1S58, and D1S53. The genes for laminin B2 (LAMB2), a basement-membrane protein, and for decay-accelerating factor (DAF) were studied as possible candidate genes on 1q. Recombinants between VWS and both LAMB2 and DAF excluded these genes from a causal role in the etiology of VWS for the families studied in this report. Multipoint linkage analysis indicated that the VWS locus was flanked by REN and D1S65 at a lod score of 10.83. This tight linkage with renin and other nearby loci provides a first step in identifying the molecular abnormality underlying this disturbance of human development. PMID:2309700

  7. Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene.

    PubMed

    Díaz-Otero, Fernando; Quesada, Mar; Morales-Corraliza, José; Martínez-Parra, Carlos; Gómez-Garre, Pilar; Serratosa, José M

    2008-03-01

    Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 600513) has been associated with mutations in the genes coding for the alfa-4 (CHRNA4), beta-2 (CHRNB2), and alpha-2 (CHRNA2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) and for the corticotropin-releasing hormone (CRH). A four-generation ADNFLE family with six affected members was identified. All affected members presented the clinical characteristics of ADNFLE. Interictal awake and sleep EEG recordings showed no epileptiform abnormalities. Ictal video-EEG recordings showed focal seizures with frontal lobe semiology. Mutation analysis of the CHRNB2 gene revealed a c.859G>A transition (Val287Met) within the second transmembrane domain, identical to that previously described in a Scottish ADNFLE family. To our knowledge, this is the third family reported presenting a mutation in CHRNB2. The clinical phenotype appears similar to that described with mutations in CHRNA4, suggesting that mutations in these two subunits lead to similar functional alterations of the nAChR. PMID:17900292

  8. A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride?channel

    PubMed Central

    Fahlke, Christoph; Beck, Carol L.; George, Alfred L.

    1997-01-01

    Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl? channel gene (CLCN1, 7q35). Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the pore properties of a recombinant human muscle Cl? channel (hClC-1) expressed in a mammalian cell line (tsA201). The G230E mutation causes substantial changes in anion and cation selectivity as well as a fundamental change in rectification of the current–voltage relationship. Whereas wild-type channels are characterized by pronounced inward rectification and a Cl > thiocyanate > Br > NO3 > I > CH3SO3 selectivity, G230E exhibits outward rectification at positive potentials and a thiocyanate > NO3 > I > Br > Cl > CH3SO3 selectivity. Furthermore, the cation-to-anion permeability ratio of the mutant is much greater than that of the wild-type channel. Voltage-dependent blocks by intracellular and extracellular iodide help to distinguish two distinct ion binding sites within the hClC-1 conduction pathway. Both binding sites are preserved in the mutant but have decreased affinities for iodide. These findings suggest that Gly 230 is critical for normal ion conductance in hClC-1 and that this residue resides within the channel pore. PMID:9122265

  9. From bone abnormalities to mineral metabolism dysregulation in autosomal dominant polycystic kidney disease.

    PubMed

    Mekahli, Djalila; Bacchetta, Justine

    2013-11-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease. PMID:23340856

  10. Autosomal dominant ataxia: Genetic evidence for locus heterogeneity from a cuban founder-effect population

    PubMed Central

    Auburger, Georg; Diaz, Guillermo Orozco; Capote, Raul Ferreira; Sanchez, Suzana Gispert; Perez, Marta Paradoa; del Cueto, Marianela Estrada; Meneses, Mirna Garcia; Farrall, Martin; Williamson, Robert; Chamberlain, Susan; Baute, Luis Heredero

    1990-01-01

    The locus for autosomal dominant ataxia with a diagnosis of olivo-ponto-cerebellar atrophy at autopsy has been previously assigned to chromosome 6p. However, evidence for two alternative locations has been reported. We have recently described a large potential founder-effect population of such patients in the Holguin province of Cuba. With an estimated 1,000 patients available for analysis, this extensive cluster of families provides a unique opportunity for the definitive localization of the genetic mutation. Linkage analysis between the disease locus in this population and markers within and flanking the HLA region on chromosome 6 were undertaken in 12 families comprising over 100 affected individuals. Despite similarity in the clinical phenotype between those families where the disease locus has been reported to be linked to the HLA locus and the Cuban patients, no evidence of linkage to this region could be demonstrated in the latter. The disease locus was excluded from a 96-cM genetic interval of the short arm of chromosome 6, encompassing the F13A1–HLA–GLO1–MUT/D6S4 loci. These data strongly support the existence of genetic heterogeneity for the disease. PMID:1971152

  11. A novel FBN1 heterozygous mutation identified in a Chinese family with autosomal dominant Marfan syndrome.

    PubMed

    Yin, Y; Liu, X-H; Li, X-H; Fan, N; Lei, D-F; Wang, Y; Cai, S-P; Zhou, X-M; Chen, X-M; Liu, X-Y

    2015-01-01

    The purpose of this study was to identify the clinical features and mutations in the fibrillin-1 gene (FBN1) in a large Chinese family with autosomal dominant Marfan syndrome (MFS). Seventeen members from a Chinese family of 4 generations were included in the study. All members underwent complete ophthalmic examination. Molecular genetic analysis was performed on all subjects. All exons of FBN1 were amplified by polymerase chain reaction, sequenced, and the sequences were compared with a reference database. Variations were evaluated in family members as well as 100 normal controls. Changes in structure and function of the protein induced by amino acid variation were predicted by bioinformatic analysis. Ectopia lentis, dolichostenomelia, arachnodactyly, and tall stature were present in all patients diagnosed with MFS. The novel heterozygous missense mutation c.2243 T>G (p.C781W) in exon 19 of FBN1 was identified in all 5 patients, but not in other family members or 100 normal controls. This mutation caused an amino acid substitution of cysteine to tryptophan at position 781 (p.C781W) of the FBN1 protein. This mutation occurred in a highly conserved region and may cause structural and functional changes in the protein according to our bioinformatic analysis. Our results suggest that the novel mutation C781W of FBN1 is responsible for the pathogenesis of MFS in this pedigree. PMID:25966184

  12. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features

    PubMed Central

    Kalachikov, Sergey; Evgrafov, Oleg; Ross, Barbara; Winawer, Melodie; Barker-Cummings, Christie; Boneschi, Filippo Martinelli; Choi, Chang; Morozov, Pavel; Das, Kamna; Teplitskaya, Elita; Yu, Andrew; Cayanis, Eftihia; Penchaszadeh, Graciela; Kottmann, Andreas H.; Pedley, Timothy A.; Hauser, W. Allen; Ottman, Ruth; Gilliam, T. Conrad

    2008-01-01

    The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures1. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances2,3. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies. PMID:11810107

  13. Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency.

    PubMed

    Dale, Russell C; Melchers, Anna; Fung, Victor S C; Grattan-Smith, Padraic; Houlden, Henry; Earl, John

    2010-06-01

    Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of L-Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals. PMID:20187889

  14. Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease Using Next-Generation Sequencing

    PubMed Central

    Tan, Adrian Y.; Michaeel, Alber; Liu, Genyan; Elemento, Olivier; Blumenfeld, Jon; Donahue, Stephanie; Parker, Tom; Levine, Daniel; Rennert, Hanna

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2. However, genetic analysis is complicated by six PKD1 pseudogenes, large gene sizes, and allelic heterogeneity. We developed a new clinical assay for PKD gene analysis using paired-end next-generation sequencing (NGS) by multiplexing individually bar-coded long-range PCR libraries and analyzing them in one Illumina MiSeq flow cell. The data analysis pipeline has been optimized and automated with Unix shell scripts to accommodate variant calls. This approach was validated using a cohort of 25 patients with ADPKD previously analyzed by Sanger sequencing. A total of 250 genetic variants were identified by NGS, spanning the entire exonic and adjacent intronic regions of PKD1 and PKD2, including all 16 pathogenic mutations. In addition, we identified three novel mutations in a mutation-negative cohort of 24 patients with ADPKD previously analyzed by Sanger sequencing. This NGS method achieved sensitivity of 99.2% (95% CI, 96.8%–99.9%) and specificity of 99.9% (95% CI, 99.7%–100.0%), with cost and turnaround time reduced by as much as 70%. Prospective NGS analysis of 25 patients with ADPKD demonstrated a detection rate comparable with Sanger standards. In conclusion, the NGS method was superior to Sanger sequencing for detecting PKD gene mutations, achieving high sensitivity and improved gene coverage. These characteristics suggest that NGS would be an appropriate new standard for clinical genetic testing of ADPKD. PMID:24374109

  15. A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance.

    PubMed Central

    Coon, H; Jensen, S; Hoff, M; Holik, J; Plaetke, R; Reimherr, F; Wender, P; Leppert, M; Byerley, W

    1993-01-01

    Manic-depressive illness (MDI), also known as "bipolar affective disorder," is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, we ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping 5 cM from the disease gene, the pedigree sample has > 97% power to detect a dominant allele under genetic homogeneity and has > 73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores < -2.0 at recombination fraction (theta) = .0, 174 DNA loci produced lod scores < -2.0 at theta = .05, and 4 DNA marker loci yielded lod scores > 1 (chromosome 5--D5S39, D5S43, and D5S62; chromosome 11--D11S85). Of the markers giving lod scores > 1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, our linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk. PMID:8503452

  16. Intermediate phenotypes in patients with autosomal dominant hyper-IgE syndrome caused by somatic mosaicism

    PubMed Central

    Hsu, Amy P.; Sowerwine, Kathryn J.; Lawrence, Monica G.; Davis, Joie; Henderson, Carolyn J.; Zarember, Kol A.; Garofalo, Mary; Gallin, John I.; Kuhns, Douglas B.; Heller, Theo; Milner, Joshua D.; Puck, Jennifer M.; Freeman, Alexandra F.; Holland, Steven M.

    2014-01-01

    Background Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes. Objective Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease. Methods Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-171 cells, IL-221 cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined. Results The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. Conclusion STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo. PMID:23623265

  17. A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia.

    PubMed

    Mencacci, Niccolo E; Rubio-Agusti, Ignacio; Zdebik, Anselm; Asmus, Friedrich; Ludtmann, Marthe H R; Ryten, Mina; Plagnol, Vincent; Hauser, Ann-Kathrin; Bandres-Ciga, Sara; Bettencourt, Conceição; Forabosco, Paola; Hughes, Deborah; Soutar, Marc M P; Peall, Kathryn; Morris, Huw R; Trabzuni, Daniah; Tekman, Mehmet; Stanescu, Horia C; Kleta, Robert; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Garavaglia, Barbara; Lohmann, Ebba; Weissbach, Anne; Klein, Christine; Hardy, John; Pittman, Alan M; Foltynie, Thomas; Abramov, Andrey Y; Gasser, Thomas; Bhatia, Kailash P; Wood, Nicholas W

    2015-06-01

    Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. PMID:25983243

  18. A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

    PubMed Central

    Mencacci, Niccolo E.; Rubio-Agusti, Ignacio; Zdebik, Anselm; Asmus, Friedrich; Ludtmann, Marthe H.R.; Ryten, Mina; Plagnol, Vincent; Hauser, Ann-Kathrin; Bandres-Ciga, Sara; Bettencourt, Conceição; Forabosco, Paola; Hughes, Deborah; Soutar, Marc M.P.; Peall, Kathryn; Morris, Huw R.; Trabzuni, Daniah; Tekman, Mehmet; Stanescu, Horia C.; Kleta, Robert; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Garavaglia, Barbara; Lohmann, Ebba; Weissbach, Anne; Klein, Christine; Hardy, John; Pittman, Alan M.; Foltynie, Thomas; Abramov, Andrey Y.; Gasser, Thomas; Bhatia, Kailash P.; Wood, Nicholas W.

    2015-01-01

    Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%–50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. PMID:25983243

  19. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance.

    PubMed

    Finsterer, Josef; Löscher, Wolfgang; Quasthoff, Stefan; Wanschitz, Julia; Auer-Grumbach, Michaela; Stevanin, Giovanni

    2012-07-15

    Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic. PMID:22554690

  20. Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics

    PubMed Central

    2013-01-01

    Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments. PMID:23331413

  1. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease?

    PubMed Central

    Higashihara, Eiji; Nutahara, Kikuo; Tanbo, Mitsuhiro; Hara, Hidehiko; Miyazaki, Isao; Kobayashi, Kuninori; Nitatori, Toshiaki

    2014-01-01

    Background The clinical effects of increased water intake on autosomal dominant polycystic kidney disease (ADPKD) progression are unknown. Methods ADPKD patients with creatinine clearance ?50 mL/min/1.73 m2 were divided into high (H-, n = 18) and free (F-, n = 16) water-intake groups, mainly according to their preference. Prior to the study, 30 patients underwent annual evaluation of total kidney volume (TKV) and 24-h urine for an average of 33 months. During the 1-year study period, TKV and 24-h urine were analyzed at the beginning and end of the study and every 4 months, respectively. Results During the pre-study period, urine volume (UV) in the H-group was higher (P = 0.034), but TKV and kidney function and their slopes were not significantly different between the two groups. After the study commenced, UV further increased (P < 0.001) in the H-group but not in the F-group. During the study period, TKV and kidney function slopes were not significantly different between the two groups (primary endpoint). Plasma copeptin was lower (P = 0.024) in the H-group than in the F-group. TKV and kidney function slopes became worse (P = 0.047 and 0.011, respectively) after high water intake (H-group) but not in the F-group. High UV was associated with increased urine sodium, and urine sodium positively correlated with the % TKV slope (P = 0.014). Conclusions Although the main endpoint was not significant, high water intake enhanced disease progression in the H-group when compared with the pre-study period. These findings necessitate a long-term randomized study before drawing a final conclusion. PMID:24739484

  2. A novel missense mutation of Wilms' Tumor 1 causes autosomal dominant FSGS.

    PubMed

    Hall, Gentzon; Gbadegesin, Rasheed A; Lavin, Peter; Wu, Guanghong; Liu, Yangfan; Oh, Edwin C; Wang, Liming; Spurney, Robert F; Eckel, Jason; Lindsey, Thomas; Homstad, Alison; Malone, Andrew F; Phelan, Paul J; Shaw, Andrey; Howell, David N; Conlon, Peter J; Katsanis, Nicholas; Winn, Michelle P

    2015-04-01

    FSGS is a clinical disorder characterized by focal scarring of the glomerular capillary tuft, podocyte injury, and nephrotic syndrome. Although idiopathic forms of FSGS predominate, recent insights into the molecular and genetic causes of FSGS have enhanced our understanding of disease pathogenesis. Here, we report a novel missense mutation of the transcriptional regulator Wilms' Tumor 1 (WT1) as the cause of nonsyndromic, autosomal dominant FSGS in two Northern European kindreds from the United States. We performed sequential genome-wide linkage analysis and whole-exome sequencing to evaluate participants from family DUK6524. Subsequently, whole-exome sequencing and direct sequencing were performed on proband DNA from family DUK6975. We identified multiple suggestive loci on chromosomes 6, 11, and 13 in family DUK6524 and identified a segregating missense mutation (R458Q) in WT1 isoform D as the cause of FSGS in this family. The identical mutation was found in family DUK6975. The R458Q mutation was not found in 1600 control chromosomes and was predicted as damaging by in silico simulation. We depleted wt1a in zebrafish embryos and observed glomerular injury and filtration defects, both of which were rescued with wild-type but not mutant human WT1D mRNA. Finally, we explored the subcellular mechanism of the mutation in vitro. WT1(R458Q) overexpression significantly downregulated nephrin and synaptopodin expression, promoted apoptosis in HEK293 cells and impaired focal contact formation in podocytes. Taken together, these data suggest that the WT1(R458Q) mutation alters the regulation of podocyte homeostasis and causes nonsyndromic FSGS. PMID:25145932

  3. Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib.

    PubMed

    Sano, Shinichiro; Iwata, Hiromi; Matsubara, Keiko; Fukami, Maki; Kagami, Masayo; Ogata, Tsutomu

    2015-06-30

    Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR. We studied 5 4/12-year-old monozygotic twins with short stature (both -3.4 SD) and GHD (peak GH values, <6.0 ?g/L after arginine and clonidine stimulations). Molecular studies revealed maternally derived STX16 microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. GNAS mutation was not identified, and neither mutation nor copy number variation was detected in GH1, POU1F1, PROP1, GHRHR, LHX3, LHX4, and HESX1 in the twins. The results, in conjunction with the previous finding that GNAS shows maternal expression in the pituitary, suggest that GHD of the twins is primarily ascribed to compromised GHRH-R signaling caused by AD-PTH-Ib. Thus, resistance to multiple hormones including GHRH should be considered in AD-PHP-Ib. PMID:25843330

  4. Bone Density and Fractures in Autosomal Dominant Hyper IgE Syndrome

    PubMed Central

    Sowerwine, Kathryn J.; Shaw, Pamela A.; Gu, Wenjuan; Ling, Jennifer C.; Collins, Michael T.; Darnell, Dirk N.; Anderson, Victoria L.; Davis, Joie; Hsu, Amy; Welch, Pamela; Puck, Jennifer M.; Holland, Steven M.

    2015-01-01

    Purpose Autosomal Dominant Hyper IgE Recurrent Infection Syndrome (AD-HIES) is caused by mutations in STAT3 and characterized by eczema, recurrent bacterial infections, and skeletal and connective tissue abnormalities. To further understand the minimal trauma fractures of AD-HIES, we examined bone mineral density (BMD) and laboratory markers of bone turnover. Methods Patients with AD-HIES enrolled in a prospective natural history study were examined with dual x-ray absorptiometry (DEXA) scans and laboratory studies of bone metabolism. The number of fractures was recorded as well as clinical features of AD-HIES including scoliosis and retained primary teeth. Patients on medications with skeletal effects, including bisphosphonates, were examined separately. Results Twenty-three AD-HIES children (6–18 years) and 33 AD-HIES adults (21–50 years) not receiving bone-active drugs were studied. Fourteen of the 23 children (61 %) had histories of minimal trauma fractures, as did 26 of the 33 adults (79 %). Osteopenia or osteoporosis was found in 79% of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. Markers of bone metabolism did not correlate with minimal trauma fractures or BMD. Patients on bone-active medications had improved BMD, but still sustained fractures. Conclusions Minimal trauma fractures and decreased BMD are common in AD-HIES. Low radial BMD is associated with fractures, but hip and spine BMD are not. Treatment with bisphosphonates increased BMD but its role in fracture prevention remains undefined. PMID:24402620

  5. Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease

    PubMed Central

    2014-01-01

    Background The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline. Methods This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR)???15 mL/min/1.73 m2 and who were followed up for?>?1 year were included in our analysis. Hyperuricemia was defined by a sUA level of???7.0 mg/dL in male and???6.0 mg/dL in female or when hypouricemic medications were prescribed. Results Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (?6.3% per year vs. ?0.9% per year, p?=?0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: ?5.3?±?8. 2 vs. 0.2?±?6.2 mL/min/1.73 m2 per year, p?=?0.001 by Wilcoxon signed-rank test). Conclusions Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency. PMID:24739095

  6. Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11).

    PubMed

    Bolz, Hanno; Bolz, Steffen-Sebastian; Schade, Götz; Kothe, Christian; Mohrmann, Gerrit; Hess, Markus; Gal, Andreas

    2004-09-01

    Both myosin 7A (MYO7A) and calmodulin (CaM) are required for transduction and adaptation processes in inner ear hair cells. We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non-syndromic hearing loss that changes an evolutionarily invariant residue of the fifth IQ motif (IQ5), a putative calmodulin (CaM) binding domain, of MYO7A. Functional effects of the p.R853C mutation were investigated in a physiological cellular environment by expressing MYO7A IQ5-containing peptides in smooth muscle cells of microarteries, in which overexpression of wildtype IQ5 (with intact calmodulin binding) would be expected to compete with myosin light chain kinase (MLCK) for CaM binding. Indeed, analysis of calmodulin-dependent vasoconstriction suggests constitutive binding of CaM to the wildtype, but not the p.R853C-mutated IQ5 motif at all physiologically relevant Ca2+ concentrations. Thus our data suggest a disturbed CaM/MYO7A binding of the p.R853C mutant, this amino acid change may result in impaired adaptation to environmental stimuli and progressive deterioration of hearing transduction in heterozygotes. A defect in CaM/MYO7A interaction represents a novel pathomechanism for genetic hearing loss. It provides an attractive molecular target for therapeutic interventions aimed to delay or prevent the onset of hearing loss in families with mutations in myosin IQ domains. PMID:15300860

  7. Molecular analysis in a family presenting with a mild form of late-onset autosomal dominant chronic progressive external ophthalmoplegia

    Microsoft Academic Search

    Roberto Negro; Stefano Zoccolella; Rosa Dell’Aglio; Angela Amati; Lucia Artuso; Luigi Bisceglia; Vito Lavolpe; Sergio Papa; Luigi Serlenga; Vittoria Petruzzella

    2009-01-01

    Nuclear genes affecting mitochondrial genome stability were screened in an Italian family presenting with autosomal dominant progressive external ophthalmoplegia (adPEO) associated with multiple mitochondrial DNA (mtDNA) deletions. We report on a heterozygous c.907C>T (p.R303W) mutation found in the N-terminal domain of the human mitochondrial DNA helicase, Twinkle protein, in six members of a family, in which two individuals manifested late-onset

  8. Autosomal dominant polycystic kidney disease (ADPKD) is associated with coronary arterial dilatation in end-stage renal failure patients

    PubMed Central

    Rangan, Gopala K.; Chapman, Jeremy R.; Thiagalingam, Aravinda

    2012-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) can affect several organs in addition to the kidney. There is paucity in the literature on the cardiac manifestations of this disease. This retrospective study aimed to assess whether ADPKD was associated with a larger coronary artery diameter and to evaluate for the presence of coronary artery aneurysm and ectasia. This study shows that subjects with ADPKD and end-stage renal failure have dilatation of coronary arteries independent of traditional coronary risk factors and medication use.

  9. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland

    Microsoft Academic Search

    S S M Razvi; R Davidson; I Bone; K W Muir

    2005-01-01

    Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations of the Notch3 gene on 19p13. Varying phenotypic expression leads to under recognition and misdiagnosis. Prevalence therefore remains uncertain. We sought to estimate the prevalence of CADASIL in the west of Scotland.Methods: A register for CADASIL was established at a regional neurosciences centre in 2002.

  10. Acute abdomen and hemorrhagic shock caused by spontaneous rupture of renal cyst in autosomal dominant polycystic kidney disease.

    PubMed

    Yaman, ?smail; Sa?lam, ?smet; Kurt, Kamile

    2013-01-01

    Autosomal dominant polycystic kidney disease is an important cause of end stage renal failure. Rarely, these patients may present with hemorrhagic shock caused by rupture of the renal cyst. The aim of this study was to report a rare case of a patient who arrived at the emergency department with autosomal dominant polycystic kidney disease presenting with acute abdominal pain and hemorrhagic shock. A 58-year-old male with chronic renal failure was admitted to the emergency department with acute abdominal pain and hemorrhagic shock. The patient was admitted to the Department of Surgery with diagnosis of acute abdomen and perirenal hematoma. Although the patient was on conservative treatment, his symptoms did not improve and the patient was operated emergently. During exploration, there was bleeding from the right polycystic kidney, which was 30×20 cm in dimension. The patient underwent nephrectomy and drainage of the hematoma, and was discharged on the fifth postoperative day without any problems. Bleeding due to rupture of a cyst in autosomal dominant polycystic kidney disease occurs rarely but it may be life threatening. Although conservative methods are often preferable in treatment, surgery can be life saving for patients in whom the clinical situation does not improve. PMID:25931844

  11. Mutation in the zonadhesin-like domain of alpha-tectorin associated with autosomal dominant non-syndromic hearing loss.

    PubMed

    Alloisio, N; Morlé, L; Bozon, M; Godet, J; Verhoeven, K; Van Camp, G; Plauchu, H; Muller, P; Collet, L; Lina-Granade, G

    1999-01-01

    A gene responsible for autosomal dominant non-syndromic hearing impairment in two families (DFNA8 and DFNA12) has recently been identified as TECTA encoding alpha-tectorin, a major component of the tectorial membrane. In these families, missense mutations within the zona pellucida domain of alpha-tectorin were associated with stable severe mid-frequency hearing loss. The present study reports linkage to DFNA12 in a new family with autosomal dominant high frequency hearing loss progressing from mild to moderate severity. The candidate region refined to 3.8 cM still contained the TECTA gene. A missense mutation (C1619S) was identified in the zonadhesin-like domain. This mutation abolishes the first of the vicinal cysteines (1619Cys-Gly-Leu- 1622Cys) present in the D4 von Willebrand factor (vWf) type D repeat. These results further support the involvement of TECTA mutations in autosomal dominant hearing impairment, and suggest that vicinal cysteines are involved in tectorial membrane matrix assembly. PMID:10196713

  12. A novel mutation (C271F) in the Notch3 gene in a Chinese man with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

    Microsoft Academic Search

    Kam-Ming Au; Ho-Lun Li; Bun Sheng; Tat-Chong Chow; Mo-Lung Chen; Kam-Cheong Lee; Albert Yan-Wo Chan

    2007-01-01

    BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset hereditary condition caused by mutations in the Notch3 gene. A Chinese man was studied.

  13. Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind.

    PubMed

    Boisson, Bertrand; Quartier, Pierre; Casanova, Jean-Laurent

    2015-02-01

    All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity. PMID:25645939

  14. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy.

    PubMed

    Heron, Sarah E; Smith, Katherine R; Bahlo, Melanie; Nobili, Lino; Kahana, Esther; Licchetta, Laura; Oliver, Karen L; Mazarib, Aziz; Afawi, Zaid; Korczyn, Amos; Plazzi, Giuseppe; Petrou, Steven; Berkovic, Samuel F; Scheffer, Ingrid E; Dibbens, Leanne M

    2012-11-01

    We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies. PMID:23086396

  15. Early Structural Anomalies Observed by High-Resolution Imaging in Two Related Cases of Autosomal-Dominant Retinitis Pigmentosa

    PubMed Central

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

    2015-01-01

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

  16. Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles

    PubMed Central

    Darbro, Benjamin W.; Mahajan, Vinit B.; Gakhar, Lokesh; Skeie, Jessica M.; Campbell, Elizabeth; Wu, Shu; Bing, Xinyu; Millen, Kathleen J.; Dobyns, William B.; Kessler, John A.; Jalali, Ali; Cremer, James; Segre, Alberto; Manak, J. Robert; Aldinger, Kimerbly A.; Suzuki, Satoshi; Natsume, Nagato; Ono, Maya; Hai, Huynh Dai; Viet, Le Thi; Loddo, Sara; Valente, Enza M.; Bernardini, Laura; Ghonge, Nitin; Ferguson, Polly J.; Bassuk, Alexander G.

    2013-01-01

    We performed whole-exome sequencing of a family with autosomal dominant Dandy-Walker malformation and occipital cephaloceles (ADDWOC) and detected a mutation in the extracellular matrix protein encoding gene NID1. In a second family, protein interaction network analysis identified a mutation in LAMC1, which encodes a NID1 binding partner. Structural modeling the NID1-LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicate the extracellular matrix in the pathogenesis of Dandy-Walker spectrum disorders. PMID:23674478

  17. Handigodu disease: a radiological study. A new variety of spondyloepi(meta)physeal dysplasia of the autosomal dominant type.

    PubMed

    Agarwal, S S; Phadke, S R; Phadke, R V; Das, S K; Singh, G K; Sharma, J P; Teotia, S P; Saxena, B N

    1994-11-01

    Handigodu disease is a new syndrome of familial spondyloepi(meta)physeal dysplasia. It is inherited as an autosomal dominant trait. The disease is prevalent in a localised area of South India. On the basis of detailed clinical, anthropometric and radiological investigations of 234 affected individuals, it has been observed that different clinical presentations reflect variation in the severity of the disease. All of them could be explained as being caused by defective development of bones as a result of monogenic disorder. PMID:7886470

  18. Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family

    PubMed Central

    Dong, Cheng; Chen, Siqi; Qi, Yu; Liu, Yuhe

    2015-01-01

    We report the genetic analysis of autosomal dominant, nonsyndromic, progressive sensorineural hearing loss in a Chinese family. Using whole exome sequencing, we identified a missense variant (c.130C>T, p.R44C) in the MCM2 gene, which has a pro-apoptosis effect and is involved in the initiation of eukaryotic genome replication. This missense variant is very likely to be the disease causing variant. It segregated with hearing loss in this pedigree, and was not found in the dbSNP database or databases of genomes and SNP in the Chinese population, in 76 patients with sporadic hearing loss, or in 145 normal individuals. We performed western blot and immunofluorescence to test the MCM2 protein expression in the cochlea of rats and guinea pigs, demonstrating that MCM2 was widely expressed in the cochlea and was also surprisingly expressed in the cytoplasm of terminally differentiated hair cells. We then transiently expressed the variant MCM2 cDNA in HEK293 cells, and found that these cells displayed a slight increase in apoptosis without any changes in proliferation or cell cycle, supporting the view that this variant is pathogenic. In summary, we have identified MCM2 as a novel gene responsible for nonsyndromic hearing loss of autosomal dominant inheritance in a Chinese family. PMID:26196677

  19. Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C.

    PubMed

    Choi, Keun Hee; Shin, Choong Ho; Yang, Sei Won; Cheong, Hae Il

    2015-04-01

    The calcium sensing receptor (CaSR) plays an important role in calcium homeostasis. Activating mutations of CaSR cause autosomal dominant hypocalcemia by affecting parathyroid hormone secretion in parathyroid gland and calcium resorption in kidney. They can also cause a type 5 Bartter syndrome by inhibiting the apical potassium channel in the thick ascending limb of the loop of Henle in the kidney. This study presents a patient who had autosomal dominant hypocalcemia with Bartter syndrome due to an activating mutation Y829C in the transmembrane domain of the CaSR. Symptoms of hypocalcemia occurred 12 days after birth and medication was started immediately. Medullary nephrocalcinosis and basal ganglia calcification were found at 7 years old and at 17 years old. Three hypercalcemic episodes occurred, one at 14 years old and two at 17 years old. The Bartter syndrome was not severe while the serum calcium concentration was controlled, but during hypercalcemic periods, the symptoms of Bartter syndrome were aggravated. PMID:25932037

  20. Exome Sequencing Identifies a Mutation in EYA4 as a Novel Cause of Autosomal Dominant Non-Syndromic Hearing Loss

    PubMed Central

    Xia, Wenjun; Hao, Lili; Ma, Jing; Ma, Duan; Ma, Zhaoxin

    2015-01-01

    Autosomal dominant non-syndromic hearing loss is highly heterogeneous, and eyes absent 4 (EYA4) is a disease-causing gene. Most EYA4 mutations founded in the Eya-homologous region, however, no deafness causative missense mutation in variable region of EYA4 have previously been found. In this study, we identified a pathogenic missense mutation located in the variable region of the EYA4 gene for the first time in a four-generation Chinese family with 57 members. Whole-exome sequencing (WES) was performed on samples from one unaffected and two affected individuals to systematically search for deafness susceptibility genes, and the candidate mutations and the co-segregation of the phenotype were verified by polymerase chain reaction amplification and by Sanger sequencing in all of the family members. Then, we identified a novel EYA4 mutation in exon 8, c.511G>C; p.G171R, which segregated with postlingual and progressive autosomal dominant sensorineural hearing loss (SNHL). This report is the first to describe a missense mutation in the variable region domain of the EYA4 gene, which is not highly conserved in many species, indicating that the potential unconserved role of 171G>R in human EYA4 function is extremely important. PMID:25961296

  1. Identification of the integrin ?3 L718P mutation in a pedigree with autosomal dominant thrombocytopenia with anisocytosis.

    PubMed

    Kobayashi, Yoshiyuki; Matsui, Hirotaka; Kanai, Akinori; Tsumura, Miyuki; Okada, Satoshi; Miki, Mizuka; Nakamura, Kazuhiro; Kunishima, Shinji; Inaba, Toshiya; Kobayashi, Masao

    2013-02-01

    ?IIb?3 integrin mutations that result in the complete loss of expression of this molecule on the platelet surface cause Glanzmann thrombasthenia. This is usually autosomal recessive, while other mutations are known to cause dominantly inherited macrothrombocytopenia (although such cases are rare). Here, we report a 4-generation pedigree including 10 individuals affected by dominantly inherited thrombocytopenia with anisocytosis. Six individuals, whose detailed clinical and laboratory data were available, carried a non-synonymous ITGB3 gene alteration resulting in mutated integrin ?3 (ITGB3)-L718P. This mutation causes partial activation of the ?IIb?3 complex, which promotes the generation of abnormal pro-platelet-like protrusions through downregulating RhoA (RHOA) activity in transfected Chinese Hamster Ovary cells. These findings suggest a model whereby the integrin ?3-L718P mutation contributes to thrombocytopenia through gain-of-function mechanisms. PMID:23253071

  2. A novel mutation in the TECTA gene in a Chinese family with autosomal dominant nonsyndromic hearing loss.

    PubMed

    Su, Yu; Tang, Wen-Xue; Gao, Xue; Yu, Fei; Dai, Zhi-Yao; Zhao, Jian-Dong; Lu, Yu; Ji, Fei; Huang, Sha-Sha; Yuan, Yong-Yi; Han, Ming-Yu; Song, Yue-Shuai; Zhu, Yu-Hua; Kang, Dong-Yang; Han, Dong-Yi; Dai, Pu

    2014-01-01

    TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The ?-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257-262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA. PMID:24586623

  3. Mapping of the autosomal dominant exudative vitreoretinopathy locus (EVR1) by multipoint linkage analysis in four families

    SciTech Connect

    Mueller, B. (Universitaet Muenchen (Germany)); Orth, U.; Duvigneau, C.; Schwinger, E.; Gal, A.; Fuhrmann, C.; Laqua, H. (Medizinische Universitaet, Lubeck (Germany)); Nouhuys, C.E. van (CW-Hospital, Nijmegan (Netherlands))

    1994-03-15

    Autosomal dominant exudative vitreoretinopathy is a disorder affecting primarily the development of the human retinal vascular system. The disease locus has recently been assigned to 11q13-q23 by linkage studies in two families. Two-point analysis on a total of four families has now revealed close linkage (z[sub max] = 8.34 at [theta] = 0.00) between the disease locus and D11S873. Multipoint linkage analysis mapped the disease locus between D11S527/D11S533 and D11S 35 with a maximum lod score of over 11 directly at D11S873. No evidence appeared for genetic/linkage heterogeneity among the four families examined. 6 refs., 1 fig., 1 tab.

  4. Genetic linkage of autosomal dominant juvenile glaucoma to 1q21-q31 in three affected pedigrees

    SciTech Connect

    Wiggs, J.L.; Paglinauan, C.; Fine, A.; Sporn, C.; Lou, D. (Tufts Univ. School of Medicine, Boston, MA (United States)); Haines, J.L. (Harvard Medical School, Boston, MA (United States))

    1994-05-15

    Glaucoma is a common disorder that results in irreversible damage to the optic nerve, causing absolute blindness. In most cases, the optic nerve is damaged by an elevation of the intraocular pressure that is the result of an abnormality in the normal drainage function of the trabecular meshwork. A family history of glaucoma is an important risk factor for the disease, suggesting that genetic defects predisposing to this condition are likely. Three pedigrees segregating an autosomal dominant juvenile glaucoma demonstrated significant linkage to a group of closely spaced markers on chromosome 1. These results confirm the initial mapping of this disease and suggest that this region on chromosome 1 contains an important locus for juvenile glaucoma. The authors describe recombination events that improve the localization of the responsible gene, reducing the size of the candidate region from 30 to 12 cM. 27 refs., 2 figs., 1 tab.

  5. High-resolution cytogenetic analysis of the peripheral blood lymphocytes of patients with autosomal dominant polycystic kidney disease.

    PubMed

    Dimitrakov, D

    1993-01-01

    High-resolution cytogenetic analysis was performed on peripheral blood lymphocytes of 11 patients (seven women and four men, range 24-56 years) with proven autosomal dominant polycystic kidney disease (ADPKD). A total of 449 metaphases (an average of 41 per patient) were analyzed. In two of the women changes in the karyotype were found in a single cell: del(3), (q21) in one of them and Int.del(6), (q11q21) in the other. Analysis of the remaining patients, including those in which ADPKD was combined with oligophrenia, did not reveal any deviations from the normal karyotype. Therefore, the established chromosome changes are non-specific and of little importance in diagnosing ADPKD. PMID:7927052

  6. Autosomal-dominant locus for Restless Legs Syndrome in French-Canadians on chromosome 16p12.1.

    PubMed

    Levchenko, Anastasia; Montplaisir, Jacques-Yves; Asselin, Géraldine; Provost, Sylvie; Girard, Simon L; Xiong, Lan; Lemyre, Emmanuelle; St-Onge, Judith; Thibodeau, Pascale; Desautels, Alex; Turecki, Gustavo; Gaspar, Claudia; Dubé, Marie-Pierre; Rouleau, Guy A

    2009-01-15

    We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family. PMID:18946881

  7. The first Indian-origin family with genetically proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

    PubMed

    Yadav, Sunaina; Bentley, Paul; Srivastava, Padma; Prasad, Kameshwar; Sharma, Pankaj

    2013-01-01

    We report the first family of Indian origin known to be affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Seventeen members of the family spanning 3 generations had neurologic syndromes compatible with CADASIL, of whom 5 were genetically confirmed carriers of the Notch3 gene R141C mutation in exon 4 (421(C?T) and 141(Cys?Arg)). Our report highlights that CADASIL not only occurs sporadically in South Asians, but also may account for stroke in South Asians with a strong family history. Furthermore, the similarity of clinical presentations described here to those typical for Caucasian case series suggests that the CADASIL phenotype is preserved across racial groups. PMID:21737310

  8. Mapping of a gene for autosomal dominant juvenile-onset open-angle glaucoma to chromosome 1 q

    SciTech Connect

    Richards, J.E.; Lichter, P.R.; Torrez, D.; Wong, D.; Johnson, A.T.; Boehnke, M.; Uro, J.L.A. (Univ. of Michigan, Ann Arbor, MI (United States))

    1994-01-01

    A large Caucasian family is presented, in which a juvenile-onset form of open-angle glaucoma is transmitted in an autosomal dominant fashion. Sixteen affected family members were identified from 31 at-risk individuals descended from the affected founder. Affected patients developed high intraocular pressures (sometimes >40 mm Hg) within the first 2 decades of life. Linkage analysis between the disease phenotype and 12 microsatellite repeat markers located on chromosome 1 q gave a maximum lod score of 8.38 at a recombination fraction of zero for marker D1S210. Analysis of recombinant haplotypes suggests a total inclusion region of about 14 cM between markers D1S194 and D1S218 at 1q21-q31. This represents the second juvenile-glaucoma family, in which the disease has been mapped to the long arm of chromosome 1. 57 refs., 2 figs., 3 tabs.

  9. Linkage analysis excludes the glaucoma locus on 1q from involvement in autosomal dominant glaucoma with iris hypoplasia

    SciTech Connect

    Heon, E.; Sheth, B.P.; Kalenak, J.W. [and others

    1994-09-01

    Genetic factors have been implicated in a variety of types of glaucoma including primary open-angle glaucoma, infantile glaucoma, pigmentary glaucoma, and juvenile open-angle glaucoma. We previously mapped the disease-causing gene for one type of juvenile open angle glaucoma to chromosome 1q21-31. Weatherill and Hart (1969) and Pearce (1983) each noted the association of iris hypoplasia and early-onset autosomal dominant glaucoma. We recently had the opportunity to study a large family (12 affected members) with this phenotype. Affected individuals developed glaucoma at an average age of 30 years. These patients also have a strikingly underdeveloped iris stroma which causes a peculiar eye color. Linkage analysis was able to completely exclude the 1q glaucoma locus from involvement in the disorder that affects this family. A complete clinical description of the family and linkage results at additional candidate loci will be presented.

  10. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.

    PubMed

    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A T J M; Wokke, John H J; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-05-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders. PMID:18325928

  11. Autosomal Dominant Familial Dyskinesia and Facial Myokymia: Single Exome Sequencing Identifies a Mutation in Adenylate Cyclase 5

    PubMed Central

    Chen, Ying-Zhang; Matsushita, Mark M.; Robertson, Peggy; Rieder, Mark; Girirajan, Santhosh; Antonacci, Francesca; Lipe, Hillary; Eichler, Evan E.; Nickerson, Deborah A.; Bird, Thomas D.; Raskind, Wendy H.

    2012-01-01

    Background Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a five-generation family of German ancestry we previously mapped FDFM to chromosome 3p21-3q21. The 72.5 Mbp linkage region was too large for traditional positional mutation identification. Objective To identify the gene responsible for FDFM by exome resequencing of a single affected individual. Design, Setting and Participants We performed whole exome sequencing in one affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or 1000 Genomes project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in three generations. Results The exome contained 23428 single nucleotide variants, of which 9391 were missense, nonsense or splice site alterations. The critical region contained 323 variants, five of which were not present in one of the sequence-databases. Adenylate cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control Caucasian exomes. This residue is highly conserved and the change is nonconservative and predicted to be damaging. Conclusions ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence in combination with linkage information to identify causative genes for rare autosomal dominant Mendelian diseases. PMID:22782511

  12. Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws

    PubMed Central

    Koutlas, Ioannis G.; Forsman, Cynthia L.; Kyrkanides, Stephanos; Oetting, William S.; Petryk, Anna

    2012-01-01

    A hereditary congenital condition characterized by a fibro-osseous lesion sharing some features with fibrous dysplasia and affecting the middle aspect of the mandible is presented. The condition was initially described as congenital monostotic fibrous dysplasia in two siblings, a male and a female. However, there is sufficient evidence that the disorder is autosomal dominant since it has been encountered in two of four children, both males, of the female propositus and one child, a boy, of the male propositus. All patients presented at birth or right after birth with enlargement of the middle part of the mandible. Radiographs from affected individuals have shown mesomandibular enlargement with irregular trabeculation akin of “ground-glass” appearance. Histologically, samples from all patients revealed woven bone proliferation in a cellular fibroblastic stroma. Interestingly, the originally described siblings, now in their 30s, have no evidence of jaw lesions either radiographically or clinically, thus indicating that the condition is self-limiting or self-resolving. An autosomal dominant mode of inheritance with apparent male predilection is favored. The molecular basis of this condition is currently unknown. However, the location of the lesions in the middle aspect of the mandible suggests dysregulation of Bone Morphogenetic Protein (BMP) signaling since BMPs regulate mandibular morphogenesis in utero, particularly in the medial region as well as postnatal bone remodeling. Immunohistochemical evaluation for a BMP-binding protein Twisted Gastrulation (TWSG1) revealed mosaic pattern of staining, with some cells, including osteoclasts, strongly stained and others exhibiting faint or no staining, thus supporting active regulation of BMP signaling within the lesion. Future investigations will determine if dysregulation of BMP signaling plays a causative role or rather reflects secondary activation of repair mechanisms and/or bone remodeling. PMID:23230423

  13. Two pedigrees of autosomal dominant atrioventricular canal defect (AVCD): Exclusion from the critical region on 8p

    SciTech Connect

    Amati, F.; Mari, A.; Mingarelli, R. [Universita Tor Vergata, Rome (Italy)] [and others

    1995-07-03

    Atrioventricular canal defects (AVCD) constitute the predominant congenital heart defect in Down`s syndrome. For this reason, a candidate gene involved in atrioventricular canal development was previously searched and excluded in dominant pedigrees of AVCD, using linkage analysis of polymorphisms from chromosome 21. Because of the striking association between 8p deletion and AVCD, a search for an AVCD gene was carried out in two pedigrees of individuals with autosomal dominant AVCD using a set of DNA markers of the 8pter{r_arrow}q12 region. These two families include affected individuals and subjects who have transmitted the defect but are not clinically affected. Two-point lod scores were significantly negative for all markers at penetrance levels of 90% and 50%. Multipoint analysis excluded the region covered by the markers LPL-D8S262 and 30 cM to either side of this area. This result corroborates heterogeneity of this heart defect and indicates that the genetic basis of familial AVCD is different from AVCD associated to either trisomy 21 or 8p deletion. 25 refs., 3 figs., 2 tabs.

  14. Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes

    PubMed Central

    Liu, Ming; Lara-Lemus, Roberto; Shan, Shu-ou; Wright, Jordan; Haataja, Leena; Barbetti, Fabrizio; Guo, Huan; Larkin, Dennis; Arvan, Peter

    2012-01-01

    Recently, missense mutations upstream of preproinsulin’s signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying ?-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER–oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY. PMID:22357960

  15. Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7

    Microsoft Academic Search

    J. J. M. Michiels; R. H. M. te Morsche; J. B. M. J. Jansen; J. P. H. Drenth

    2005-01-01

    BACKGROUND: Autosomal dominant primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm, and painful hands and\\/or feet. OBJECTIVE: To describe the phenotypes and molecular data of a 10-member family with 5 symptomatic living patients with erythermalgia. RESULTS: The clinical phenotype of this family was featured by episodic or continuous symmetrical red swelling, irritating warmth, and burning

  16. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD)

    Microsoft Academic Search

    Patricia R. Wahl; Andreas L. Serra; Michel Le Hir; Klaus D. Molle; Michael N. Hall; Rudolf P. Wuthrich

    2006-01-01

    Background. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by dysregulated tubular epithelial cell growth, resulting in the forma- tion of multiple renal cysts and progressive renal failure. To date, there is no effective treatment for ADPKD. The mammalian target of rapamycin (mTOR) is an atypical protein kinase and a central controller of cell growth and proliferation. We examined the

  17. Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24

    Microsoft Academic Search

    Penelope J. Spring; Cindy Kok; Garth A. Nicholson; Alvin J. Ing; Judith M. Spies; Mark L. Bassett; John Cameron; Paul Kerlin; Simon Bowler; Roger Tuck; John D. Pollard

    2005-01-01

    Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals

  18. Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: Clinical and pathological variability within a kindred

    Microsoft Academic Search

    David O. Hutchinson; Amanda Charlton; Nigel G. Laing; Biljana Ilkovski; Kathryn N. North

    2006-01-01

    Nemaline Myopathy with Intranuclear Rods is a rare variant of nemaline myopathy, due in almost all instances to mutation of ACTA1, the gene encoding skeletal muscle ?-actin. We describe the novel autosomal dominant occurrence in a three-generation kindred, and review previously reported cases. Onset of myopathic symptoms in our kindred was in infancy or early childhood. Beyond infancy, limb muscle

  19. C-terminal truncations in human 3?-5? DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    Microsoft Academic Search

    Anna Richards; Arn M J M van den Maagdenberg; Joanna C Jen; David Kavanagh; Paula Bertram; Dirk Spitzer; M Kathryn Liszewski; Maria-Louise Barilla-LaBarca; Gisela M Terwindt; Yumi Kasai; Mike McLellan; Mark Gilbert Grand; Kaate R J Vanmolkot; Boukje de Vries; Jijun Wan; Michael J Kane; Hafsa Mamsa; Ruth Schäfer; Anine H Stam; Joost Haan; Paulus T V M de Jong; Caroline W Storimans; Mary J van Schooneveld; Jendo A Oosterhuis; Andreas Gschwendter; Martin Dichgans; Katya E Kotschet; Suzanne Hodgkinson; Todd A Hardy; Martin B Delatycki; Rula A Hajj-Ali; Parul H Kothari; Stanley F Nelson; Rune R Frants; Robert W Baloh; Michel D Ferrari; John P Atkinson

    2007-01-01

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to

  20. Congenital fibrosis of the extraocular muscles (autosomal dominant congenital external ophthalmoplegia): Genetic homogeneity, linkage refinement, and physical mapping on chromosome 12

    Microsoft Academic Search

    E. C. Engle; A. H. Beggs; I. Marondel

    1995-01-01

    Congenital fibrosis of the extraocular muscles (CFEOM) is an autosomal dominant syndrome of congenital external ophthalmoplegia and bilateral ptosis. We previously reported linkage of this disorder in two unrelated families to an 8-cM region near the centromere of human chromosome 12. We now present refinement of linkage in the original two families, linkage analysis of five additional families, and a

  1. KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease

    Microsoft Academic Search

    Mamdouh Albaqumi; Shekhar Srivastava; Zhai Li; Olga Zhdnova; Heike Wulff; Omar Itani; Darren P Wallace; Edward Y Skolnik

    2008-01-01

    Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by numerous fluid-filled kidney cysts. Net fluid secretion into renal cysts is caused by transepithelial transport mediated by the apical cystic fibrosis transmembrane conductance regulator chloride channel, which leads to cyst enlargement. Here we found that forskolin, a potent adenylyl cyclase agonist, stimulated anion secretion by monolayers of kidney cells derived from patients

  2. Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2)

    Microsoft Academic Search

    Catherine Boucher; Richard Sandford

    2004-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy affecting over 1:1000 of the worldwide population. It is a systemic condition with frequent hepatic and cardiovascular manifestations in addition to the progressive development of renal cysts that eventually result in loss of renal function in the majority of affected individuals. The diagnosis of ADPKD is typically made using

  3. A Novel Mutation in the Notch3 Gene in an Italian Family With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Genetic and Magnetic Resonance Spectroscopic Findings

    Microsoft Academic Search

    Rosario L. Oliveri; Maria Muglia; Nicole De Stefano; Rosalucia Mazzei; Angelo Labate; Francesca L. Conforti; Allessandra Patitucci; Anna L. Gabriele; Giuseppe Tagarelli; Angela Magariello; Mario Zappia; Antonio Gambardella; Antonio Federico; Aldo Quattrone

    2001-01-01

    Background: Cerebral autosomal dominant arteriopa- thy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary syndrome caused by mutations of the Notch3 gene, usually localized to exons 3 and 4. Objectives: To report a novel pathogenetic mutation occurring in exon 6 of the Notch3 gene, a location not previously recognized in patients with CADASIL, and to report the results of

  4. Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

    Microsoft Academic Search

    Sung-Chun Tang; Ming-Jen Lee; Jiann-Shing Jeng; Ping-Keung Yip

    2005-01-01

    The phenotype and genotype of cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL) in Caucasians have been well characterized, but CADASIL is less recognized in Asian populations. Here we investigated the first known Taiwanese family affected by CADASIL and identified an uncommon NOTCH3 mutation. The family had clinical manifestations in affected members including recurrent strokes, early dementia, and

  5. No association between multiple sclerosis and the Notch3 gene responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

    Microsoft Academic Search

    S A Broadley; S J Sawcer; S J S Chataway; F Coraddu; A Coles; J Gray; R Roxburgh; D Clayton; D A S Compston

    2001-01-01

    The clinical and radiological overlap between multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; MIM 125310) raises the possibility of diagnostic confusion and suggests that pleiotropic effects of the Notch3 gene might include influencing susceptibility to multiple sclerosis. To investigate these possibilities three microsatellites markers closely flanking the Notch 3 gene in 745 simplex families

  6. Expression and localization of nuclear proteins in autosomal-dominant Emery-Dreifuss muscular dystrophy with LMNA R377H mutation

    Microsoft Academic Search

    Beate Reichart; Ruth Klafke; Christine Dreger; Eleonora Krüger; Isabell Motsch; Andrea Ewald; Jochen Schäfer; Heinz Reichmann; Clemens R Müller; Marie-Christine Dabauvalle

    2004-01-01

    BACKGROUND: The autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) is caused by mutations in the gene encoding for the lamins A and C (LMNA). Lamins are intermediate filament proteins which form the nuclear lamina underlying the inner nuclear membrane. We have studied the expression and the localization of nuclear envelope proteins in three different cell types and muscle tissue

  7. Autosomal Dominant Hypercalciuria in a Mouse Model Due to a Mutation of the Epithelial Calcium Channel, TRPV5

    PubMed Central

    Loh, Nellie Y.; Verkaart, Sjoerd; Tammaro, Paolo; Gorvin, Caroline M.; Stechman, Michael J.; Ahmad, Bushra N.; Hannan, Fadil M.; Piret, Sian E.; Evans, Holly; Bellantuono, Ilaria; Hough, Tertius A.; Fraser, William D.; Hoenderop, Joost G. J.; Ashcroft, Frances M.; Brown, Steve D. M.; Bindels, René J. M.; Cox, Roger D.; Thakker, Rajesh V.

    2013-01-01

    Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1). Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5) and 6 (Trpv6) genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P). Compared to wild-type littermates, heterozygous (Trpv5682P/+) and homozygous (Trpv5682P/682P) mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ?10% of males developed tubulointerstitial nephritis. Trpv5682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5682P/+ and Trpv5682P/682P mice consistent with a trafficking defect. In addition, Trpv5682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings indicate that the TRPV5 S682P mutant is functionally significant and study of HCALC1, a novel model for autosomal dominant hypercalciuria, may help further our understanding of renal calcium reabsorption and hypercalciuria. PMID:23383183

  8. Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression

    PubMed Central

    Giorgio, Elisa; Rolyan, Harshvardhan; Kropp, Laura; Chakka, Anish Baswanth; Yatsenko, Svetlana; Gregorio, Eleonora Di; Lacerenza, Daniela; Vaula, Giovanna; Talarico, Flavia; Mandich, Paola; Toro, Camilo; Pierre, Eleonore Eymard; Labauge, Pierre; Capellari, Sabina; Cortelli, Pietro; Vairo, Filippo Pinto; Miguel, Diego; Stubbolo, Danielle; Marques, Lourenco Charles; Gahl, William; Boespflug-Tanguy, Odile; Melberg, Atle; Hassin-Baer, Sharon; Cohen, Oren S; Pjontek, Rastislav; Grau, Armin; Klopstock, Thomas; Fogel, Brent; Meijer, Inge; Rouleau, Guy; Bouchard, Jean-Pierre L; Ganapathiraju, Madhavi; Vanderver, Adeline; Dahl, Niklas; Hobson, Grace; Brusco, Alfredo; Brussino, Alessandro; Padiath, Quasar Saleem

    2013-01-01

    ABSTRACT Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels. PMID:23649844

  9. Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre- or peri-pubertal onset gynecomastia.

    PubMed

    Fukami, Maki; Miyado, Mami; Nagasaki, Keisuke; Shozu, Makio; Ogata, Tsutomu

    2014-03-01

    Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown. PMID:24716396

  10. Signal peptide variants that impair secretion of pancreatic secretory trypsin inhibitor (SPINK1) cause autosomal dominant hereditary pancreatitis.

    PubMed

    Király, Orsolya; Boulling, Arnaud; Witt, Heiko; Le Maréchal, Cédric; Chen, Jian-Min; Rosendahl, Jonas; Battaggia, Cinzia; Wartmann, Thomas; Sahin-Tóth, Miklós; Férec, Claude

    2007-05-01

    Variants of the SPINK1 gene encoding pancreatic secretory trypsin inhibitor have been described in association with chronic pancreatitis (CP). These alterations are believed to cause a loss of function by either impairing the trypsin inhibitory activity or reducing expression. Here we report two novel SPINK1 variants in exon 1 that affect the secretory signal peptide. The disease-associated c.41T>G (p.L14R) alteration was found in two European families with autosomal dominant hereditary pancreatitis, whereas the c.36G>C (p.L12F) variant was identified as a frequent alteration in subjects of African descent. The functional effects of both alterations and the previously reported c.41T>C (p.L14P) variant were characterized by activity assays and Western blots of wild-type and mutant SPINK1 expressed in human embryonic kidney 293T and Chinese hamster ovary cells. Alterations p.L14R and p.L14P destined the inhibitor for rapid intracellular degradation and thereby abolished SPINK1 secretion, whereas the p.L12F variant showed no detrimental effect. The results provide the first clear experimental demonstration that alterations that markedly reduce SPINK1 expression are associated with classic hereditary pancreatitis. Therefore, these variants should be classified as severe and regarded as disease-causing rather than disease-modifiers. PMID:17274009

  11. Signal Peptide Variants that Impair Secretion of Pancreatic Secretory Trypsin Inhibitor (SPINK1) Cause Autosomal Dominant Hereditary Pancreatitis

    PubMed Central

    Király, Orsolya; Boulling, Arnaud; Witt, Heiko; Maréchal, Cédric Le; Chen, Jian-Min; Rosendahl, Jonas; Battaggia, Cinzia; Wartmann, Thomas; Sahin-Tóth, Miklós; Férec, Claude

    2009-01-01

    Variants of the SPINK1 gene encoding pancreatic secretory trypsin inhibitor have been described in association with chronic pancreatitis. These alterations are believed to cause a loss of function by either impairing the trypsin inhibitory activity or reducing expression. Here we report two novel SPINK1 variants in exon 1 that affect the secretory signal peptide. The disease-associated c.41T>G (p.L14R) alteration was found in two European families with autosomal dominant hereditary pancreatitis, whereas the c.36G>C (p.L12F) variant was identified as a frequent alteration in subjects of African descent. The functional effects of both alterations and the previously reported c.41T>C (p.L14P) variant were characterized by activity assays and Western blots of wild-type and mutant SPINK1 expressed in human embryonic kidney 293T and Chinese hamster ovary cells. Alterations p.L14R and p.L14P destined the inhibitor for rapid intracellular degradation and thereby abolished SPINK1 secretion, whereas the p.L12F variant showed no detrimental effect. The results provide the first clear experimental demonstration that alterations which markedly reduce SPINK1 expression are associated with classic hereditary pancreatitis. Therefore, these variants should be classified as severe and regarded as disease-causing rather than disease-modifiers. PMID:17274009

  12. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32.

    PubMed Central

    Varret, M; Rabès, J P; Saint-Jore, B; Cenarro, A; Marinoni, J C; Civeira, F; Devillers, M; Krempf, M; Coulon, M; Thiart, R; Kotze, M J; Schmidt, H; Buzzi, J C; Kostner, G M; Bertolini, S; Pocovi, M; Rosa, A; Farnier, M; Martinez, M; Junien, C; Boileau, C

    1999-01-01

    Autosomal dominant hypercholesterolemia (ADH), one of the most frequent hereditary disorders, is characterized by an isolated elevation of LDL particles that leads to premature mortality from cardiovascular complications. It is generally assumed that mutations in the LDLR and APOB genes account for ADH. We identified one large French pedigree (HC2) and 12 additional white families with ADH in which we excluded linkage to the LDLR and APOB, implicating a new locus we named "FH3." A LOD score of 3.13 at a recombination fraction of 0 was obtained at markers D1S2892 and D1S2722. We localized the FH3 locus to a 9-cM interval at 1p34.1-p32. We tested four regional markers in another set of 12 ADH families. Positive LOD scores were obtained in three pedigrees, whereas linkage was excluded in the others. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB ADH families and implied a fourth locus. Radiation hybrid mapping located four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3. Our results show that ADH is genetically more heterogeneous than conventionally accepted. PMID:10205269

  13. High-resolution en face images of microcystic macular edema in patients with autosomal dominant optic atrophy.

    PubMed

    Gocho, Kiyoko; Kikuchi, Sachiko; Kabuto, Takenori; Kameya, Shuhei; Shinoda, Kei; Mizota, Atsushi; Yamaki, Kunihiko; Takahashi, Hiroshi

    2013-01-01

    The purpose of this study was to investigate the characteristics of microcystic macular edema (MME) determined from the en face images obtained by an adaptive optics (AO) fundus camera in patients with autosomal dominant optic atrophy (ADOA) and to try to determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL by using the advantage of AO. Six patients from 4 families with ADOA underwent detailed ophthalmic examinations including spectral domain optical coherence tomography (SD-OCT). Mutational screening of all coding and flanking intron sequences of the OPA1 gene was performed by DNA sequencing. SD-OCT showed a severe reduction in the retinal nerve fiber layer (RNFL) thickness in all patients. A new splicing defect and two new frameshift mutations with premature termination of the Opa1 protein were identified in three families. A reported nonsense mutation was identified in one family. SD-OCT of one patient showed MME in the inner nuclear layer (INL) of the retina. AO images showed microcysts in the en face images of the INL. Our data indicate that AO is a useful method to identify MME in neurodegenerative diseases and may also help determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL. PMID:24369534

  14. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel

    PubMed Central

    González-Perrett, Silvia; Kim, Keetae; Ibarra, Cristina; Damiano, Alicia E.; Zotta, Elsa; Batelli, Marisa; Harris, Peter C.; Reisin, Ignacio L.; Arnaout, M. Amin; Cantiello, Horacio F.

    2001-01-01

    Defects in polycystin-2, a ubiquitous transmembrane glycoprotein of unknown function, is a major cause of autosomal dominant polycystic kidney disease (ADPKD), whose manifestation entails the development of fluid-filled cysts in target organs. Here, we demonstrate that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states, and a high perm-selectivity to Ca2+. This channel was inhibited by anti-polycystin-2 antibody, Ca2+, La3+, Gd3+, and the diuretic amiloride. Channel function by polycystin-2 was confirmed by patch-clamping experiments of polycystin-2 heterologously infected Sf9 insect cells. Further, purified insect cell-derived recombinant polycystin-2 and in vitro translated human polycystin-2 had similar ion channel activity. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD. PMID:11252306

  15. High-Resolution En Face Images of Microcystic Macular Edema in Patients with Autosomal Dominant Optic Atrophy

    PubMed Central

    Kikuchi, Sachiko; Kabuto, Takenori; Mizota, Atsushi; Yamaki, Kunihiko; Takahashi, Hiroshi

    2013-01-01

    The purpose of this study was to investigate the characteristics of microcystic macular edema (MME) determined from the en face images obtained by an adaptive optics (AO) fundus camera in patients with autosomal dominant optic atrophy (ADOA) and to try to determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL by using the advantage of AO. Six patients from 4 families with ADOA underwent detailed ophthalmic examinations including spectral domain optical coherence tomography (SD-OCT). Mutational screening of all coding and flanking intron sequences of the OPA1 gene was performed by DNA sequencing. SD-OCT showed a severe reduction in the retinal nerve fiber layer (RNFL) thickness in all patients. A new splicing defect and two new frameshift mutations with premature termination of the Opa1 protein were identified in three families. A reported nonsense mutation was identified in one family. SD-OCT of one patient showed MME in the inner nuclear layer (INL) of the retina. AO images showed microcysts in the en face images of the INL. Our data indicate that AO is a useful method to identify MME in neurodegenerative diseases and may also help determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL. PMID:24369534

  16. Stable rhodopsin/arrestin complex leads to retinal degeneration in a transgenic mouse model of autosomal dominant retinitis pigmentosa.

    PubMed

    Chen, Jiayan; Shi, Guang; Concepcion, Francis A; Xie, Guifu; Oprian, Daniel; Chen, Jeannie

    2006-11-15

    Over 100 rhodopsin mutation alleles have been associated with autosomal dominant retinitis pigmentosa (ADRP). These mutations appear to cause photoreceptor cell death through diverse molecular mechanisms. We show that K296E, a rhodopsin mutation associated with ADRP, forms a stable complex with arrestin that is toxic to mouse rod photoreceptors. This cell death pathway appears to be conserved from flies to mammals. A genetics approach to eliminate arrestin unmasked the constitutive activity of K296E and caused photoreceptor cell death through a transducin-dependent mechanism that is similar to light damage. Expressing K296E in the arrestin/transducin double knock-out background prevented transducin signaling and led to substantially improved retinal morphology but did not fully prevent cell death caused by K296E. The adverse effect of K296E in the arrestin/transducin knock-out background can be mimicked by constant exposure to low light. Furthermore, we found that arrestin binding causes K296E to mislocalize to the wrong cellular compartment. Accumulation of stable rhodopsin/arrestin complex in the inner segment may be an important mechanism for triggering the cell death pathway in the mammalian photoreceptor cell. PMID:17108167

  17. Cyst infection in autosomal dominant polycystic kidney disease: causative microorganisms and susceptibility to lipid-soluble antibiotics.

    PubMed

    Suwabe, T; Araoka, H; Ubara, Y; Kikuchi, K; Hazue, R; Mise, K; Hamanoue, S; Ueno, T; Sumida, K; Hayami, N; Hoshino, J; Imafuku, A; Kawada, M; Hiramatsu, R; Hasegawa, E; Sawa, N; Takaichi, K

    2015-07-01

    Cyst infection is a frequent and serious complication of autosomal dominant polycystic kidney disease (ADPKD). Lipid-soluble antibiotics like fluoroquinolones show good penetration into cysts and are recommended for cyst infection, but causative microorganisms are often resistant to these agents. This study investigated the profile of the microorganisms causing cyst infection in ADPKD, their susceptibility to lipid-soluble antibiotics, and clinical outcomes. This retrospective study reviewed all ADPKD patients admitted to Toranomon Hospital with a diagnosis of cyst infection from January 2004 to March 2014. All patients who underwent cyst drainage and had positive cyst fluid cultures were enrolled. Patients with positive blood cultures who satisfied our criteria for cyst infection or probable infection were also enrolled. There were 99 episodes with positive cyst fluid cultures and 93 episodes with positive blood cultures. The majority of patients were on dialysis. The death rate was high when infection was caused by multiple microorganisms or when there were multiple infected cysts. Gram-negative bacteria accounted for 74-79 % of the isolates in all groups, except for patients with positive hepatic cyst fluid cultures. The susceptibility of Escherichia coli to fluoroquinolones was very low in patients with hepatic cyst infection, especially those with frequent episodes and those with hepatomegaly. Fungi were detected in two episodes. Fluoroquinolone-resistant microorganisms showed a high prevalence in cyst infection. It is important to identify causative microorganisms to avoid the overuse of fluoroquinolones and to improve the outcome of cyst infection in ADPKD. PMID:25851811

  18. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel.

    PubMed

    González-Perrett, S; Kim, K; Ibarra, C; Damiano, A E; Zotta, E; Batelli, M; Harris, P C; Reisin, I L; Arnaout, M A; Cantiello, H F

    2001-01-30

    Defects in polycystin-2, a ubiquitous transmembrane glycoprotein of unknown function, is a major cause of autosomal dominant polycystic kidney disease (ADPKD), whose manifestation entails the development of fluid-filled cysts in target organs. Here, we demonstrate that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states, and a high perm-selectivity to Ca2+. This channel was inhibited by anti-polycystin-2 antibody, Ca2+, La3+, Gd3+, and the diuretic amiloride. Channel function by polycystin-2 was confirmed by patch-clamping experiments of polycystin-2 heterologously infected Sf9 insect cells. Further, purified insect cell-derived recombinant polycystin-2 and in vitro translated human polycystin-2 had similar ion channel activity. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD. PMID:11252306

  19. Whole-exome sequencing identifies OR2W3 mutation as a cause of autosomal dominant retinitis pigmentosa.

    PubMed

    Ma, Xiangyu; Guan, Liping; Wu, Wei; Zhang, Yao; Zheng, Wei; Gao, Yu-Tang; Long, Jirong; Wu, Na; Wu, Long; Xiang, Ying; Xu, Bin; Shen, Miaozhong; Chen, Yanhua; Wang, Yuewen; Yin, Ye; Li, Yingrui; Xu, Haiwei; Xu, Xun; Li, Yafei

    2015-01-01

    Retinitis pigmentosa (RP), a heterogeneous group of inherited ocular diseases, is a genetic condition that causes retinal degeneration and eventual vision loss. Though some genes have been identified to be associated with RP, still a large part of the clinical cases could not be explained. Here we reported a four-generation Chinese family with RP, during which 6 from 9 members of the second generation affected the disease. To identify the genetic defect in this family, whole-exome sequencing together with validation analysis by Sanger sequencing were performed to find possible pathogenic mutations. After a pipeline of database filtering, including public databases and in-house databases, a novel missense mutation, c. 424 C > T transition (p.R142W) in OR2W3 gene, was identified as a potentially causative mutation for autosomal dominant RP. The mutation co-segregated with the disease phenotype over four generations. This mutation was validated in another independent three-generation family. RT-PCR analysis also identified that OR2W3 gene was expressed in HESC-RPE cell line. The results will not only enhance our current understanding of the genetic basis of RP, but also provide helpful clues for designing future studies to further investigate genetic factors for familial RP. PMID:25783483

  20. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Phenotypic and mutational spectrum in patients from mainland China.

    PubMed

    Yin, Xinzhen; Wu, Dingwen; Wan, Jinping; Yan, Shenqiang; Lou, Min; Zhao, Guohua; Zhang, Baorong

    2014-09-01

    Aims: To analyze the NOTCH3 gene mutations in patients from mainland China clinically suspected to have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and evaluate large intracranial arteries in CADASIL patients. Methods: We performed clinical, neuroimaging and NOTCH3 gene (exons 2-23) examinations in 47 subjects from 34 families. Large intracranial arteries were assessed using magnetic resonance angiography (MRA) in 19 cases with NOTCH3 gene variants. Results: Screening of exons 3 and 4 identified six different known mutations in eight families and two novel mutations in two families. Further screening of the remaining exons identified p.R1175W, a variant of unknown significance. The incidence of NOTCH3 mutations was 29.4% (10/34). Five cases with NOTCH3 mutations showed intracranial atherosclerosis. One patient developed cerebral infarction due to left middle cerebral artery occlusion (M2 segment). Conclusions: The NOTCH3 mutation spectrum in our group was diverse and consistent with those in Caucasians but differed from those in Korea and Taiwan. The screening strategy used in Caucasian populations can be applied to mainland Chinese patients. Atherosclerosis of the large intracranial arteries involvement does not exclude CADASIL diagnosis. PMID:25105908

  1. Four New Families with Autosomal Dominant Partial Epilepsy with Auditory Features: Clinical Description and Linkage to Chromosome 10q24

    PubMed Central

    Winawer, Melodie R.; Boneschi, Filippo Martinelli; Barker-Cummings, Christie; Lee, Joseph H.; Liu, Jianjun; Mekios, Constantine; Gilliam, T. Conrad; Pedley, Timothy A.; Hauser, W. Allen; Ottman, Ruth

    2009-01-01

    Summary Purpose Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a rare form of nonprogressive lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. The gene predisposing to this syndrome was localized to a 10-cM region on chromosome 10q24. We assessed clinical features and linkage evidence in four newly ascertained families with ADPEAF, to refine the clinical phenotype and confirm the genetic localization. Methods We genotyped 41 individuals at seven microsatellite markers spanning the previously defined 10-cM minimal genetic region. We conducted two-point linkage analysis with the ANALYZE computer package, and multipoint parametric and nonparametric linkage analyses as implemented in GENEHUNTER2. Results In the four families, the number of individuals with idiopathic epilepsy ranged from three to nine. Epilepsy was focal in all of those with idiopathic epilepsy who could be classified. The proportion with auditory symptoms ranged from 67 to 100%. Other ictal symptoms also were reported; of these, sensory symptoms were most common. Linkage analysis showed a maximum 2-point LOD score of 1.86 at (? = 0.0 for marker D10S603, and a maximum multipoint LOD score of 2.93. Conclusions These findings provide strong confirmation of linkage of a gene causing ADPEAF to chromosome 10q24. The results suggest that the susceptibility gene has a differential effect on the lateral temporal lobe, thereby producing the characteristic clinical features described here. Molecular studies aimed at the identification of the causative gene are underway. PMID:11879388

  2. Somatotroph Pituitary Adenoma with Acromegaly and Autosomal Dominant Polycystic Kidney Disease – SSTR5 polymorphism and PKD1 mutation

    PubMed Central

    Syro, Luis V.; Sundsbak, Jamie L.; Scheithauer, Bernd W.; Toledo, Rodrigo A.; Camargo, Mauricio; Heyer, Christina M.; Sekiya, Tomoko; Uribe, Humberto; Escobar, Jorge I.; Vasquez, Martin; Rotondo, Fabio; Toledo, Sergio P. A.; Kovacs, Kalman; Horvath, Eva; Babovic-Vuksanovic, Dusica; Harris, Peter C.

    2014-01-01

    A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0–5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48–255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.143C>A (p.L48M, rs4988483) change in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subject to extensive morphological, ultrastructural, cytogenetic and molecular studies. The question arises whether the physical proximity of the PKD1 and SSTR5 genes on chromosome 16 indicates a causal relationship between ADPKD and the somatotroph adenoma. PMID:21744088

  3. White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

    PubMed Central

    Craggs, L J L; Yamamoto, Y; Ihara, M; Fenwick, R; Burke, M; Oakley, A E; Roeber, S; Duering, M; Kretzschmar, H; Kalaria, R N

    2014-01-01

    Background Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. Methods We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. Results The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P?

  4. Laparoscopic Nephrectomy versus Open Nephrectomy for Patients with Autosomal Dominant Polycystic Kidney Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Li, Huibo; Ren, Tong; Ni, Shaobin; Ren, Minghua

    2015-01-01

    Objective To compare efficacy and safety of laparoscopicnephrectomy (LN) versusopen nephrectomy (ON) in the management of autosomal dominant polycystic kidney disease (ADPKD), we conducted a systematic review and meta-analysis. Methods A systematic search of the electronic databases PubMed, Scopus, and the Cochrane Library was performed up to October 2014.This systematic review was performed based on observational comparative studies that assessed the two techniques. The weighted mean difference (WMD) and risk ratio (RR), with their corresponding 95% confidence interval (CI), were calculated to compare continuous and dichotomous variables, respectively. Results Seven studies were identified, including 195 cases (118 LN / 77 ON). Although LN was associated with longer operative time (WMD 30.236, 95%CI 14.541 ?45.932, P<0.001) and the specimen might not have been resected as heavy as the ON group (WMD -986.516, 95%CI -1883.24–-89.795, P = 0.031), patients in this group might benefit from a shorter length of hospital stay (WMD -3.576, 95%CI 4.976–-2.176, P <0.001), less estimated blood loss (WMD -180.245, 95%CI -317.939–-42.556, P = 0.010), and lower need of transfusion (RR 0.345, 95%CI 0.183–0.650, P = 0.001). The LN group also had less overall complications (RR 0.545, 95%CI 0.329–0.903, P = 0.018). The need of narcotic analgesics between the two groups might have no significant difference (WMD -54.66, 95%CI -129.76–20.44, P = 0.154). Conclusion LN for giant symptomatic ADPKD was feasible, safe and efficacious. Morbidity was significantly reduced compared with the open approach. For an experienced laparoscopist, LN might be a better alternative. PMID:26053633

  5. A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.

    PubMed Central

    Torra, R; Badenas, C; San Millán, J L; Pérez-Oller, L; Estivill, X; Darnell, A

    1999-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci (PKD1, PKD2, and PKD3) that account for the disease. Mutations in the PKD2 gene, on the long arm of chromosome 4, are expected to be responsible for approximately 15% of cases of ADPKD. Although ADPKD is a systemic disease, it shows a focal expression, because <1% of nephrons become cystic. A feasible explanation for the focal nature of events in PKD1, proposed on the basis of the two-hit theory, suggests that cystogenesis results from the inactivation of the normal copy of the PKD1 gene by a second somatic mutation. The aim of this study is to demonstrate that somatic mutations are present in renal cysts from a PKD2 kidney. We have studied 30 renal cysts from a patient with PKD2 in which the germline mutation was shown to be a deletion that encompassed most of the disease gene. Loss-of-heterozygosity (LOH) studies showed loss of the wild-type allele in 10% of cysts. Screening of six exons of the gene by SSCP detected eight different somatic mutations, all of them expected to produce truncated proteins. Overall, >/=37% of the cysts studied presented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 were observed in those cysts, which demonstrates that somatic alterations are specific. We have identified second-hit mutations in human PKD2 cysts, which suggests that this mechanism could be a crucial event in the development of cystogenesis in human ADPKD-type 2. PMID:10417277

  6. Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

    PubMed

    Kim, Young-Eun; Yoon, Cindy W; Seo, Sang Won; Ki, Chang-Seok; Kim, Young Bum; Kim, Jong-Won; Bang, Oh Young; Lee, Kwang Ho; Kim, Gyeong-Moon; Chung, Chin-Sang; Na, Duk L

    2014-03-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene on chromosome 19. Previous studies showed that NOTCH3 contains mutational hotspots that can vary among individuals of different ethnic backgrounds. In this study, we investigated the spectrum of NOTCH3 mutations in Korean patients with CADASIL. We retrospectively analyzed 156 patients who underwent NOTCH3 gene testing for molecular diagnosis of CADASIL using Sanger sequencing with a tiered approach. First, we screened previously reported mutational hotspots (exons 2-6, 8, 11, 18, 19, and 22). If no mutation was detected and samples were available, we extended our analysis to additional exons (7, 9, 10, 14, 15, 20, 21, 23, and 25). In 45 of 156 patients (28.8%), 29 mutations and 16 novel variants of unknown significance (VUS) were identified. The p.R544C mutation in exon 11 of NOTCH3 was the most frequently observed mutation (n = 8), followed by p.R75P in exon 3 (n = 7), p.R332C in exon 6 (n = 3), p.R54C in exon 2 (n = 2), and p.R90C in exon 3 (n = 2). Among the VUS, p.R1175W in exon 22, p.S414C in exon 8, and p.N1207S in exon 22 were found in 5, 3, and 2 patients, respectively. Other mutations and VUS were observed in 1 patient each. Although this was not a prospective, nationwide cohort study, the results above suggested that the spectrum of NOTCH3 mutations might be different in Koreans than in individuals of Caucasian ethnicity. Therefore, further analysis of Koreans with CADASIL might be necessary to implement a Korean-specific mutation screening paradigm. PMID:24139282

  7. Refinement of the RP17 locus for autosomal dominant retinitis pigmentosa, construction of a YAC contig and investigation of the candidate gene retinal fascin

    Microsoft Academic Search

    Soraya Bardien-Kruger; Jacquie Greenberg; Benjamin Tubb; Joseph Bryan; Lurdes Queimado; Michael Lovett; Rajkumar S Ramesar

    1999-01-01

    The RP17 locus for autosomal dominant retinitis pigmentosa has previously been mapped to chromosome 17q by linkage analysis. Two unrelated South African families are linked to this locus and the identification of key recombination events assigned the RP17 locus to a 10 cM interval on 17q22. The work reported here refines the mapping of the locus from a 10 cM

  8. Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling

    Microsoft Academic Search

    Steffi Goffart; Helen M. Cooper; Henna Tyynismaa; Sjoerd Wanrooij; Anu Suomalainen; Johannes N. Spelbrink

    2009-01-01

    Mutations in the mitochondrial helicase Twinkle underlie autosomal dominant progressive external ophthal- moplegia (PEO), as well as recessively inherited infantile-onset spinocerebellar ataxia and rare forms of mito- chondrial DNA (mtDNA) depletion syndrome. Familial PEO is typically associated with the occurrence of multiple mtDNA deletions, but the mechanism by which Twinkle dysfunction induces deletion formation has been under debate. Here we

  9. A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions

    Microsoft Academic Search

    Henna Tyynismaa; Emil Ylikallio; Mehul Patel; Maria J. Molnar; Ronald G. Haller; Anu Suomalainen

    2009-01-01

    Autosomal-dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder that is characterized by accumulation of multiple mitochondrial DNA (mtDNA) deletions in postmitotic tissues. The disorder is heterogeneous, with five known nuclear disease genes that encode the proteins ANT1, Twinkle, POLG, POLG2, and OPA1. Defects in these proteins affect mtDNA maintenance, probably leading to stalled replication forks, consequent mtDNA deletion formation,

  10. Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10)

    Microsoft Academic Search

    Lawrence C. S. Tam; Anna-Sophia Kiang; Avril Kennan; Paul F. Kenna; Naomi Chadderton; Marius Ader; Arpad Palfi; Aileen Aherne; Carmen Ayuso; Matthew Campbell; Alison Reynolds; Alex McKee; Marian M. Humphries; G. Jane Farrar; Pete Humphries

    2008-01-01

    Mutations within the inosine 50-monophosphate dehydrogenase 1 (IMPDH1) gene cause the RP10 form of autosomal dominant retinitis pigmentosa (adRP), an early-onset retinopathy resulting in extensive visual handicap owing to progressive death of photoreceptors. Apart from the prevalence of RP10, estimated to account for 5-10% of cases of adRP in United States and Europe, two observations render this form of RP

  11. A new family of Greek origin maps to the CRD locus for autosomal dominant cone-rod dystrophy on 19q

    Microsoft Academic Search

    M Papaioannou; D Bessant; A Payne; J Bellingham; C Rougas; A Loutradis-Anagnostou; C Gregory-Evans; A Balassopoulou; S Bhattacharya

    1998-01-01

    Retinal photoreceptor dystrophies (RD) are a highly heterogeneous group of genetic disorders of the retina, representing the most frequently inherited form of visual handicap, affecting approximately 1.5 million people world wide. To date, more than 40 genetic loci have been implicated in RD. One of them, the CORD2 locus, for an autosomal dominant form of cone-rod dystrophy (CRD), maps to

  12. A Large Homozygous or Heterozygous In-Frame Deletion within the Calcium-Sensing Receptor's Carboxylterminal Cytoplasmic Tail That Causes Autosomal Dominant Hypocalcemia

    Microsoft Academic Search

    ANNE LIENHARDT; MICHELE GARABEDIAN; MEI BAI; CHRISTIANE SINDING; ZAIXIANG ZHANG; JEAN-PIERRE LAGARDE; JEAN BOULESTEIX; MICHEL RIGAUD; EDWARD M. BROWN; MARIE-LAURE KOTTLER

    Autosomal dominant hypocalcemia (ADH) can result from het- erozygous missense activating mutations of the calcium-sensing re- ceptor (CaSR) gene, a G-protein-coupled receptor playing key roles in mineral ion metabolism. We now describe an ADH kindred of three generations caused by a novel CaSR mutation, a large in-frame de- letion of 181 amino acids within its carboxylterminal-tail from S895 to V1075.

  13. The Aromatase Excess Syndrome Is Associated with Feminization of Both Sexes and Autosomal Dominant Transmission of Aberrant P450 Aromatase Gene Transcription

    Microsoft Academic Search

    CONSTANTINE A. STRATAKIS; ALESSANDRA VOTTERO; ANGELA BRODIE; LAWRENCE S. KIRSCHNER; DAVID DEATKINE; QING LU; WEI YUE; CONSTANTINE S. MITSIADES; ARMANDO W. FLOR; GEORGE P. CHROUSOS

    Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and\\/or gynecomastia, and affected females had isosexual precocity and\\/or macromastia. The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old sister had precocious puberty, and their father and

  14. High recurrence of the R1006C NOTCH3 mutation in central Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

    Microsoft Academic Search

    Alessia Cappelli; Michele Ragno; Gabriella Cacchiò; Maria Scarcella; Paolo Staffolani; Luigi Pianese

    2009-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a heritable small-vessel disease caused by mutations in NOTCH3 gene and clinically characterized by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. Direct sequencing of NOTCH3 gene in 90 Italian patients of sixty-three unrelated families identified four heterozygous mutations (R141C and C144F in exon 4,

  15. Identification of lamin A\\/C ( LMNA ) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B

    Microsoft Academic Search

    Chang-Seok Ki; Jong Seo Hong; Gyu-Young Jeong; Kyoung Ju Ahn; Kwang-Mo Choi; Duk-Kyung Kim; Jong-Won Kim

    2002-01-01

    Mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found to cause at least four different kinds of genetic disorders:\\u000a autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD2; MIM 181350); limb-girdle muscular dystrophy type 1B (LGMD1B;\\u000a MIM 159001); dilated cardiomyopathy type 1A (CMD1A; MIM 115200); and familial partial lipodystrophy (FPLD; MIM 151660). Recently,\\u000a we have studied

  16. A new locus on 3p23–p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H

    Microsoft Academic Search

    Luigi Bisceglia; Stefano Zoccolella; Alessandra Torraco; Maria Rosaria Piemontese; Rosa Dell'Aglio; Angela Amati; Patrizia De Bonis; Lucia Artuso; Massimiliano Copetti; Filippo Maria Santorelli; Luigi Serlenga; Leopoldo Zelante; Enrico Bertini; Vittoria Petruzzella

    2010-01-01

    Limb-girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of neuromuscular disorders with a selective or predominant involvement of shoulder and pelvic girdles. We clinically examined 19 members in a four-generation Italian family with autosomal-dominant LGMD. A total of 11 subjects were affected. Clinical findings showed variable expressivity in terms of age at onset and disease severity. Five subjects presented

  17. A Comparison of Progressive Loss of the Ellipsoid Zone (EZ) Band in Autosomal Dominant and X-Linked Retinitis Pigmentosa

    PubMed Central

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

    2014-01-01

    Purpose. In patients with retinitis pigmentosa (RP), the inner segment ellipsoid zone (EZ; also known as the inner segment/outer segment [IS/OS] border) is a marker of the usable visual field at a given point in time and of the progression of the disease over time. Here we compare the change in the width per year of the EZ band in patients with autosomal dominant (ad) and x-linked (xl) RP. Methods. Using optical coherence tomography (OCT), 9-mm horizontal and vertical line scans through the fovea were obtained for one eye of 26 xlRP patients and 33 adRP patients. Scans were repeated on average 2.0 years later (range, 0.6–4.8 years). Using a manual segmentation procedure, the EZ band was delineated and its horizontal width (HW) and vertical width (VW) were determined. Results. The adRP and xlRP patients had similar initial EZ HW (xlRP: 11.8 ± 5.4°, adRP: 12.4 ± 6.3°, P = 0.69) and VW (xlRP: 8.5 ± 4.9°, adRP: 11.4 ± 7.1°, P = 0.09). However, between visits the absolute loss and percent loss of the EZ width per year was significantly greater for xlRP than adRP for both HW (xlRP: 1.0 ± 0.6°/y, 9.6 ± 5.6%/y; adRP: 0.4 ± 0.5°/y, 3.4 ± 5.4%/y; P < 0.001) and VW (xlRP: 0.8 ± 0.8°/y, 9.2 ± 8.9%/y; adRP: 0.3 ± 0.5°/y, 4.2 ± 6.4%/y; P < 0.01). There was a weak correlation between the loss of EZ width per year and the initial width for xlRP (r2 = 0.17, P = 0.036), but no correlation for adRP (r2 = 0.004, P = 0.73). The test–retest difference of EZ HW was 0.2 ± 0.5°. Conclusions. The OCT data here support a faster rate of loss per year in the case of xlRP. (ClinicalTrials.gov number, NCT00100230.) PMID:25342618

  18. The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia ("pallido-ponto-nigral degeneration").

    PubMed

    Reed, L A; Schmidt, M L; Wszolek, Z K; Balin, B J; Soontornniyomkij, V; Lee, V M; Trojanowski, J Q; Schelper, R L

    1998-06-01

    A group of similar autosomal dominant hereditary neurodegenerative disorders have been linked to chromosome 17 in thirteen kindreds. One of these disorders, known as pallido-ponto-nigral degeneration (PPND), is characterized by extensive degeneration of the globus pallidus and substantia nigra as well as accumulation of abnormally phosphorylated tau proteins. The authors now present comprehensive data on the cellular and molecular pathology of PPND, allowing its classification among chromosome 17-linked neurodegenerative disorders as well as its classification among sporadic and other familial tauopathies. First, we showed that PPND is characterized by abundant ballooned neurons in neocortical and subcortical regions as well as by tau-rich inclusions in the cytoplasm of neurons and oligodendroglia morphologically similar to those seen in corticobasal degeneration (CBD), but in a distribution pattern resembling progressive supranuclear palsy (PSP). Second, we demonstrated that antibodies to phosphorylation-independent (Alz50, 133, 304, Tau-2, T-46) as well as phosphorylation-dependent (AT8, PHF-6, 12E8, PHF-1, T3P, pS422) epitopes in human tau proteins stain these glial and neuronal inclusions as intensely as they stain CBD or PSP inclusions. Third, we probed PPND brain by Western blots using some of the same anti-tau antibodies to reveal 2 tau immunobands with molecular weights of 69 kD and 64 kD in gray and white matter extracts, as reported for both PSP and CBD. Finally, electron microscopy showed that these abnormal tau proteins formed flat twisted ribbons with a maximum diameter of 20 nanometers (nm) and a periodicity of about 200 nm, resembling those reported in CBD. Based on this, we conclude that PPND is a hereditary neurodegenerative disorder characterized by neuronal and glial tau-rich inclusions formed from aggregated filaments and hyperphosphorylated tau proteins and, hence, can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders. Further, since the morphologic and biochemical lesions of PPND overlap with those seen in sporadic CBD and PSP, we speculate that these disorders share common pathogenetic mechanisms. PMID:9630238

  19. Isolated and syndromic brachydactylies: Diagnostic value of hand X-rays.

    PubMed

    David, A; Vincent, M; Quéré, M-P; Lefrançois, T; Frampas, E; David, A

    2015-05-01

    Brachydactyly, or shortening of the digits, is due to the abnormal development of phalanges, metacarpals and/or metatarsals. This congenital malformation is common, easily detectable clinically but often requires additional radiological exploration. Radiographs are essential to characterize the type of brachydactyly and to show the location of the bone shortening, as well as any associated malformation. This article reviews the radiological findings for isolated brachydactylies (according to the types classified by Bell, and Temtamy and McKusick) and for brachydactylies that are part of complex multisystem malformation syndromes. If warranted by the clinical and radiological examinations, a genetic analysis (molecular and/or cytogenetic) can confirm the etiologic diagnosis. PMID:25758756

  20. Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a mutation in the arginine-vasopressin II gene in four generations of a Korean family

    PubMed Central

    Kim, Myo-Jing; Kim, Young-Eun; Ki, Chang-Seok

    2014-01-01

    Autosomal dominant neurohypophyseal diabetes insipidus is a rare form of central diabetes insipidus that is caused by mutations in the vasopressin-neurophysin II (AVP-NPII) gene. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). Here we report a case of familial neurohypophyseal diabetes insipidus in four generations of a Korean family, caused by heterozygous missense mutation in exon 2 of the AVP-NPII gene (c.286G>T). This is the first report of such a case in Korea. PMID:25654069

  1. Post transplant urinary tract infection in Autosomal dominant polycystic kidney disease a perpetual diagnostic dilema - 18-fluorodeoxyglucose - Positron emission computerized tomography - A valuable tool

    PubMed Central

    Sainaresh, VV; Jain, SH; Patel, HV; Shah, PR; Vanikar, AV; Trivedi, HL

    2011-01-01

    Urinary tract infection (UTI) is the most common infection contracted by renal allograft recipients. In patients of autosomal dominant polycystic kidney disease (ADPKD), cyst infection presents a complex diagnostic and therapeutic challenge especially in the post transplant period. Accurate diagnosis forms the cornerstone in salvaging the graft from potentially catastrophic outcome. We describe a case of xanthogranulomatous pyelonephritis (XPN) in the native kidney in a patient of post transplant ADPKD which presented as frequently relapsing UTI with graft dysfunction where in accurate diagnosis was made possible with the aid of 18-fluorodeoxyglucose (FDG) - Positron emission computerized tomography (PET/CT). PMID:22174521

  2. c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family

    PubMed Central

    Dantas, Vitor G.L.; Lezirovitz, Karina; Yamamoto, Guilherme L.; Moura de Souza, Carolina Fischinger; Ferreira, Simone Gomes; Mingroni-Netto, Regina C.

    2014-01-01

    We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR – c.G894A:p.R298R and PTGER2 – c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family. PMID:25505834

  3. c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family.

    PubMed

    Dantas, Vitor G L; Lezirovitz, Karina; Yamamoto, Guilherme L; Moura de Souza, Carolina Fischinger; Ferreira, Simone Gomes; Mingroni-Netto, Regina C

    2014-10-01

    We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR - c.G894A:p.R298R and PTGER2 - c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family. PMID:25505834

  4. Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation.

    PubMed

    Wang, Xue; Xin, Qian; Li, Lin; Li, Jiangxia; Zhang, Changwu; Qiu, Rongfang; Qian, Chenmin; Zhao, Hailing; Liu, Yongchao; Shan, Shan; Dang, Jie; Bian, Xianli; Shao, Changshun; Gong, Yaoqin; Liu, Qiji

    2014-09-01

    Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G>T (p.(Gln186His)), in distal-less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1. PMID:24496061

  5. Renal involvement in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): report of a case with a six-year follow-up.

    PubMed

    Ragno, Michele; Trojano, Luigi; Pianese, Luigi; Boni, Maria Virginia; Silvestri, Serena; Mambelli, Vladimiro; Lorenzi, Teresa; Scarpelli, Marina; Morroni, Manrico

    2012-10-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a disorder of the cerebral small blood vessels caused by a mutation in the NOTCH3 gene, which encodes a large transmembrane receptor NOTCH3. It is associated with systemic arteriopathy involving small arteries, besides the brain, in skin, spleen, liver, muscle, aorta and in the kidney. The key pathological finding is the accumulation of granular osmiophilic material (GOM) on degenerating vascular smooth muscle cells. In the kidney GOMs have been described only in a very limited number of CADASIL patients. We describe a genetically confirmed CADASIL patient with mild renal dysfunction and GOMs in the interlobular and juxtaglomerular arteries and, for the first time, also within the glomerulus, whose nephrology conditions remained stable, whereas the neurological manifestations markedly worsened over a six-year follow-up period. The reasons for this discrepancy are probably related to differences in the structure and function of brain and kidney blood vessels. PMID:22936449

  6. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) associated with a novel C82R mutation in the NOTCH3 gene.

    PubMed

    Zea-Sevilla, M Ascensión; Bermejo-Velasco, Pedro; Serrano-Heranz, Regino; Calero, Miguel

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease associated with mutations in the NOTCH3 gene on chromosome 19, and represents the most common hereditary stroke disorder. We describe a pedigree, which suffered the classical clinical CADASIL pattern of migraine headaches, recurrent subcortical infarcts, and subcortical dementia, associated with a previously undescribed missense mutation (c.[244T>C], p.[C82R]) in NOTCH3. This new mutation extends the list of known pathogenic mutations responsible for CADASIL, which are associated with an odd number of cysteine residues within any of the epidermal growth factor-like repeats of Notch3 receptor protein. PMID:25096610

  7. Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred

    SciTech Connect

    Andermann, F.; Andermann, E.; Carpenter, S. [and others

    1994-09-01

    Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.

  8. A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly

    PubMed Central

    Doucette, Lance; Green, Jane; Fernandez, Bridget; Johnson, Gordon J; Parfrey, Patrick; Young, Terry-Lynn

    2011-01-01

    Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G>T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients. PMID:21150893

  9. Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT Syndrome

    PubMed Central

    Boczek, Nicole J.; Best, Jabe M.; Tester, David J.; Giudicessi, John R.; Middha, Sumit; Evans, Jared M.; Kamp, Timothy J.; Ackerman, Michael J.

    2013-01-01

    Background Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results We combined whole exome sequencing (WES) and bioinformatic/systems biology to identify the pathogenic substrate responsible for non-syndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree and established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with “genotype-negative/phenotype-positive” LQTS. WES was utilized on three members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, co-segregated with the disease within the pedigree, was ranked by three disease-network algorithms as the most probable LQTS-susceptibility gene, and involves a conserved residue localizing to the PEST domain in the II–III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain-of-function with increased ICa,L and increased surface membrane expression of the channel compared to wildtype. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2’s PEST domain. Conclusions This study provides evidence that coupling WES and bioinformatic/systems biology is an effective strategy for the identification of potential disease causing genes/mutations. The identification of a functional CACNA1C mutation co-segregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome. PMID:23677916

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

    PubMed Central

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

    2015-01-01

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

  11. Combined Liver and Kidney Transplant in a Patient with Budd-Chiari Syndrome Secondary to Autosomal Dominant Polycystic Kidney Disease Associated with Polycystic Liver Disease: Report of a Case with a 9-Year Follow-Up

    PubMed Central

    Ramírez de la Piscina, Patricia; Duca, Ileana; Estrada, Silvia; Calderón, Rosario; Ganchegui, Idoia; Campos, Amaia; Spicakova, Katerina; Salvador, Marta; Delgado, Elvira; Bengoa, Raquel; García-Campos, Francisco

    2014-01-01

    Polycystic liver disease (PLD) is a hereditary disease inherited by autosomal dominant trait that occurs as a frequent extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). We report a case of a 59-year-old woman diagnosed with ADPKD associated with PLD. End-stage chronic renal failure with a secondary Budd-Chiari syndrome developed during the patient's clinical course. She underwent combined liver and kidney transplantation, with a successful response over a 9-year follow-up period. PMID:24987537

  12. Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene

    Microsoft Academic Search

    G. Siciliano; A. Tessa; S. Petrini; M. Mancuso; C. Bruno; G. S. Grieco; A. Malandrini; L. DeFlorio; B. Martini; A. Federico; G. Nappi; F. M. Santorelli; L. Murri

    2003-01-01

    The authors report on a family with dominantly inherited progressive external ophthalmoplegia and a diagnostic and statistical manual (fourth revised edition) diagnosis of bipolar psychiatric disorder in several members. Skeletal muscle biopsy from the proposita showed decreased cytochrome c oxidase staining, several ragged-red fibers, and multiple mtDNA deletions. The authors identified a missense mutation (leucine 98?proline) in the adenine nucleotide

  13. Autosomal Recessive Transmission of a Rare KRT74 Variant Causes Hair and Nail Ectodermal Dysplasia: Allelism with Dominant Woolly Hair/Hypotrichosis

    PubMed Central

    Raykova, Doroteya; Klar, Joakim; Azhar, Aysha; Khan, Tahir Naeem; Malik, Naveed Altaf; Iqbal, Muhammad; Tariq, Muhammad; Baig, Shahid Mahmood; Dahl, Niklas

    2014-01-01

    Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH. PMID:24714551

  14. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    PubMed

    Raykova, Doroteya; Klar, Joakim; Azhar, Aysha; Khan, Tahir Naeem; Malik, Naveed Altaf; Iqbal, Muhammad; Tariq, Muhammad; Baig, Shahid Mahmood; Dahl, Niklas

    2014-01-01

    Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH. PMID:24714551

  15. U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer’s disease due to autosomal dominant genetic mutations and trisomy 21

    PubMed Central

    2014-01-01

    Background We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer’s disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders. Findings We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF). Conclusions These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant ?-amyloid processing may influence U1 snRNP aggregate formation. PMID:24773620

  16. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family.

    PubMed

    Zhao, Yali; Wang, Dayong; Zong, Liang; Zhao, Feifan; Guan, Liping; Zhang, Peng; Shi, Wei; Lan, Lan; Wang, Hongyang; Li, Qian; Han, Bing; Yang, Ling; Jin, Xin; Wang, Jian; Wang, Jun; Wang, Qiuju

    2014-01-01

    Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear. PMID:24827932

  17. Recovery of Dominant, Autosomal Flightless Mutants of Drosophila Melanogaster and Identification of a New Gene Required for Normal Muscle Structure and Function

    PubMed Central

    Cripps, R. M.; Ball, E.; Stark, M.; Lawn, A.; Sparrow, J. C.

    1994-01-01

    To identify further mutations affecting muscle function and development in Drosophila melanogaster we recovered 22 autosomal dominant flightless mutations. From these we have isolated eight viable and lethal alleles of the muscle myosin heavy chain gene, and seven viable alleles of the indirect flight muscle (IFM)-specific Act88F actin gene. The Mhc mutations display a variety of phenotypic effects, ranging from reductions in myosin heavy chain content in the indirect flight muscles only, to reductions in the levels of this protein in other muscles. The Act88F mutations range from those which produce no stable actin and have severely abnormal myofibrillar structure, to those which accumulate apparently normal levels of actin in the flight muscles but which still have abnormal myofibrils and fly very poorly. We also recovered two recessive flightless mutants on the third chromosome. The remaining five dominant flightless mutations are all lethal alleles of a gene named lethal(3)Laker. The Laker alleles have been characterized and the gene located in polytene bands 62A10,B1-62B2,4. Laker is a previously unidentified locus which is haplo-insufficient for flight. In addition, adult wild-type heterozygotes and the lethal larval trans-heterozygotes show abnormalities of muscle structure indicating that the Laker gene product is an important component of muscle. PMID:8056306

  18. Linkage of a polymorphic marker for the type III collagen gene (COL3A1) to atypical autosomal dominant Ehlers-Danlos syndrome type IV in a large Belgian pedigree

    Microsoft Academic Search

    A. C. Nicholls; A. De Paepe; P. Narcisi; R. Dalgleish; F. De Keyser; M. Matton; F. M. Pope

    1988-01-01

    We have examined a large family in which eleven members have a form of autosomal dominant Ehlers-Danlos syndrome type IV. Analysis of fibroblast cultures from affected individuals showed a partial deficiency of type III collagen production. The protein produced was, however, normal in all aspects examined. Using a restriction site polymorphism associated with the structural gene for human type III

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

    PubMed Central

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

    2015-01-01

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

  20. Disease Progression in Autosomal Dominant Cone-Rod Dystrophy Caused by a Novel Mutation (D100G) in the GUCA1A Gene

    PubMed Central

    Nong, Eva; Lee, Winston; Merriam, Joanna E.; Allikmets, Rando; Tsang, Stephen H.

    2014-01-01

    Purpose To document longitudinal fundus autofluorescence (FAF) and electroretinogram (ERG) findings in a family with cone-rod dystrophy (CRD) caused by a novel missense mutation (D100G) in the GUCA1A gene. Methods Observational case series. Results Three family members 26 to 49 years old underwent complete clinical examinations. In all patients, funduscopic findings showed intraretinal pigment migration, loss of neurosensory retinal pigment epithelium (RPE), and macular atrophy. Fundus autofluorescence (FAF) imaging revealed the presence of a progressive hyperautofluorescent ring around a hypoautofluorescent center corresponding to macular atrophy. Full-field electroretinograms (ERG) showed a more severe loss of cone than rod function in each patient. 30 Hz flicker responses fell far below normal limits. Longitudinal FAF and ERG findings in one patient suggested progressive cone-rod dystrophy. Two more advanced patients exhibited reduced rod response consistent with disease stage. Direct sequencing of the GUCA1A gene revealed a new missense mutation, p.Asp100Gly (D100G), in each patient. Conclusion Patients with autosomal dominant CRD caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG characteristics and subsequent genetic testing. PMID:24352742

  1. Congenital fibrosis of the extraocular muscles (autosomal dominant congenital external ophthalmoplegia): Genetic homogeneity, linkage refinement, and physical mapping on chromosome 12

    SciTech Connect

    Engle, E.C.; Beggs, A.H. [Harvard Medical School, Boston, MA (United States); Marondel, I. [and others

    1995-11-01

    Congenital fibrosis of the extraocular muscles (CFEOM) is an autosomal dominant syndrome of congenital external ophthalmoplegia and bilateral ptosis. We previously reported linkage of this disorder in two unrelated families to an 8-cM region near the centromere of human chromosome 12. We now present refinement of linkage in the original two families, linkage analysis of five additional families, and a physical map of the critical region for the CFEOM gene. In each of the seven families the disease gene is linked to the pericentromeric region of chromosome 12. D12S345, D12S59, D12S331, and D12S1048 do not recombine with the disease gene and have combined lod scores of 35.7, 35.6, 16.0, and 31.4, respectively. AFM136xf6 and AFMb320wd9 flank the CFEOM locus, defining a critical region of 3 cM spanning the centromere of chromosome 12. These data support the concept that this may be a genetically homogeneous disorder. We also describe the generation of a YAC contig encompassing the critical region of the CFEOM locus. This interval has been assigned cytogenetically to 12p11.2-q12 and spans the centromere of chromosome 12. These results provide the basis for further molecular analyses of the structure and organization of the CFEOM locus and will help in the identification of candidate genes. 24 refs., 4 figs., 2 tabs.

  2. Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma

    PubMed Central

    Mackay, Donna S.; Bennett, Thomas M.; Shiels, Alan

    2015-01-01

    Primary open-angle glaucoma (POAG) is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp) in exon-5 of the gene coding for epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H) on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic. PMID:26162006

  3. The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss.

    PubMed

    Kwon, Tae-Jun; Oh, Se-Kyung; Park, Hong-Joon; Sato, Osamu; Venselaar, Hanka; Choi, Soo Young; Kim, SungHee; Lee, Kyu-Yup; Bok, Jinwoong; Lee, Sang-Heun; Vriend, Gert; Ikebe, Mitsuo; Kim, Un-Kyung; Choi, Jae Young

    2014-07-01

    Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene. PMID:25080041

  4. Physical and transcript map of the autosomal dominant colobomatous microphthalmia locus on chromosome 15q12-q15 and refinement to a 4.4 Mb region.

    PubMed

    Michon, Laetitia; Morlé, Laurette; Bozon, Muriel; Duret, Laurent; Zech, Jean-Christophe; Godet, Jacqueline; Plauchu, Henry; Edery, Patrick

    2004-07-01

    Congenital microphthalmia is a developmental disorder characterized by shortened axial length of the eye. We have previously mapped the gene responsible for autosomal dominant colobomatous microphthalmia in a 5-generation family to chromosome 15q12-q15. Here, we set up a physical and transcript map of the 13.8 cM critical region, flanked by loci D15S1002 and D15S1040. Physical mapping and genetic linkage analysis using 20 novel polymorphic markers allowed the refinement of the disease locus to two intervals in close vicinity, namely a centromeric interval, bounded by microsatellite DNA markers m3-m17, and a telomeric interval, m76-m24, encompassing respectively 1.9 and 2.5 Mb. Moreover, we excluded three candidate genes, CKTSF1B1, KLF13 and CX36. Finally, although a phenomenon of anticipation was suggested by phenotypic and pedigree data, no abnormal expansion of three trinucleotide repeats mapping to the refine interval was found in affected individuals. PMID:15083168

  5. The effect of novel mutations on the structure and enzymatic activity of unconventional myosins associated with autosomal dominant non-syndromic hearing loss

    PubMed Central

    Kwon, Tae-Jun; Oh, Se-Kyung; Park, Hong-Joon; Sato, Osamu; Venselaar, Hanka; Choi, Soo Young; Kim, SungHee; Lee, Kyu-Yup; Bok, Jinwoong; Lee, Sang-Heun; Vriend, Gert; Ikebe, Mitsuo; Kim, Un-Kyung; Choi, Jae Young

    2014-01-01

    Mutations in five unconventional myosin genes have been associated with genetic hearing loss (HL). These genes encode the motor proteins myosin IA, IIIA, VI, VIIA and XVA. To date, most mutations in myosin genes have been found in the Caucasian population. In addition, only a few functional studies have been performed on the previously reported myosin mutations. We performed screening and functional studies for mutations in the MYO1A and MYO6 genes in Korean cases of autosomal dominant non-syndromic HL. We identified four novel heterozygous mutations in MYO6. Three mutations (p.R825X, p.R991X and Q918fsX941) produce a premature truncation of the myosin VI protein. Another mutation, p.R205Q, was associated with diminished actin-activated ATPase activity and actin gliding velocity of myosin VI in an in vitro analysis. This finding is consistent with the results of protein modelling studies and corroborates the pathogenicity of this mutation in the MYO6 gene. One missense variant, p.R544W, was found in the MYO1A gene, and in silico analysis suggested that this variant has deleterious effects on protein function. This finding is consistent with the results of protein modelling studies and corroborates the pathogenic effect of this mutation in the MYO6 gene. PMID:25080041

  6. SNP Linkage Analysis and Whole Exome Sequencing Identify a Novel POU4F3 Mutation in Autosomal Dominant Late-Onset Nonsyndromic Hearing Loss (DFNA15)

    PubMed Central

    Park, Kyoung-Jin; Hong, Sung Hwa; Ki, Chang-Seok; Cho, Sang Sun; Venselaar, Hanka; Vriend, Gert; Kim, Jong-Won

    2013-01-01

    Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3rd alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL. PMID:24260153

  7. A Missense Mutation in the Alpha-Actinin 1 Gene (ACTN1) Is the Cause of Autosomal Dominant Macrothrombocytopenia in a Large French Family

    PubMed Central

    Guéguen, Paul; Rouault, Karen; Chen, Jian-Min; Raguénès, Odile; Fichou, Yann; Hardy, Elisabeth; Gobin, Eric; Pan-petesch, Brigitte; Kerbiriou, Mathieu; Trouvé, Pascal; Marcorelles, Pascale; Abgrall, Jean-francois; Le Maréchal, Cédric; Férec, Claude

    2013-01-01

    Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22) with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln) in the alpha-actinin 1 gene (ACTN1) that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes. PMID:24069336

  8. Missense Mutations in POU4F3 Cause Autosomal Dominant Hearing Impairment DFNA15 and Affect Subcellular Localization and DNA Binding

    PubMed Central

    Collin, Rob W.J.; Chellappa, Ramesh; Pauw, Robert-Jan; Vriend, Gert; Oostrik, Jaap; van Drunen, Wendy; Huygen, Patrick L.; Admiraal, Ronald; Hoefsloot, Lies H.; Cremers, Frans P.M.; Xiang, Mengqing; Cremers, Cor W.R.J.; Kremer, Hannie

    2008-01-01

    In a Dutch pedigree suffering from autosomal dominant nonsyndromic hearing impairment (ADNSHI), linkage was found to the locus for DFNA15, with a two-point logarithm of the odds (LOD) score of 5.1. Sequence analysis of the POU4F3 gene that is involved in DFNA15 revealed the presence of a missense mutation (c.865C>T), segregating with the deafness in this family. The mutation is predicted to result in the substitution of a phenylalanine residue for a leucine residue (p.L289F) in the POU homeodomain of the transcription factor POU4F3. Mutation analysis of the POU4F3 gene in 30 patients suffering from dominantly inherited hearing impairment revealed a second novel missense mutation (c.668T>C), resulting in the substitution of a proline for a leucine residue (p.L223P) within the POU-specific DNA-binding domain of the protein. In a computer model describing the structure of the two DNA-binding domains, the alterations are predicted to affect the tertiary structure of these domains. Transient transfection studies showed that whereas the wild-type POU4F3 is located almost exclusively in the nucleus, part of the mutant proteins was also present in the cytoplasm. In addition, both mutant proteins showed greatly reduced capability for binding to DNA as well as transcriptionally activating reporter gene expression. Together, our results describe the identification of the first missense mutations in POU4F3 causing DFNA15. Furthermore, mutations in this gene do not seem to be a rare cause of hearing impairment in the Dutch population, and the POU4F3 gene may thus be suitable for implementation in diagnostic testing. PMID:18228599

  9. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.

    PubMed

    Rendtorff, Nanna D; Lodahl, Marianne; Boulahbel, Houda; Johansen, Ida R; Pandya, Arti; Welch, Katherine O; Norris, Virginia W; Arnos, Kathleen S; Bitner-Glindzicz, Maria; Emery, Sarah B; Mets, Marilyn B; Fagerheim, Toril; Eriksson, Kristina; Hansen, Lars; Bruhn, Helene; Möller, Claes; Lindholm, Sture; Ensgaard, Stefan; Lesperance, Marci M; Tranebjaerg, Lisbeth

    2011-06-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. PMID:21538838

  10. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment

    PubMed Central

    Rendtorff, Nanna D.; Lodahl, Marianne; Boulahbel, Houda; Johansen, Ida R.; Pandya, Arti; Welch, Katherine O.; Norris, Virginia W.; Arnos, Kathleen S.; Bitner-Glindzicz, Maria; Emery, Sarah B.; Mets, Marilyn B.; Fagerheim, Toril; Eriksson, Kristina; Hansen, Lars; Bruhn, Helene; Möller, Claes; Lindholm, Sture; Ensgård, Stefan; Lesperance, Marci M.; Tranebjærg, Lisbeth

    2011-01-01

    Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome. PMID:21538838

  11. Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Grantham, Jared J.

    2010-01-01

    Shortly after being elbowed in the flank during a pickup basketball game, a 35-year-old healthy man has severe, colicky abdominal pain followed by gross hematuria. He is hospitalized, and a renal ultrasound scan reveals bilateral polycystic kidneys and liver cysts, previously unknown to the patient. The blood pressure is 160/100 mm Hg. The serum creatinine concentration is 0.9 mg per deciliter (80 ?mol per liter). The pain subsides in 2 days with analgesics, rest, and fluids; the gross hematuria resolves in 4 days, although microscopic hematuria persists. How should his case be further evaluated and managed? PMID:20009161

  12. Mutational Analysis of the Adaptor Protein 2 Sigma Subunit (AP2S1) Gene: Search for Autosomal Dominant Hypocalcemia Type 3 (ADH3)

    PubMed Central

    Rogers, Angela; Nesbit, M. Andrew; Hannan, Fadil M.; Howles, Sarah A.; Gorvin, Caroline M.; Cranston, Treena; Allgrove, Jeremy; Bevan, John S.; Bano, Gul; Brain, Caroline; Datta, Vipan; Grossman, Ashley B.; Hodgson, Shirley V.; Izatt, Louise; Millar-Jones, Lynne; Pearce, Simon H.; Robertson, Lisa; Selby, Peter L.; Shine, Brian; Snape, Katie; Warner, Justin

    2014-01-01

    Context: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-?11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2? 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3. Objective: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3. Design: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1. Results: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients. Conclusion: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder. PMID:24708097

  13. A detailed phenotypic description of autosomal dominant cone dystrophy due to a de novo mutation in the GUCY2D gene

    PubMed Central

    Mukherjee, R; Robson, A G; Holder, G E; Stockman, A; Egan, C A; Moore, A T; Webster, A R

    2014-01-01

    Purpose The purpose of this study is to describe the phenotype of a family with de novo mutation in the GUCY2D. Materials and methods Five subjects, including two monozygotic twins, underwent ophthalmic clinical examination while some had autofluorescence imaging (AF) and optical coherence tomography (OCT). Symptomatic individuals underwent electrophysiological testing. The youngest subject (21 years) was also evaluated psychophysically. DNA obtained from the individuals was screened for mutations in GUCY2D. Microsatellite markers were used to determine the haplotype of 17p surrounding the GUCY2D gene. Results The youngest subject had 6/18 visual acuity, an annulus of hyper-autofluorescence in the perifoveal region, and a subfoveal absence of outer segments on OCT. In the older individuals, severe thinning of inner retina and a patchy loss of photoreceptors and retinal pigment epithelium were observed in the perifoveal region. All three showed generalised cone system dysfunction with preserved rod function on electrophysiology. Psychophysical evaluation was consistent with poor cone function. Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals and was absent in the asymptomatic patients. Haplotyping showed that the mutation originated from the unaffected mother. Conclusions Autosomal dominant cone dystrophy due to GUCY2D can occur without a history in the antecedents due to a de novo mutation. This is important to consider in any simplex case with a similar phenotype. The phenotype description of this disorder is expanded with detailed description of the OCT findings. This paper describes the concordance of the phenotypic findings in the monozygotic twins. PMID:24480840

  14. Comprehensive Genetic Screening of KCNQ4 in a Large Autosomal Dominant Nonsyndromic Hearing Loss Cohort: Genotype-Phenotype Correlations and a Founder Mutation

    PubMed Central

    Naito, Takehiko; Nishio, Shin-ya; Iwasa, Yoh-ichiro; Yano, Takuya; Kumakawa, Kozo; Abe, Satoko; Ishikawa, Kotaro; Kojima, Hiromi; Namba, Atsushi; Oshikawa, Chie; Usami, Shin-ichi

    2013-01-01

    The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions. PMID:23717403

  15. Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome Molecular, Cellular, and Clinical Features From a French National Survey

    PubMed Central

    Chandesris, Marie-Olivia; Melki, Isabelle; Natividad, Angels; Puel, Anne; Fieschi, Claire; Yun, Ling; Thumerelle, Caroline; Oksenhendler, Eric; Boutboul, David; Thomas, Caroline; Hoarau, Cyrille; Lebranchu, Yvon; Stephan, Jean-Louis; Cazorla, Celine; Aladjidi, Nathalie; Micheau, Marguerite; Tron, Fran[cedil]cois; Baruchel, Andre; Barlogis, Vincent; Palenzuela, Gilles; Mathey, Catherine; Dominique, Stephane; Body, Gerard; Munzer, Martine; Fouyssac, Fanny; Jaussaud, Rolland; Bader-Meunier, Brigitte; Mahlaoui, Nizar; Blanche, Stephane; Debre, Marianne; Le Bourgeois, Muriel; Gandemer, Virginie; Lambert, Nathalie; Grandin, Virginie; Ndaga, Stephanie; Jacques, Corinne; Harre, Chantal; Forveille, Monique; Alyanakian, Marie-Alexandra; Durandy, Anne; Bodemer, Christine; Suarez, Felipe; Hermine, Olivier; Lortholary, Olivier; Casanova, Jean-Laurent; Fischer, Alain; Picard, Capucine

    2013-01-01

    Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented. PMID:22751495

  16. End-stage renal disease in autosomal dominant polycystic kidney disease: a comparison of dialysis-related utilization and costs with other chronic kidney diseases

    PubMed Central

    Brunelli, Steven M; Blanchette, Christopher M; Claxton, Ami J; Roy, Debosree; Rossetti, Sandro; Gutierrez, Benjamin

    2015-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD) and one of the leading causes of ESRD overall. ADPKD patients differ from the overall dialysis population; however, there is little published data regarding health care costs for ADPKD patients on dialysis. Methods This retrospective observational cohort study was designed to quantify health care utilization and costs for ADPKD patients with ESRD who received initial services at a single large dialysis organization between January 1, 2007 and December 31, 2009. Parallel results and baseline patient characteristics for control patients with ESRD etiologies other than ADPKD were performed for reference. Dialysis-related utilization and health care costs for patients with ADPKD in ESRD overall and during time horizons that correspond to Medicare-eligibility benchmarks were analyzed. Baseline patient characteristics were described for all patients and included demographics, comorbid illnesses, and clinical characteristics. Dialysis-related utilization, hospitalization rates, and health care costs were considered longitudinally. Results Total health care costs for ADPKD patients were high at US$51,048 per patient-year based on the overall analysis. Total health care costs were lower for ADPKD patients than for control patients on dialysis. Patients with ADPKD were generally younger, had a lower Charlson Comorbidity Index, and had lower rates of comorbid conditions, which may have contributed to the lower overall costs seen for patients with ADPKD. Conclusion Health care resource utilization and costs for patients with ADPKD in ESRD requiring dialysis were high, and therapeutic interventions that can prevent or delay the progression to ESRD may increase dialysis-free life for patients with ADPKD. PMID:25609987

  17. First report of OPA1 screening in Greek patients with autosomal dominant optic atrophy and identification of a previously undescribed OPA1 mutation

    PubMed Central

    Koutsodontis, George; Tsilimbaris, Miltiadis; Fitsios, Athanasios; Chrousos, Georgia

    2014-01-01

    Purpose To describe the genotype–phenotype correlation in four Greek pedigrees with autosomal dominant optic atrophy (ADOA) and OPA1 mutations. Methods Seven patients from four unrelated families (F1, F2, F3, F4) were clinically assessed for visual acuity, color vision, ptosis, afferent pupillary defects, and visual fields and underwent orthoptic assessment, slit-lamp biomicroscopy, and fundus examination to establish their clinical status. Genomic DNA was extracted from peripheral blood samples from all participants. The coding region (exons 1–28), including the intron-exon boundaries of the OPA1 gene, was screened in the probands of the four families, as well as in seven additional family members (four affected and three unaffected) with PCR and direct DNA sequencing. Results All patients presented bilateral decrease in best-corrected visual acuity and temporal pallor of the optic disc. The visual fields of the adult patients showed characteristic scotomata. Other signs were present in some patients such as decreased color discrimination and a gray crescent within the neuroretinal rim. After the OPA1 gene was sequenced, a previously undescribed heterozygous splice-site mutation c.784–1G>T in intron 7 was detected in family F2. In families F1, F3, and F4, a previously reported in-frame deletion c.876_878delTGT/p.(Val294del), the frameshift c.2366delA/p.(Asn789Metfs*11), and splice-site c.1140+5G>C mutations were detected, respectively. Conclusions This is the first report of molecular characterization of Greek patients with ADOA. Our findings provide additional information regarding the genotype-phenotype correlation and establish the role of the OPA1 gene in Greek patients with ADOA. PMID:24883014

  18. A kindred exhibiting cosegregation of an overlap connective tissue disorder and the chromosome 16 linked form of autosomal dominant polycystic kidney disease.

    PubMed

    Somlo, S; Rutecki, G; Giuffra, L A; Reeders, S T; Cugino, A; Whittier, F C

    1993-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a disorder of adult onset manifested by bilaterally enlarged cystic kidneys frequently associated with progressive renal failure. The mutated gene (PKD1) responsible for 85 to 95% of cases has been localized to a small segment on the distal tip of the short arm of chromosome 16. A clinical spectrum of heritable connective tissue disorders that remain unclassifiable under the present nosology but that contain elements of the Marfan's syndrome have previously been described. The genetic localization and molecular basis of such overlap connective tissue disorders (OCTD) have not been elucidated. In this report, a kindred in which ADPKD and OCTD appear to cosegregate is described. The connective tissue phenotype in this family includes aortic root dilation, aortic and vertebral artery aneurysms with dissection, and aortic valve incompetence, as well as pectus abnormalities, pes planus, joint laxity, arachnodactyly, scoliosis, dolichostenomelia, and high arched palate. ADPKD was manifest primarily as bilateral renal cysts with or without renal failure. The DNA of all living family members was studied with markers recognizing polymorphic loci flanking the PKD1 region (3'HVR and O90a), as well as markers from the loci of chromosomes 15 and 5, associated with fibrillin genes FBN1 and FBN2, respectively. In this kindred of 20 family members traced through five generations, cosegregation of ADPKD and the OCTD phenotype was observed in 12 of 12 meioses and 3 of 3 phase known. Both markers for PKD1 were tightly linked to both ADPKD and OCTD, whereas there was no evidence for linkage with either fibrillin locus. In this family, the ADPKD and OCTD mutations are genetically linked. The presence of OCTD with ADPKD identifies a group of patients at significantly greater risk for sudden death from aortic root and other vascular aneurysmal dissection and rupture. PMID:8130364

  19. Mapping of a First Locus for Autosomal Dominant Myxomatous Mitral-Valve Prolapse to Chromosome 16p11.2-p12.1

    PubMed Central

    Disse, Sandra; Abergel, Eric; Berrebi, Alain; Houot, Anne-Marie; Le Heuzey, Jean-Yves; Diebold, Benoît; Guize, Louis; Carpentier, Alain; Corvol, Pierre; Jeunemaitre, Xavier

    1999-01-01

    Summary Myxomatous mitral-valve prolapse (MMVP), also called Barlow disease, is a common cardiac abnormality and affects up to 5% of the population. It is characterized by an excess of tissue that leads to billowing of the mitral leaflets, sometimes complicated by prolapse. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Previous reports have proposed an autosomal dominant inheritance of the trait, with age- and sex-dependent expression. By systematic echocardiographic screening of the first-degree relatives of 17 patients who underwent mitral-valve repair, we have identified four pedigrees showing such an inheritance. Genomewide linkage analysis of the most informative pedigree (24 individuals, three generations) showed a significant linkage for markers mapping to chromosome 16p, with a two-point maximum LOD score for D16S3068 (Zmax=3.30 at ?=0). Linkage to D16S3068 was confirmed in a second family (Zmax=2.02 at ?=0) but was excluded for the two remaining families, thus demonstrating the genetic heterogeneity of the disease. Multipoint linkage analysis performed, with nine additional markers, on the two families with linkage gave maximum multipoint LOD scores of 5.45 and 5.68 for D16S3133, according to a conservative and a stringent model, respectively. Haplotype analysis defined a 5-cM minimal MMVP-1 locus between D16S3068 (16p11.2) and D16S420 (16p12.1) and a 34-cM maximal interval between D16S404 and D16S3068 when recombination events were taken into account only in affected individuals. The identification of this locus represents a first step toward a new molecular classification of mitral-valve prolapse. PMID:10521289

  20. Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Kojis, T.L.; Heinzmann, C.; Ngo, J.T. [UCLA School of Medicine, LA (United States)] [and others

    1996-02-01

    In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families. 39 refs., 4 figs., 3 tabs.

  1. Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.

    PubMed

    Farrow, Emily G; Yu, Xijie; Summers, Lelia J; Davis, Siobhan I; Fleet, James C; Allen, Matthew R; Robling, Alexander G; Stayrook, Keith R; Jideonwo, Victoria; Magers, Martin J; Garringer, Holly J; Vidal, Ruben; Chan, Rebecca J; Goodwin, Charles B; Hui, Siu L; Peacock, Munro; White, Kenneth E

    2011-11-15

    Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR. PMID:22006328

  2. Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome

    PubMed Central

    Kruszka, Paul; Li, Dong; Harr, Margaret H; Wilson, Nathan R; Swarr, Daniel; McCormick, Elizabeth M; Chiavacci, Rosetta M; Li, Mindy; Martinez, Ariel F; Hart, Rachel A; McDonald-McGinn, Donna M; Deardorff, Matthew A; Falk, Marni J; Allanson, Judith E; Hudson, Cindy; Johnson, John P; Saadi, Irfan; Hakonarson, Hakon; Muenke, Maximilian; Zackai, Elaine H

    2015-01-01

    Background Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated. Methods and results In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A ( p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family. Conclusions Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2. PMID:25412741

  3. Urinary excretion of AQP2 and ENaC in autosomal dominant polycystic kidney disease during basal conditions and after a hypertonic saline infusion.

    PubMed

    Graffe, Carolina Cannillo; Bech, Jesper Nørgaard; Lauridsen, Thomas Guldager; Pedersen, Erling Bjerregaard

    2012-04-15

    Renal handling of sodium and water is abnormal in chronic kidney diseases. To study the function and regulation of the aquaporin-2 water channel (AQP2) and the epithelial sodium channel (ENaC) in autosomal dominant polycystic kidney disease (ADPKD), we measured urinary excretion of AQP2 (u-AQP2), the ?-subunit of ENaC (u-ENaC(?)), cAMP (u-cAMP), and prostaglandin E(2) (u-PGE(2)); free water clearance (C(H2O)); fractional sodium excretion (FE(Na)); and plasma vasopressin (p-AVP), renin (p-Renin), angiotensin II (p-ANG II), aldosterone (p-Aldo), and atrial and brain natriuretic peptide (p-ANP, p-BNP) in patients with ADPKD and healthy controls during 24-h urine collection and after hypertonic saline infusion during high sodium intake (HS; 300 mmol sodium/day) and low sodium intake (LS; 30 mmol sodium/day). No difference in u-AQP2, u-ENaC(?), u-cAMP, u-PGE(2), C(H2O), and vasoactive hormones was found between patients and controls at baseline, but during HS the patients had higher FE(Na). The saline caused higher increases in FE(Na) in patients than controls during LS, but the changes in u-ENaC(?), p-Aldo, p-ANP, p-BNP, p-Renin, and p-ANG II were similar. Higher increases in u-AQP2 and p-AVP were seen in patients during both diets. In conclusion, u-AQP2 and u-ENaC(?) were comparable in patients with ADPKD and controls at baseline. In ADPKD, the larger increase in u-AQP2 and p-AVP in response to saline could reflect an abnormal water absorption in the distal nephron. During LS, the larger increase in FE(Na) in response to saline could reflect a defective renal sodium retaining capacity in ADPKD, unrelated to changes in u-ENaC(?). PMID:22262484

  4. Rationale and Design of the DIPAK 1 Study: A Randomized Controlled Clinical Trial Assessing the Efficacy of Lanreotide to Halt Disease Progression in Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Meijer, Esther; Drenth, Joost P.H.; d’Agnolo, Hedwig; Casteleijn, Niek F.; de Fijter, Johan W.; Gevers, Tom J.; Kappert, Peter; Peters, Dorien J.M.; Salih, Mahdi; Soonawala, Darius; Spithoven, Edwin M.; Torres, Vicente E.; Visser, Folkert W.; Wetzels, Jack F.M.; Zietse, Robert; Gansevoort, Ron T.

    2014-01-01

    Background There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. Study Design The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. Setting & Participants We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 who are aged 18-60 years. Intervention Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. Outcomes Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. Measurements Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. Results Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m2 per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided ? = 0.05, and 20% protocol violators and/or dropouts. Limitations The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. Conclusions The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD. PMID:24342522

  5. Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese

    Microsoft Academic Search

    Hisakuni Fukuoka; Yukihiko Kanda; Shuji Ohta; Shin-ichi Usami

    2007-01-01

    Mutations in WFS1 are reported to be responsible for two conditions with distinct phenotypes; DFNA6\\/14\\/38 and autosomal recessive Wolfram syndrome.\\u000a They differ in their associated symptoms and inheritance mode, and although their most common clinical symptom is hearing\\u000a loss, it is of different types. While DNFA6\\/14\\/38 is characterized by low frequency sensorineural hearing loss (LFSNHL), in\\u000a contrast, Wolfram syndrome is

  6. Non-Syndromic Brachydactyly Type D and Type E Mapped to 7p15 in Healthy Children and Adults from the Jirel Ethnic Group in Eastern Nepal

    PubMed Central

    Williams, Kimberly D.; Blangero, John; Subedi, Janardan; Jha, Bharat; Dyer, Thomas; VandeBerg, John L.; Towne, Bradford; Williams-Blangero, Sarah

    2014-01-01

    Objectives There is phenotypic overlap between Brachydactyly Type D (BDD) and Brachydactyly Type E (BDE) that suggests a possible common underlying etiology. We seek to understand the genetic underpinnings of, and relationship between, these skeletal anomalies. Methods The Jirel ethnic group of eastern Nepal participates in various genetic epidemiologic studies, including those in which hand-wrist radiographs have been taken to examine skeletal development. 2,130 individuals (969 males; 1,161 females) were phenotyped for BDD/BDE. Of these, 1,722 individuals (773 males; 949 females) were genotyped for 371 STR markers spanning the autosomal genome. Variance components-based linkage analysis was used to conduct a genome-wide linkage scan for QTL influencing the BDD/BDE phenotype. Results BDD was present in 3.55%, and BDE was present in 0.39%, of the study sample. Because of the phenotypic overlap between two traits, affecteds of either type were considered as affected by a single combined phenotype (BDD/BDE) having a prevalence of 3.94%. The additive genetic heritability of BDD/BDE was highly significant (h2 ± SE = 0.89 ± 0.13; p = 1.7×10?11). Significant linkage of BDD/BDE was found to markers on chromosome 7p21-7p14 (peak LOD score = 3.74 at 7p15 between markers D7S493 and D7S516). Conclusions Possible positional candidate genes in the one-lod support interval of this QTL include TWIST and the HOXA1-A13 cluster. This is the first study to report significant linkage results for BDD/BDE using a large extended pedigree, and the first to suggest that mutations in TWIST and/or the HOXA1-A13 cluster may contribute to these specific skeletal anomalies. PMID:24022874

  7. Sex-linked dominant

    MedlinePLUS

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... type of chromosome that is affected (autosomal or sex chromosome). It also depends on whether the trait ...

  8. Nuclear gene causing multiple mtDNA deletions in autosomal dominant ophthalmoplegia maps to a distinct chromosomal region - involvement of both nuclear and mitochondrial DNA in a single disorder

    SciTech Connect

    Suomalainen, A.; Kaukonen, J.; Timonen, R. [Univ. of Helsinki (Finland)] [and others

    1994-09-01

    Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by muscle weakness, most prominent in ocular muscles. The symptoms are caused by accumulation of multiple large deletions of mitochondrial DNA (mtDNA) in the tissues of the patient, especially in those tissues that are most dependent on oxidative metabolism: brain, skeletal muscle and heart. However, the disorder shows autosomal dominant way of transmission, suggesting a primary defect in a nuclear encoded protein, which only secondarily results in mtDNA deletions. The candidate genes could be those actively participating in the mtDNA replication, or those associated with oxidative metabolism and e.g. via overproduction or inefficient elimination of fire oxygen radicals fragmenting mtDNA. We applied random mapping approach to localize the autosomal adPEO gene locus in a large Finnish family. The affected subjects were identified by detection of multiple mtDNA deletions in the Southern blot analysis of DNA extracted from the muscle biopsy specimens. All the family members underwent muscle biopsy. After analysis of 248 highly polymorphic dinucleotide repeat markets dispersed throughout the genome we were able to assign the adPEO gene locus to a distinct chromosomal region with the maximum pairwise lod score of 4.52, recombination fraction 0.0. This is the first evidence that a mutation in a nuclear gene may interfere mtDNA. The pathogenesis of adPEO involves both the genomes: the primary nuclear gene defect leads to secondary mtDNA mutations that cause the symptoms of the patients.

  9. Two novel homozygous missense mutations in the GDF5 gene cause brachydactyly type C.

    PubMed

    Al-Qattan, Mohammad M; Al-Motairi, Muhammed I; Al Balwi, Mohammed A

    2015-07-01

    Mutations of the GDF5 gene cause a variable phenotype including brachydactyly type C. A review of the literature showed that it is caused either by heterozygous frameshift mutations within the prodomain or heterozygous missense/nonsense mutations within the active domain. Only a single patient with a homozygous mutation (c.517A?>?G, which predicts p. Met173Val) has been reported in this disorder. In this paper, we report two children with novel homozygous missense mutations in the GDF5 gene associated with brachydactyly type C: one mutation was within the region coding for the prodomain (c.608C?>?A, which predicts p.Thr203Asn) and the other was within the region coding for the active domain (c.1456 G?>?A, which predicts p.Val486Met). The genotype-phenotype correlations in the mutational spectrum of the GDF5 gene are discussed. © 2015 Wiley Periodicals, Inc. PMID:25820810

  10. Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature.

    PubMed

    Wang, Jian; Wang, Zhigang; An, Yu; Wu, Chunxing; Xu, Yunlan; Fu, Qihua; Shen, Yiping; Zhang, Qinghua

    2015-06-15

    Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated. PMID:25801215

  11. Syndrome of Ichthyosis congenita, Neurosensory Deafness, Oligophrenia, Dental Aplasia, Brachydactyly, Clinodactyly, Accessory Cervical Ribs and Carcinoma of the Thyroid

    Microsoft Academic Search

    Thomas Ruzicka; Günter Goerz; Ingrun Anton-Lamprecht

    1981-01-01

    We report the case of a 15-year-old girl with an uneventful family history. Her skin condition was clinically, histologically and ultrastructurally compatible with the diagnosis of ichthyosis congenita. She suffered from neurosensory deafness and oligophrenia. Further findings included dental aplasia, brachydactyly, clinodactyly and accessory cervical ribs. At the age of 14, a thyroid carcinoma was diagnosed. Therapy with a retinoid

  12. Complete Heart Block with Diastolic Heart Failure and Pulmonary Edema Secondary to Enlarging Previously Diagnosed Thrombosed Aneurysm of Sinus of Valsalva in a Patient with History of Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Eltawansy, Sherif Ali; Thomas, Maria Joana; Daniels, Jeffrey

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is associated with vascular aneurysms that can affect any part of the vascular tree, like ascending aorta or coronary arteries. Sinus of Valsalva is known as an anatomical dilation at the root of aorta above the aortic valve and very few cases show aneurysm at that site in patients with ADPKD. Sinus of Valsalva aneurysm (SVA) can present with rupture and acute heart failure and infective endocarditis or could be asymptomatic accidentally discovered during cardiac catheterization. We report a case of a 76-year-old male with a unique constellation of cardiovascular anomalies associated with ADPKD. Patient was previously diagnosed with aneurysms affecting ascending aorta, sinus of Valsalva, and coronary arteries. Several years later, he came with complete heart block which was discovered later to be secondary to enlargement of his previously diagnosed thrombosed SVA. His case was complicated with acute heart failure and pulmonary edema. Conclusion. Patients with ADPKD can present with extrarenal manifestations. In our case, aneurysm at sinus of Valsalva was progressively enlarging and presented with complete heart block. PMID:25861484

  13. Complete heart block with diastolic heart failure and pulmonary edema secondary to enlarging previously diagnosed thrombosed aneurysm of sinus of valsalva in a patient with history of autosomal dominant polycystic kidney disease.

    PubMed

    Eltawansy, Sherif Ali; Amor, Martin Miguel; Thomas, Maria Joana; Daniels, Jeffrey

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is associated with vascular aneurysms that can affect any part of the vascular tree, like ascending aorta or coronary arteries. Sinus of Valsalva is known as an anatomical dilation at the root of aorta above the aortic valve and very few cases show aneurysm at that site in patients with ADPKD. Sinus of Valsalva aneurysm (SVA) can present with rupture and acute heart failure and infective endocarditis or could be asymptomatic accidentally discovered during cardiac catheterization. We report a case of a 76-year-old male with a unique constellation of cardiovascular anomalies associated with ADPKD. Patient was previously diagnosed with aneurysms affecting ascending aorta, sinus of Valsalva, and coronary arteries. Several years later, he came with complete heart block which was discovered later to be secondary to enlargement of his previously diagnosed thrombosed SVA. His case was complicated with acute heart failure and pulmonary edema. Conclusion. Patients with ADPKD can present with extrarenal manifestations. In our case, aneurysm at sinus of Valsalva was progressively enlarging and presented with complete heart block. PMID:25861484

  14. Dissociation of Pupillary Post-Illumination Responses from Visual Function in Confirmed OPA1 c.983A?>?G and c.2708_2711delTTAG Autosomal Dominant Optic Atrophy

    PubMed Central

    Nissen, Claus; Rönnbäck, Cecilia; Sander, Birgit; Herbst, Kristina; Milea, Dan; Larsen, Michael; Lund-Andersen, Henrik

    2015-01-01

    Purpose: To test whether the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs), as evaluated by examination of the pupillary light reflex (PLR), are preserved in genetically confirmed autosomal dominant optic atrophy (ADOA). Method: Twenty-nine patients with either the c.983A?>?G (n?=?14) or the c.2708_ 2711delTTAG mutation (n?=?15) were examined with monochromatic pupillometry, using isoluminant (300?cd/m2), red (660?nm) or blue (470?nm) light, optical coherence tomography, automated visual field analysis, and with determination of best corrected visual acuity (BCVA). Since we examined two different mutations, initially we compared all outcome variables between the two, and finding no statistically significant difference, pooled them. Results: Despite a poor BCVA (56 letters, ETDRS) in the ADOA patients, their post-illuminatory pupil responses did not differ significantly from those of healthy controls (blue, p?=?0.45, red, p?=?0.49, t-test), and no statistically significant effect was noted of peripapillary retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, or age. Conclusion: The PLR to blue light of high luminance (300?cd/m2) was preserved in both c.983A?>?G and c.2708_2711delTTAG ADOA despite severe visual loss and optic nerve atrophy. The study confirms, in a large sample of two genetically homogenous groups, that the ipRGCs are spared in ADOA. PMID:25699009

  15. Recurrence risks for Mendelian traits Autosomal Dominant

    E-print Network

    Dellaire, Graham

    ;· Definition ­ Multifactorial Trait · Trait determined by multiple genetic and environmental factors, which by genetic and environmental factors #12;#12;#12;#12;#12;#12;HIV Environmental exposure Mutated CCR5 receptor

  16. Genetics Home Reference: Autosomal dominant vitreoretinochoroidopathy

    MedlinePLUS

    ... the back of the eye called the retinal pigment epithelium. This cell layer supports and nourishes the ... that detect light and color. In the retinal pigment epithelium, bestrophin-1 functions as a channel that ...

  17. A Point Mutation in the Ubiquitin Ligase RNF170 That Causes Autosomal Dominant Sensory Ataxia Destabilizes the Protein and Impairs Inositol 1,4,5-Trisphosphate Receptor-mediated Ca2+ Signaling.

    PubMed

    Wright, Forrest A; Lu, Justine P; Sliter, Danielle A; Dupré, Nicolas; Rouleau, Guy A; Wojcikiewicz, Richard J H

    2015-05-29

    RNF170 is an endoplasmic reticulum membrane ubiquitin ligase that contributes to the ubiquitination of activated inositol 1,4,5-trisphosphate (IP3) receptors, and also, when point mutated (arginine to cysteine at position 199), causes autosomal dominant sensory ataxia (ADSA), a disease characterized by neurodegeneration in the posterior columns of the spinal cord. Here we demonstrate that this point mutation inhibits RNF170 expression and signaling via IP3 receptors. Inhibited expression of mutant RNF170 was seen in cells expressing exogenous RNF170 constructs and in ADSA lymphoblasts, and appears to result from enhanced RNF170 autoubiquitination and proteasomal degradation. The basis for these effects was probed via additional point mutations, revealing that ionic interactions between charged residues in the transmembrane domains of RNF170 are required for protein stability. In ADSA lymphoblasts, platelet-activating factor-induced Ca(2+) mobilization was significantly impaired, whereas neither Ca(2+) store content, IP3 receptor levels, nor IP3 production were altered, indicative of a functional defect at the IP3 receptor locus, which may be the cause of neurodegeneration. CRISPR/Cas9-mediated genetic deletion of RNF170 showed that RNF170 mediates the addition of all of the ubiquitin conjugates known to become attached to activated IP3 receptors (monoubiquitin and Lys(48)- and Lys(63)-linked ubiquitin chains), and that wild-type and mutant RNF170 have apparently identical ubiquitin ligase activities toward IP3 receptors. Thus, the Ca(2+) mobilization defect seen in ADSA lymphoblasts is apparently not due to aberrant IP3 receptor ubiquitination. Rather, the defect likely reflects abnormal ubiquitination of other substrates, or adaptation to the chronic reduction in RNF170 levels. PMID:25882839

  18. Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome.

    PubMed

    Morris, Benjamin; Etoubleau, Cécile; Bourthoumieu, Sylvie; Reynaud-Perrine, Sandrine; Laroche, Cécile; Lebbar, Aziza; Yardin, Catherine; Elsea, Sarah H

    2012-08-01

    Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage-dependent manner. PMID:22753018

  19. Brachydactyly and mental retardation: An Albright hereditary osteodystrophy-like syndrome localized to 2q37

    SciTech Connect

    Wilson, L.C. [Univ. of Leicester (United Kingdom)]|[Institute of Child Health, London (United Kingdom); Oude Luttikhuis, M.E.M. [Univ. of Leicester (United Kingdom); Duckett, D.P.; Barrow, M.A. [Leicestershire Genetics Centre, Leicester (United Kingdom); Leverton, K.; Read, A.P. [St. Mary`s Hospital, Manchester (United Kingdom); Oley, C.A.; Wolstenholme, J. [Univ. of Newcastle upon Tyne (United Kingdom); Flint, J. [Institute of Molecular Medicine, Oxford (United Kingdom); Leonard, J.V. [Institute of Child Health, London (United Kingdom)] [and others

    1995-02-01

    We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the {alpha} subunit of Gs (Gs{alpha}), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly. 28 refs., 6 figs., 1 tab.

  20. Molecular analysis of two novel missense mutations in the GDF5 proregion that reduce protein activity and are associated with brachydactyly type C.

    PubMed

    Stange, Katja; Thieme, Tino; Hertel, Karen; Kuhfahl, Silke; Janecke, Andreas R; Piza-Katzer, Hildegunde; Penttinen, Maila; Hietala, Marja; Dathe, Katarina; Mundlos, Stefan; Schwarz, Elisabeth; Seemann, Petra

    2014-09-23

    Growth and differentiation factor 5 (GDF5) plays a central role in bone and cartilage development by regulating the proliferation and differentiation of chondrogenic tissue. GDF5 is synthesized as a preproprotein. The biological function of the proregion comprising 354 residues is undefined. We identified two families with a heterozygosity for the novel missense mutations p.T201P or p.L263P located in the proregion of GDF5. The patients presented with dominant brachydactyly type C characterized by the shortening of skeletal elements in the distal extremities. Both mutations gave rise to decreased biological activity in in vitro analyses. The variants reduced the GDF5-induced activation of SMAD signaling by the GDF5 receptors BMPR1A and BMPR1B. Ectopic expression in micromass cultures yielded relatively low protein levels of the variants and showed diminished chondrogenic activity as compared to wild-type GDF5. Interestingly, stimulation of micromass cells with recombinant human proGDF5(T201P) and proGDF5(L263P) revealed their reduced chondrogenic potential compared to the wild-type protein. Limited proteolysis of the mutant recombinant proproteins resulted in a fragment pattern profoundly different from wild-type proGDF5. Modeling of a part of the GDF5 proregion into the known three-dimensional structure of TGF?1 latency-associated peptide revealed that the homologous positions of both mutations are conserved regions that may be important for the folding of the mature protein or the assembly of dimeric protein complexes. We hypothesize that the missense mutations p.T201P and p.L263P interfere with the protein structure and thereby reduce the amount of fully processed, biologically active GDF5, finally causing the clinical loss of function phenotype. PMID:25092592

  1. De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly

    SciTech Connect

    Fukushima, Yoshimitsu; Ohashi, Hirofumi; Wakui, Keiko [Saitama Children`s Medical Center (Japan)

    1995-07-03

    We report on a girl with Klippel-Feil anomaly, type A1 brachydactyly, and minor facial anomalies. She has an apparently balanced de novo reciprocal translocation between 5q11.2 and 17q23. The possible significance of this chromosomal abnormality is discussed. 7 refs., 3 figs.

  2. Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B

    PubMed Central

    Wang, Bing; Sinha, Tanvi; Jiao, Kai; Serra, Rosa; Wang, Jianbo

    2011-01-01

    Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a. Wnt5a/Ror2 can activate multiple branches of non-canonical Wnt signaling, but it is unclear which branch(es) mediates Wnt5a/Ror2 function in limb skeletal development. Here, we provide evidence implicating the planar cell polarity (PCP) pathway as the downstream component of Wnt5a in the limb. We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges. Halving the dosage of Wnt5a in Vangl2 mutants enhances the severity and penetrance of the digit defects and causes long bone defects reminiscent of RRS, suggesting that Wnt5a and Vangl2 function in the same pathway and disruption of PCP signaling may underlie both BDB1 and RRS. Consistent with a role for PCP signaling in tissue morphogenesis, mutation of Vangl2 alters the shape and dimensions of early limb buds: the width and thickness are increased, whereas the length is decreased. The digit pre-chondrogenic condensates also become wider, thicker and shorter. Interestingly, altered limb bud dimensions in Vangl2 mutants also affect limb growth by perturbing the signaling network that regulates the balance between Fgf and Bmp signaling. Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect. These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS. PMID:20962035

  3. Autosomal recessive congenital ichthyosis.

    PubMed

    Rodríguez-Pazos, L; Ginarte, M; Vega, A; Toribio, J

    2013-05-01

    The term autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. This group was traditionally divided into lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) but today it also includes harlequin ichthyosis, self-healing collodion baby, acral self-healing collodion baby, and bathing suit ichthyosis. The combined prevalence of LI and CIE has been estimated at 1 case per 138 000 to 300 000 population. In some countries or regions, such as Norway and the coast of Galicia, the prevalence may be higher due to founder effects. ARCI is genetically highly heterogeneous and has been associated with 6 genes to date: TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, and ABCA12. In this article, we review the current knowledge on ARCI, with a focus on clinical, histological, ultrastructural, genetic, molecular, and treatment-related aspects. PMID:23562412

  4. How many entities exist for the spectrum of disorders associated with brachydactyly, syndactyly, short stature, microcephaly, and intellectual disability?

    PubMed

    Ravel, Aimé; Chouery, Eliane; Stora, Samantha; Jalkh, Nadine; Villard, Laurent; Temtamy, Samia; Mégarbané, André

    2011-04-01

    We describe a French young man with digital anomalies consisting of brachydactyly, F1-5 bilateral camptodactyly, interdigital webbing, F5 bilateral radial clinodactyly, and partial syndactyly of some fingers and toes. He had psychomotor retardation, short stature, umbilical hernia, a secundum atrial septal defect, seizures, hearing impairment, and dysmorphic features consisting of microcephaly, a prominent metopic ridge, upslanting palpebral fissures, synophrys, enophthalmia, large ears, a bulbous nose, a high palate, a smooth and short philtrum, a low hanging columella, a thin upper vermillion, an everted lower lip, prognathism, pectum excavatum, and supernumerary nipples. Osteotendinous reflexes were brisk. Mild nystagmus, myopia, and astigmatia were also noted. Total body X-rays showed short terminal phalanges of the hands, short middle phalanges of the index and little fingers, clinodactyly of the little fingers, short and fused proximal 4th and 5th metacarpals of the right hand, a short 5th metacarpal of the left hand, a fused left lunate-triquetrum, fused capitate-hamates, a prominent mandibula, and partial sacral agenesis. A thin posterior corpus callosum was apparent by MRI. Differential diagnoses for mainly the Rubinstein-Taybi syndrome, the Tsukahara syndrome, the Filippi syndrome, the Feingold syndrome, and the Tonoki syndrome are discussed, and the possibility that we might be reporting a novel entity is raised. © 2011 Wiley-Liss, Inc. PMID:21416592

  5. Loss of CHSY1, a Secreted FRINGE Enzyme, Causes Syndromic Brachydactyly in Humans via Increased NOTCH Signaling

    PubMed Central

    Tian, Jing; Ling, Ling; Shboul, Mohammad; Lee, Hane; O'Connor, Brian; Merriman, Barry; Nelson, Stanley F.; Cool, Simon; Ababneh, Osama H.; Al-Hadidy, Azmy; Masri, Amira; Hamamy, Hanan; Reversade, Bruno

    2010-01-01

    We delineated a syndromic recessive preaxial brachydactyly with partial duplication of proximal phalanges to 16.8 Mb over 4 chromosomes. High-throughput sequencing of all 177 candidate genes detected a truncating frameshift mutation in the gene CHSY1 encoding a chondroitin synthase with a Fringe domain. CHSY1 was secreted from patients' fibroblasts and was required for synthesis of chondroitin sulfate moieties. Noticeably, its absence triggered massive production of JAG1 and subsequent NOTCH activation, which could only be reversed with a wild-type but not a Fringe catalytically dead CHSY1 construct. In vitro, depletion of CHSY1 by RNAi knockdown resulted in enhanced osteogenesis in fetal osteoblasts and remarkable upregulation of JAG2 in glioblastoma cells. In vivo, chsy1 knockdown in zebrafish embryos partially phenocopied the human disorder; it increased NOTCH output and impaired skeletal, pectoral-fin, and retinal development. We conclude that CHSY1 is a secreted FRINGE enzyme required for adjustment of NOTCH signaling throughout human and fish embryogenesis and particularly during limb patterning. PMID:21129727

  6. Autosomal recessive spino-olivo-cerebellar degeneration without ataxia.

    PubMed Central

    Staal, A; Stefanko, S Z; Jennekens, F G; Vries-Bos, L H; van Gijn, J

    1983-01-01

    Five adult siblings from a sibship of ten suffering from an external ophthalmoplegia with a spastic paraplegia are reported. In addition, optic nerve atrophy was present in three of the patients and dementia in two; extrapyramidal signs and cerebellar ataxia were found only in one patient. Contrary to earlier studies of patients with comparable neurological signs the pattern of inheritance was autosomal recessive. Neuropathological investigation of the index case, who had never shown ataxia, nevertheless showed demyelination of the spinocerebellar and the olivocerebellar pathways, and also a severe loss of Purkinje cells, of cells in Clarke's column and in the inferior olives. The dentate nucleus was severely gliotic but showed no cell loss. Earlier neuropathological investigations of this disorder, but with an autosomal dominant heredity, were incomplete. It is concluded that the five siblings of this family have a unique autosomal recessive disorder, which should be considered a distinct entity. Images PMID:6886703

  7. Genetics Home Reference: Autosomal dominant nocturnal frontal lobe epilepsy

    MedlinePLUS

    ... brain are involved in many critical functions, including reasoning, planning, judgment, and problem-solving. It is unclear ... more about genetic testing , particularly the difference between clinical tests and research tests . To locate a healthcare ...

  8. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts and Leukoencephalopathy (CADASIL)

    MedlinePLUS

    ... functions such as sensation, voluntary muscle movement, thought, reasoning, memory, etc. Infarcts : areas of tissue that have ... therapy are instituted for rehabilitation from stroke. Other Clinical Names for CADASIL Hereditary multi-infarct dementia Chronic ...

  9. A Transgenic Mouse Model for Human Autosomal Dominant Cataract

    PubMed Central

    Hsu, Cheng-Da; Kymes, Steven; Petrash, J. Mark

    2007-01-01

    Purpose To characterize lenses from transgenic mice designed to express mutant and wild-type ?A-crystallin subunits. Methods A series of transgenic mouse strains was created to express mutant (R116C) and wild-type human ?A-crystallin in fiber cells of the lens. Dissected lenses were phenotypically scored for the presence and extent of opacities, fiber cell morphology, and posterior suture morphology. Gene transcripts derived from integrated transgenes were detected by reverse transcriptase-PCR. Distribution of expressed transgenic protein was determined by immunohistochemical staining of lens tissue sections. The abundance of endogenous and transgenic lens proteins was estimated by quantitative Western blot analysis. Results Expression of R116C mutant ?A-crystallin subunits resulted in posterior cortical cataracts and abnormalities associated with the posterior suture. The severity of lens abnormalities did not increase between the ages of 9 and 30 weeks. With respect to opacities and morphologic abnormalities, lenses from transgenic mice that express wild-type human ?A-crystallin subunits were indistinguishable from age-matched non-transgenic control mice. Similar phenotypes were observed in different independent lines of R116C transgenic mice that differed by at least two orders of magnitude in the expression level of the mutant transgenic protein. Conclusions The results show that lens opacities and posterior sutural defects occur when mutant R116C ?A-crystallin subunits are expressed on the background of wild-type endogenous mouse ?-crystallins. Low levels of R116C ?A-crystallin subunits are sufficient to induce lens opacities and sutural defects. PMID:16639013

  10. Inheritance of astigmatism: evidence for a major autosomal dominant locus.

    PubMed Central

    Clementi, M; Angi, M; Forabosco, P; Di Gianantonio, E; Tenconi, R

    1998-01-01

    Although astigmatism is a frequent refractive error, its mode of inheritance remains uncertain. Complex segregation analysis was performed, by the POINTER and COMDS programs, with data from a geographically well-defined sample of 125 nuclear families of individuals affected by astigmatism. POINTER could not distinguish between alternative genetic models, and only the hypothesis of no familial transmission could be rejected. After inclusion of the severity parameter, COMDS results defined a genetic model for corneal astigmatism and provided evidence for single-major-locus inheritance. These results suggest that genetic linkage studies could be implemented and that they should be limited to multiplex families with severely affected individuals. PMID:9718344

  11. [Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy].

    PubMed

    Chabriat, Hugues

    2014-06-01

    CADASIL is an inherited small vessel disease of the brain caused by mutations of the NOTCH3 gene encoding a receptor of smooth muscle cells and pericytes within the wall of arterioles and capillaries. The mutated gene is responsible for accumulation of NOTCH3 protein and aggregation of various proteins in the vascular wall. The disease occurs during mid-adulthood and is responsible for attacks of migraine with aura, ischemic stroke, mood disorders and cognitive impairment ranging from mild alterations of attentional performances and executive functions to severe dementia. The disease develops in adults with aging and is responsible at the latest stage of gait and balance troubles associated with cognitive impairment that may lead to severe disability and dependence. MRI shows widespread white matter lesions that may involve the anterior part of temporal lobes often associated with small cerebral infarcts and with microbleeds. The clinical severity is related to accumulation of small infarcts and the development of cerebral atrophy over time. The diagnosis of the disease is confirmed by genetic testing or skin biopsy. PMID:24939405

  12. Autosomal Recessive Polycystic Kidney Disease

    Microsoft Academic Search

    Jodi M. Smith; Ruth A. McDonald

    \\u000a Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disorder involving cystic dilatation of the renal collecting\\u000a ducts as well as varying degrees of hepatic abnormalities consisting of cysts, fibrosis, and portal hypertension. The ARPKD\\u000a locus has been mapped to chromosome 6p21 and encodes a novel protein product named fibrocystin or polyductin. There are several\\u000a modes of presentation depending on

  13. Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies

    Microsoft Academic Search

    Rafaëlle Bernard; Annachiara De Sandre-Giovannoli; Valérie Delague; Nicolas Lévy

    2006-01-01

    Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families with CMT. On the other\\u000a hand, in countries with a high prevalence of consanguinity this mode of inheritance accounts, likely, for the vast majority\\u000a of CMT phenotypes. Like dominant forms, autosomal-recessive forms are generally subdivided into demyelinating forms (autosomal-recessive\\u000a CMT1: ARCMT1 or CMT4) and axonal forms (ARCMT2).

  14. THE ENTIRE COMPOUND AUTOSOMES OF DROSOPHILA MELANOGASTER

    Microsoft Academic Search

    E. NOVITSKI; D. GRACE; C. STROMMEN

    Three new unusual compound chromosomes have been synthesized in Drosophila melanogaster. They consist of two homologous autosomes joined together in the new order: right arm, left arm, centromere, left arm, right arm, for each of the two major autosomes, and one in which chromosomes 2 and 3 have been combined in the order: right arm of 2, left arm of

  15. Domination Bounds Domination in Graphs

    E-print Network

    Laison, Josh

    Examples Defenitions 1958 - Claude Berge introduced the domination number of a graph. In a graph G, a set) is the minimum size of a dominating set in G. Jose Alvarado Domination in Graphs #12;Intro Domination Domination, the neighbors of a single vertex form a dominating set. Jose Alvarado Domination in Graphs #12;Intro Domination

  16. Sotos syndrome and de novo balanced autosomal translocation (t(3;6)(p21;p21))

    PubMed

    Schrander-Stumpel, C T; Fryns, J P; Hamers, G G

    1990-03-01

    In this report we describe a 6-year-old boy with Sotos syndrome and a de novo apparently balanced 3/6 translocation (karyotype: 46,XY,t(3;6)(p21;p21)). Pre- and postnatal overgrowth are observed in an increasing number of conditions of variable etiology. In the Sotos syndrome autosomal dominant inheritance with variable expression has been documented. Here we discuss the importance of the cytogenetic findings and postulate a relationship between the invisible loss of chromosomal material at 3p21 and/or 6p21 and the expression of the autosomal dominant gene. PMID:2323093

  17. Genetics Home Reference: Autosomal recessive axonal neuropathy with neuromyotonia

    MedlinePLUS

    ... OMIM Genetic disorder catalog Conditions > Autosomal recessive axonal neuropathy with neuromyotonia On this page: Description Genetic changes ... Reviewed September 2014 What is autosomal recessive axonal neuropathy with neuromyotonia? Autosomal recessive axonal neuropathy with neuromyotonia ...

  18. NEW BEST1 MUTATIONS IN AUTOSOMAL RECESSIVE BESTROPHINOPATHY

    PubMed Central

    FUNG, ADRIAN T.; YZER, SUZANNE; GOLDBERG, NAOMI; WANG, HAO; NISSEN, MICHAEL; GIOVANNINI, ALFONSO; MERRIAM, JOANNA E.; BUKANOVA, ELENA N.; CAI, CAROLYN; YANNUZZI, LAWRENCE A.; TSANG, STEPHEN H.; ALLIKMETS, RANDO

    2015-01-01

    Purpose To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. Methods Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. Results Five affected patients from four families were identified. Mean age was 16 years (range, 6–42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. Conclusion Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy–associated dominant mutations. PMID:25545482

  19. Characterization of the mutation causative for autosomal recessive hereditary nephropathy in the english cocker spaniel and analysis of gene expression in multiple models of hereditary nephropathy 

    E-print Network

    Davidson, Ashley Greene

    2009-05-15

    syndrome (AS), a group of heterogeneous, hereditary renal diseases, is one example of such a human disease. The disease is transmitted in three fashions: X-linked, autosomal recessive, and autosomal dominant. AS is caused by mutations in COL4?3, COL4?4...

  20. Characterization of the mutation causative for autosomal recessive hereditary nephropathy in the english cocker spaniel and analysis of gene expression in multiple models of hereditary nephropathy

    E-print Network

    Davidson, Ashley Greene

    2009-05-15

    syndrome (AS), a group of heterogeneous, hereditary renal diseases, is one example of such a human disease. The disease is transmitted in three fashions: X-linked, autosomal recessive, and autosomal dominant. AS is caused by mutations in COL4?3, COL4?4...

  1. Novel large deletion in the ACTA1 gene in a child with autosomal recessive nemaline myopathy.

    PubMed

    Friedman, Bethany; Simpson, Kara; Tesi-Rocha, Carolina; Zhou, Delu; Palmer, Cheryl A; Suchy, Sharon F

    2014-04-01

    Nemaline myopathy (NM) is a genetically and clinically heterogeneous disorder resulting from a disruption of the thin filament proteins of the striated muscle sarcomere. The disorder is typically characterized by muscle weakness including the face, neck, respiratory, and limb muscles and is clinically classified based on the age of onset and severity. Mutations in the ACTA1 gene contribute to a significant proportion of NM cases. The majority of ACTA1 gene mutations are missense mutations causing autosomal dominant NM by producing an abnormal protein. However, approximately 10% of ACTA1 gene mutations are associated with autosomal recessive NM; these mutations are associated with loss of protein function. We report the first case of a large deletion in the ACTA1 gene contributing to autosomal recessive NM. This case illustrates the importance of understanding disease mechanisms at the molecular level to accurately infer the inheritance pattern and potentially aid with clinical management. PMID:24447884

  2. FOXE3 plays a significant role in autosomal recessive microphthalmia

    PubMed Central

    Reis, Linda M.; Tyler, Rebecca C.; Schneider, Adele; Bardakjian, Tanya; Stoler, Joan M.; Melancon, Serge B.; Semina, Elena V.

    2010-01-01

    FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract and microphthalmia. We undertook sequencing of FOXE3 in 116 probands with a spectrum of ocular defects ranging from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral microphthalmia (15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype). FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects; no other associated systemic anomalies were observed in FOXE3-positive families. The previously reported c.720C>A (p.C240X) nonsense mutation was identified in two additional families in our sample and therefore appears to be recurrent, now reported in three independent microphthalmia families of varied ethnic backgrounds. Several missense variants were identified at varying frequencies in patient and control groups with some apparently being race-specific, which underscores the importance of utilizing race/ethnicity-matched control populations in evaluating the relevance of genetic screening results. In conclusion, FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia. PMID:20140963

  3. Centromeric heterochromation exchange by an autosomal reciprocal

    E-print Network

    Boyer, Edmond

    Centromeric heterochromation exchange by an autosomal reciprocal 1/16 translocation in the pig (Sus of the centromeric regions in pig chromosomes. All bi-armed chromosomes are strongly stained in the centromere fluorescence on the centromeres of all one-armed chro- mosomes. In the pig, chromosome 1 is a large

  4. Genetics Home Reference: Autosomal recessive cerebellar ataxia type 1

    MedlinePLUS

    ... disorder catalog Conditions > Autosomal recessive cerebellar ataxia type 1 (often shortened to ARCA1 ) On this page: Description ... What is ARCA1? Autosomal recessive cerebellar ataxia type 1 (ARCA1) is a condition characterized by progressive problems ...

  5. Autosomal recessive cutis laxa syndrome revisited

    PubMed Central

    Morava, Éva; Guillard, Maïlys; Lefeber, Dirk J; Wevers, Ron A

    2009-01-01

    The clinical spectrum of the autosomal recessive cutis laxa syndromes is highly heterogeneous with respect to organ involvement and severity. One of the major diagnostic criteria is to detect abnormal elastin fibers. In several other clinically similar autosomal recessive syndromes, however, the classic histological anomalies are absent, and the definite diagnosis remains uncertain. In cutis laxa patients mutations have been demonstrated in elastin or fibulin genes, but in the majority of patients the underlying genetic etiology remains unknown. Recently, we found mutations in the ATP6V0A2 gene in families with autosomal recessive cutis laxa. This genetic defect is associated with abnormal glycosylation leading to a distinct combined disorder of the biosynthesis of N- and O-linked glycans. Interestingly, similar mutations have been found in patients with wrinkly skin syndrome, without the presence of severe skin symptoms of elastin deficiency. These findings suggest that the cutis laxa and wrinkly skin syndromes are phenotypic variants of the same disorder. Interestingly many phenotypically similar patients carry no mutations in the ATP6V0A2 gene. The variable presence of protein glycosylation abnormalities in the diverse clinical forms of the wrinkled skin-cutis laxa syndrome spectrum necessitates revisiting the diagnostic criteria to be able to offer adequate prognosis assessment and counseling. This paper aims at describing the spectrum of clinical features of the various forms of autosomal recessive cutis laxa syndromes. Based on the recently unraveled novel genetic entity we also review the genetic aspects in cutis laxa syndromes including genotype–phenotype correlations and suggest a practical diagnostic approach. PMID:19401719

  6. The Skeletal Muscle Chloride Channel in Dominant and Recessive Human Myotonia

    Microsoft Academic Search

    Manuela C. Koch; Klaus Steinmeyer; Claudius Lorenz; Kenneth Ricker; Friedrich Wolf; Michael Otto; Barbara Zoll; Frank Lehmann-Horn; Karl-Heinz Grzeschik; Thomas J. Jentsch

    1992-01-01

    Autosomal recessive generalized myotonia (Becker's disease) (GM) and autosomal dominant myotonia congenita (Thomsen's disease) (MC) are characterized by skeletal muscle stiffness that is a result of muscle membrane hyperexcitability. For both diseases, alterations in muscle chloride or sodium currents or both have been observed. A complementary DNA for a human skeletal muscle chloride channel (CLC-1) was cloned, physically localized on

  7. The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics

    Microsoft Academic Search

    LUCIANA M. B. OLIVEIRA; STEPHANIE B. SEMINARA; MILENA BERANOVA; FRANCES J. HAYES; SARAH B. VALKENBURGH; ERNESTINA SCHIPANI; ELAINE MARIA F. COSTA; ANA CLAUDIA LATRONICO; WILLIAM F. CROWLEY; MARIO VALLEJO

    Kallmann syndrome (KS) consists of congenital, isolated, idio- pathic hypogonadotropic hypogonadism (IHH) and anosmia. The gene responsible for the X-linked form of KS, KAL, encodes a protein, anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus. In addition to X-linked pedi- grees, autosomal dominant and recessive kindreds with KS have been

  8. Homozygous Missense Mutation in Fibulin-5 in an Iranian Autosomal Recessive Cutis Laxa Pedigree and Associated Haplotype

    Microsoft Academic Search

    Elahe Elahi; Reza Kalhor; Setareh S Banihosseini; Noorossadat Torabi; Hamid Pour-Jafari; Massoud Houshmand; Seyed S H Amini; Ahmad Ramezani; Bart Loeys

    2006-01-01

    Cutis laxa is a rare group of inherited and acquired disorders characterized by loose and redundant skin with reduced elasticity. Mutations in the elastin coding gene have been shown to cause autosomal dominant cutis laxa in three families. A homozygous mutation in the fibulin-5 coding gene was discovered in a Turkish pedigree showing recessive inheritance, and a different mutation in

  9. A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.

    PubMed

    Wasano, Koichiro; Mutai, Hideki; Obuchi, Chie; Masuda, Sawako; Matsunaga, Tatsuo

    2015-08-01

    Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel. PMID:26036578

  10. Autosomal recessive nonsyndromic deafness genes: a review

    PubMed Central

    Duman, Duygu; Tekin, Mustafa

    2013-01-01

    More than 50 percent of prelingual hearing loss is genetic in origin, and of these up to 93 percent are monogenic autosomal recessive traits. Some forms of genetic deafness can be recognized by their associated syndromic features, but in most cases, hearing loss is the only finding and is referred to as nonsyndromic deafness. To date, more than 700 different mutations have been identified in one of 42 genes in individuals with autosomal recessive nonsyndromic hearing loss (ARNSHL). Reported mutations in GJB2, encoding connexin 26, makes this gene the most common cause of hearing loss in many populations. Other relatively common deafness genes include SLC26A4, MYO15A, OTOF, TMC1, CDH23, and TMPRSS3. In this report we summarize genes and mutations reported in families with ARNSHL. Founder effects were demonstrated for some recurrent mutations but the most significant findings are the extreme locus and allelic heterogeneity and different spectrum of genes and mutations in each population. PMID:22652773

  11. VSX2 mutations in autosomal recessive microphthalmia

    PubMed Central

    Reis, Linda M.; Khan, Ayesha; Kariminejad, Ariana; Ebadi, Farhad; Tyler, Rebecca C.

    2011-01-01

    Purpose To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia. Methods We screened 95 probands with syndromic or isolated developmental ocular conditions (including 55 with anophthalmia/microphthalmia) for mutations in VSX2. Results Homozygous mutations in VSX2 were identified in two out of five consanguineous families with isolated microphthalmia. A novel missense mutation, c.668G>C (p.G223A), was identified in a large Pakistani family with multiple sibships affected with bilateral microphthalmia. This p.G223A mutation affects the conserved CVC motif that was shown to be important for DNA binding and repression activities of VSX2. The second mutation, c.249delG (p.Leu84SerfsX57), was identified in an Iranian family with microphthalmia; this mutation has been previously reported and is predicted to generate a severely truncated mutant protein completely lacking the VSX2 homeodomain, CVC domain and COOH-terminal regions. Conclusions Mutations in VSX2 represent an important cause of autosomal recessive microphthalmia in consanguineous pedigrees. Identification of a second missense mutation in the CVC motif emphasizes the importance of this region for normal VSX2 function. PMID:21976963

  12. Mutation rate analysis at 19 autosomal microsatellites.

    PubMed

    Qian, Xiao-Qin; Yin, Cai-Yong; Ji, Qiang; Li, Kai; Fan, Han-Ting; Yu, Yan-Fang; Bu, Fan-Li; Hu, Ling-Li; Wang, Jian-Wen; Mu, Hao-Fang; Haigh, Steven; Chen, Feng

    2015-07-01

    Previous studies have demonstrated that a large sample size is needed to reliably estimate population- and locus-specific microsatellite mutation rates. Therefore, we conducted a long-term collaboration study and performed a comprehensive analysis on the mutation characteristics of 19 autosomal short tandem repeat (STR) loci. The STR loci located on 15 of 22 autosomal chromosomes were analyzed in a total of 21?106 samples (11?468 parent-child meioses) in a Chinese population. This provided 217?892 allele transfers at 19 STR loci. An overall mutation rate of 1.20 × 10(-3) (95% CI, 1.06-1.36 × 10(-3) ) was observed in the populations across 18 of 19 STR loci, except for the TH01 locus with no mutation found. Most STR mutations (97.7%) were single-step mutations, and only a few mutations (2.30%) comprised two and multiple steps. Interestingly, approximately 93% of mutation events occur in the male germline. The mutation ratios increased with the paternal age at child birth (r = 0.99, p<0.05), but not maternal age. Last, with the combination analysis of the data from the southern Chinese population, we drew a picture of 19 STR mutations in China. In conclusion, the data from this study will provide useful information in parentage testing, kinship analysis, and population genetics. PMID:25820688

  13. CASE REPORT Open Access Autosomal recessive cerebellar ataxia caused

    E-print Network

    Paris-Sud XI, Université de

    (ARCA) include Friedreich ataxia, ataxia telangiectasia and oculomotor apraxia type 1 and 2 [1CASE REPORT Open Access Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene Objective: To expand the spectrum of genetic causes of autosomal recessive cerebellar ataxia (ARCA). Case

  14. A balancing act between the X chromosome and the autosomes

    Microsoft Academic Search

    Mimi K Cheng; Christine M Disteche

    2006-01-01

    ABSTRACT: Dosage compensation equalizes gene dosage between males and females, but its role in balancing expression between the X chromosome and the autosomes may be far more important. Now, DNA microarrays have shown equality between the average expression of X-linked genes and that of autosomal genes, in male and female tissues of flies, worms and mice.

  15. Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.

    PubMed

    Tazir, Meriem; Bellatache, Mounia; Nouioua, Sonia; Vallat, Jean-Michel

    2013-06-01

    The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT. PMID:23781959

  16. Autosomal Trisomies and Partial Trisomy Syndromes

    PubMed Central

    Zaleski, W. A.

    1963-01-01

    The establishing of 46 chromosomes as the normal complement in man and the report of the sex chromatin bodies in buccal smears were followed by reports of trisomies and other abnormal patterns of the X and Y chromosomes in Klinefelter's and Turner's syndromes. Abnormal autosomal complements were described in mongolism, in the E-trisomy syndrome, the D-trisomy syndrome, in the Sturge-Weber syndrome, Waldenstrom's macroglobulinemia, benign congenital hypotonia, atrial septal defect and in the schizoid personality. Certain of these conditions, as well as the “oral-facial-digital” syndrome, were also found to exist as partial trisomies. The mechanism of a trisomy is one of non-disjunction and of partial trisomy translocation or insertion. Two cases of the partial trisomy in the E group are described; these are of especial interest because of the familial incidence, longer survival and male sex occurrence, features which are rarely seen in the full E-trisomy syndrome. ImagesFig. 4Fig. 5Fig. 6 PMID:20327419

  17. Other autosomal recessive and childhood ataxias.

    PubMed

    De Michele, Giuseppe; Filla, Alessandro

    2012-01-01

    The label of "early-onset cerebellar ataxia with retained tendon reflexes" (EOCA) has been created to differentiate it from Friedreich ataxia (FRDA) patients with preserved knee jerks and absence of cardiomyopathy, optic atrophy, and diabetes mellitus. However, EOCA is a heterogeneous syndrome and several FRDA patients present with an EOCA-like phenotype. Cerebellar ataxia with hypogonadism is another heterogeneous syndrome for which no locus has been mapped yet. Two peculiar ataxic syndromes have been identified in genetically isolated populations: autosomal recessive ataxia of Charlevoix-Saguenay (ARSACS) in Quebec and infantile-onset spinocerebellar ataxia (IOSCA) in Finland. Both conditions present usually within the second year of life. ARSACS is characterized by marked spasticity and IOSCA by a complex phenotype which includes, besides ataxia, epilepsy, optic atrophy, ophthalmoplegia, hearing loss, and areflexia. The responsible genes are SACS, encoding sacsin, a protein which may act as a chaperone, and C10orf2, encoding Twinkle, a mitochondrial DNA-specific helicase. Marinesco-Sjögren syndrome, clinically characterized by cerebellar ataxia, cataracts, myopathy, and mental retardation, is genetically heterogeneous. One gene, SIL1, encodes a nucleotide exchange factor for the heat-shock protein 70 chaperone HSPA5. Five conditions account for most cases of progressive myoclonic ataxia: Unverricht-Lundborg disease, Lafora disease, myoclonic epilepsy with ragged-red fibers, neuronal ceroid lipofuscinoses, and sialidoses. PMID:21827899

  18. X Chromosome and Autosome Dosage Responses in Drosophila melanogaster Heads

    PubMed Central

    Chen, Zhen-Xia; Oliver, Brian

    2015-01-01

    X chromosome dosage compensation is required for male viability in Drosophila. Dosage compensation relative to autosomes is two-fold, but this is likely to be due to a combination of homeostatic gene-by-gene regulation and chromosome-wide regulation. We have baseline values for gene-by-gene dosage compensation on autosomes, but not for the X chromosome. Given the evolutionary history of sex chromosomes, these baseline values could differ. We used a series of deficiencies on the X and autosomes, along with mutations in the sex-determination gene transformer-2, to carefully measure the sex-independent X-chromosome response to gene dosage in adult heads by RNA sequencing. We observed modest and indistinguishable dosage compensation for both X chromosome and autosome genes, suggesting that the X chromosome is neither inherently more robust nor sensitive to dosage change. PMID:25850426

  19. Estimating locus heterogeneity in autosomal dominant polycystic kidney disease (ADPKD) in the Spanish population.

    PubMed Central

    Peral, B; San Millán, J L; Hernández, C; Valero, A; Lathrop, G M; Beckmann, J S; Moreno, F

    1993-01-01

    Although most mutations causing ADPKD in European populations have been mapped to the PKD1 locus on chromosome 16, some of them appear to be unlinked to this locus. To evaluate the incidence of unlinked mutations in Spain we have typed 31 Spanish families from different geographical sites for six closely linked DNA polymorphic marker loci flanking PKD1 detected by probes D16S85, D16S21, D16S259, D16S125, D16S246, and D16S80. Multilocus linkage analysis indicated that in 26 families the disease resulted from PKD1 mutations, whereas in three families it resulted from mutations in a locus other than PKD1. The two other families were not informative. Using the HOMOG test, the incidence of the PKD1 linked mutations in Spain is 85%. Multipoint linkage analysis in the 26 PKD1 families showed that the disease locus lies in the interval between D16S259(pGGG1) and D16S125(26.6). PMID:7905535

  20. A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia

    Microsoft Academic Search

    Marcus Deschauer; Gavin Hudson; Tobias Müller; Robert W. Taylor; Patrick F. Chinnery; Stephan Zierz

    2005-01-01

    Only four different mutations in the adenine nucleotide translocator 1 (ANT1) gene have been found in families with progressive external ophthalmoplegia (PEO). We report a novel heterozygous C to A transversion at nucleotide 269 in the ANT1 gene in a German family with PEO, predicted to convert a highly conserved alanine at codon 90 to aspartic acid. The mutation was

  1. O2-06-02 FDG METABOLISM IN THE DIAN STUDY OF AUTOSOMAL DOMINANT ALZHEIMER'S

    E-print Network

    Thompson, Paul

    Ghetti6, Colin Masters9, Chester Mathis12, Michael Weiner13, Randall Bateman4, Anne Fagan4, Alison Goate4 Ghetti6, Colin Masters9, Chester Mathis12, Michael Weiner13, Randall Bateman4, Anne Fagan4, Alison Goate4

  2. Genetics Home Reference: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

    MedlinePLUS

    ... region of the brain, which is involved in reasoning and memory, can cause progressive loss of intellectual ... more about genetic testing , particularly the difference between clinical tests and research tests . To locate a healthcare ...

  3. Autosomal dominant nemaline myopathy caused by a novel ?-tropomyosin 3 mutation

    Microsoft Academic Search

    I. C. Kiphuth; S. Krause; H. B. Huttner; G. Dekomien; T. Struffert; R. Schröder

    2010-01-01

    Nemaline myopathy (NM) is a genetically and clinically heterogenous muscle disorder, which is myopathologically characterized\\u000a by nemaline bodies [1]. Mutations in six genes have been reported to cause NM: Nebulin (NEB Pelin 1999), ?-skeletal muscle actin (ACTA1 Nowak 1999), ?-slow tropomyosin (TPM3 Laing 1995), ?-tropomyosin (TPM2 Donner 2002), slow troponin T (TNNT1 Johnston 2000) and cofilin 2 (CFL2 Agrawal 2007)

  4. Mutations in SCO2 Are Associated with Autosomal-Dominant High-Grade Myopia

    PubMed Central

    Tran-Viet, Khanh-Nhat; Powell, Caldwell; Barathi, Veluchamy A.; Klemm, Thomas; Maurer-Stroh, Sebastian; Limviphuvadh, Vachiranee; Soler, Vincent; Ho, Candice; Yanovitch, Tammy; Schneider, Georg; Li, Yi-Ju; Nading, Erica; Metlapally, Ravikanth; Saw, Seang-Mei; Goh, Liang; Rozen, Steve; Young, Terri L.

    2013-01-01

    Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than ?6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of ?22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a ?15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development. PMID:23643385

  5. New Locus for Autosomal Dominant Mitral Valve Prolapse on Chromosome 13 Clinical Insights From Genetic Studies

    Microsoft Academic Search

    Francesca Nesta; Maire Leyne; Chaim Yosefy; Charles Simpson; Daisy Dai; Jane E. Marshall; Judy Hung; Susan A. Slaugenhaupt; Robert A. Levine

    2010-01-01

    Background—Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation, endocarditis, heart failure, and sudden death. To date, 2 MVP loci have been described, but the defective genes have yet to be discovered. In the present study, we analyzed a large family segregating MVP, and identified a new locus, MMVP3. This study and others have enabled us to

  6. A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia.

    PubMed

    Choquet, Karine; La Piana, Roberta; Brais, Bernard

    2015-07-01

    Episodic ataxias (EAs) are a heterogeneous group of neurological disorders characterized by recurrent attacks of ataxia. Mutations in KCNA1 and CACNA1A account for the majority of EA cases worldwide. We recruited a two-generation family affected with EA of unknown subtype and performed whole-exome sequencing on two affected members. This revealed a novel heterozygous mutation c.211_212insA (p.I71NfsX27) leading to a premature stop codon in FGF14. Mutations in FGF14 are known to cause spinocerebellar ataxia type 27 (SCA27). Sanger sequencing confirmed segregation within the family. Our findings expand the phenotypic spectrum of SCA27 by underlining the possible episodic nature of this ataxia. PMID:25566820

  7. Clinical and molecular diagnosis of a Costa Rican family with autosomal recessive myotonia congenita (Becker disease) carrying a new mutation in the CLCN1 gene

    Microsoft Academic Search

    Fernando Morales; Patricia Cuenca; Gerardo del Valle; Melissa Vásquez; Roberto Brian; Mauricio Sittenfeld; Keith Johnson; Xi Lin; Tetsuo Ashizawa

    2008-01-01

    Myotonia congenita is a muscular disease characterized by myotonia, hypertrophy, and stiffness. It is inherited as either autosomal dominant or recessive known as Thomsen and Becker diseases, respectively. Here we confirm the clinical diagnosis of a family diagnosed with a myotonic condition many years ago and report a new mutation in the CLCN1 gene. The clinical diagnosis was established using

  8. An Autosomal-Recessive Form of Cutis Laxa Is Due to Homozygous Elastin Mutations, and the Phenotype May Be Modified by a Heterozygous Fibulin 5 Polymorphism

    Microsoft Academic Search

    Hala Mégarbané; Jobard Florence; Jörn Oliver Sass; Susanne Schwonbeck; Mario Foglio; Rafael de Cid; Susan Cure; Safa Saker; André Mégarbané; Judith Fischer

    2009-01-01

    Cutis laxa (CL) is a heterogeneous group of connective tissue disorders characterized by loose, sagging skin and variable involvement of other organs. Autosomal-dominant forms are relatively mild, and may be caused by mutations in the elastin gene, whereas the more severe recessive forms have been associated with mutations in the fibulin 4 and fibulin 5 genes, as well as in

  9. Dominant GDAP1 mutations cause predominantly mild CMT phenotypes

    PubMed Central

    Zimo?, M.; Baets, J.; Fabrizi, G.M.; Jaakkola, E.; Kabzi?ska, D.; Pilch, J.; Schindler, A.B.; Cornblath, D.R.; Fischbeck, K.H.; Auer-Grumbach, M.; Guelly, C.; Huber, N.; De Vriendt, E.; Timmerman, V.; Suter, U.; Hausmanowa-Petrusewicz, I.; Niemann, A.; Kocha?ski, A.; De Jonghe, P.; Jordanova, A.

    2012-01-01

    Objective Ganglioside-induced differentiation associated-protein 1 (GDAP1) mutations are commonly associated with autosomal recessive Charcot-Marie-Tooth (ARCMT) neuropathy; however, in rare instances, they also lead to autosomal dominant Charcot-Marie-Tooth (ADCMT). We aimed to investigate the frequency of disease-causing heterozygous GDAP1 mutations in ADCMT and their associated phenotype. Methods We performed mutation analysis in a large cohort of ADCMT patients by means of bidirectional sequencing of coding regions and exon-intron boundaries of GDAP1. Intragenic GDAP1 deletions were excluded using an allele quantification assay. We confirmed the pathogenic character of one sequence variant by in vitro experiments assaying mitochondrial morphology and function. Results In 8 Charcot-Marie-Tooth disease (CMT) families we identified 4 pathogenic heterozygous GDAP1 mutations, 3 of which are novel. Three of the mutations displayed reduced disease penetrance. Disease onset in the affected individuals was variable, ranging from early childhood to adulthood. Disease progression was slow in most patients and overall severity milder than typically seen in autosomal recessive GDAP1 mutations. Electrophysiologic changes are heterogeneous but compatible with axonal neuropathy in the majority of patients. Conclusions With this study, we broaden the phenotypic and genetic spectrum of autosomal dominant GDAP1-associated neuropathies. We show that patients with dominant GDAP1 mutations may display clear axonal CMT, but may also have only minimal clinical and electrophysiologic abnormalities. We demonstrate that cell-based functional assays can be reliably used to test the pathogenicity of unknown variants. We discuss the implications of phenotypic variability and the reduced penetrance of autosomal dominant GDAP1 mutations for CMT diagnostic testing and counseling. PMID:21753178

  10. Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.

    PubMed

    Courcet, Jean-Benoît; Elalaoui, Siham Chafai; Duplomb, Laurence; Tajir, Mariam; Rivière, Jean-Baptiste; Thevenon, Julien; Gigot, Nadège; Marle, Nathalie; Aral, Bernard; Duffourd, Yannis; Sarasin, Alain; Naim, Valeria; Courcet-Degrolard, Emilie; Aubriot-Lorton, Marie-Hélène; Martin, Laurent; Abrid, Jamal Eddin; Thauvin, Christel; Sefiani, Abdelaziz; Vabres, Pierre; Faivre, Laurence

    2015-07-01

    SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer. PMID:25315659

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

    PubMed Central

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

    2015-01-01

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

  12. Mutations in EOGT Confirm the Genetic Heterogeneity of Autosomal-Recessive Adams-Oliver Syndrome

    PubMed Central

    Shaheen, Ranad; Aglan, Mona; Keppler-Noreuil, Kim; Faqeih, Eissa; Ansari, Shinu; Horton, Kim; Ashour, Adel; Zaki, Maha S.; Al-Zahrani, Fatema; Cueto-González, Anna M.; Abdel-Salam, Ghada; Temtamy, Samia; Alkuraya, Fowzan S.

    2013-01-01

    Adams-Oliver syndrome (AOS) is a rare, autosomal-dominant or -recessive disorder characterized primarily by aplasia cutis congenita and terminal transverse limb defects. Recently, we demonstrated that homozygous mutations in DOCK6 cause an autosomal-recessive form of AOS. In this study, we sought to determine the contribution of DOCK6 mutations to the etiology of AOS in several consanguineous families. In two of the five families studied, we identified two homozygous truncating mutations (a splice-site mutation and a frameshift duplication). DOCK6 sequencing revealed no mutation in the remaining three families, consistent with their autozygosity mapping and linkage-analysis results, which revealed a single candidate locus in 3p14.1 on three different haplotype backgrounds in the three families. Indeed, exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins. It has a documented role in epithelial-cell-matrix interactions in Drosophila, in which deficiency of its ortholog causes wing blistering. Our findings highlight a developmental role of O-GlcNAcylation in humans and expand the genetic heterogeneity of autosomal-recessive AOS. PMID:23522784

  13. A novel HSF4 gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

    PubMed Central

    Sajjad, Naheed; Goebel, Ingrid; Kakar, Naseebullah; Cheema, Abdul Majeed; Kubisch, Christian; Ahmad, Jamil

    2008-01-01

    Background Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667). Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene. Methods A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438) was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4) were sequenced. A mutation-specific restriction enzyme digest (HphI) was performed for all family members and unrelated controls. Results The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at ? = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X). Conclusion We identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract. PMID:19014451

  14. The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery

    PubMed Central

    Mishra, Sanjay K.; Watkins, Simon C.; Traub, Linton M.

    2002-01-01

    The low density lipoprotein (LDL) receptor plays a pivotal role in cholesterol metabolism. Inherited mutations that disturb the activity of the receptor lead to elevations in plasma cholesterol levels and early-onset coronary atherosclerosis. Defects in either the LDL receptor or apolipoprotein B, the proteinaceous component of LDL particles that binds the LDL receptor, elevate circulating LDL-cholesterol levels in an autosomal-dominant fashion, with heterozygotes displaying values between homozygous and normal individuals. Rarely, similar clinical phenotypes occur with a recessive pattern of inheritance, and several genetic lesions in the autosomal recessive hypercholesterolemia (ARH) gene on chromosome 1 have been mapped in this class of patients. ARH has an N-terminal phosphotyrosine-binding (PTB) domain evolutionarily related to that found in Disabled-2 and numb, two endocytic proteins. PTB domains bind to the consensus sequence FXNPXY, corresponding to the internalization motif of the LDL receptor. We show here that in addition to the FXNPXY sequence, ARH binds directly to soluble clathrin trimers and to clathrin adaptors by a mode involving the independently folded appendage domain of the ? subunit. At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes. Because ARH also binds directly to phosphoinositides, which regulate clathrin bud assembly at the cell surface, our data suggest that in ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia. PMID:12451172

  15. Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker)

    Microsoft Academic Search

    M C Koch; K Ricker; M Otto; F Wolf; B Zoll; C Lorenz; K Steinmeyer; T J Jentsch

    1993-01-01

    Generalised myotonia Becker (GM) is an autosomal recessively inherited muscle disorder. Affected subjects exhibit myotonic muscle stiffness in all skeletal muscles with marked hypertrophy in the legs. A transient muscle weakness is particularly pronounced in the arms and hands and is a typical symptom of the disorder. Recently, we showed complete linkage of the disorder GM to the gene (CLCN1)

  16. For many autosomal genes in diploid organisms, expression is almost

    E-print Network

    , as signals of transient random monoallelic expression from each allele will cancel each other out when to fully deci- pher the mechanistic underpinnings of stable versus transient random monoallelic expressionFor many autosomal genes in diploid organisms, expression is almost exclusively from one allele

  17. Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies

    Microsoft Academic Search

    Jean-Michel Rozet; Sylvie Gerber; Eric Souied; Isabelle Perrault; Sophie Châtelin; Imad Ghazi; Corinne Leowski; Jean-Louis Dufier; Arnold Munnich; Josseline Kaplan; J-M Rozet

    1998-01-01

    Stargardt disease (STGD) and late-onset fundus flavimaculatus (FFM) are autosomal recessive conditions leading to macular degenerations in childhood and adulthood, respectively. Recently, mutations of the photoreceptor cell-specific ATP binding transporter gene (ABCR) have been reported in Stargardt disease. Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM

  18. The Autosomal Flp-Dfs Technique for Generating Germline Mosaics in Drosophila Melanogaster

    PubMed Central

    Chou, T. B.; Perrimon, N.

    1996-01-01

    The production of female germline chimeras is invaluable for analyzing the tissue specificity of recessive female sterile mutations as well as detecting the maternal effect of recessive zygotic lethal mutations. Previously, we developed the ``FLP-DFS'' technique to efficiently generate germline clones. This technique uses the X-linked germline-dependent dominant female sterile mutation ovo(D1) as a selection for the detection of germline recombination events, and the FLP-FRT recombination system to promote site-specific chromosomal exchange. This method allows the efficient production of germline mosaics only on the X chromosome. In this paper we have built chromosomes that allow the use of this technique to the autosomes. We describe the various steps involved in the development of this technique as well as the properties of the chromosomes utilized. PMID:8978054

  19. A case report on autosomal recessive total congenital anonychia.

    PubMed

    Balta, Ilknur; Kalkan, Goknur

    2013-01-01

    A 21-year-old woman presented with a history of the absence of the nails of all her fingers and toes since birth. Her grandfathers were first degree relatives. Her two brothers (26 and 28 years old) had the same anomalies. Autosomal recessive inheritance of this disease was supported in our cases because the parents were consanguineous and the disease occurred in two brothers and a sister. PMID:23679125

  20. De Barsy syndrome--an autosomal recessive, progeroid syndrome.

    PubMed

    Kunze, J; Majewski, F; Montgomery, P; Hockey, A; Karkut, I; Riebel, T

    1985-11-01

    We report two families with seven siblings with de Barsy syndrome. Characteristic features include severe mental retardation, hypermobility with athetoid movements, grimacing, muscular hypotonia, laxity of small joints and brisk deep tendon reflexes, progeroid aspect with cutis laxa, atrophy of skin with hyperpigmentation, isolated depigmentations, reduction of subcutaneous fatty tissue, translucent vein pattern, short stature, frontal bossing in the young child, large prominent ears with dysplastic helices and corneal clouding or cataracts. The syndrome probably has autosomal recessive inheritance. PMID:4076251

  1. Unusual molecular findings in autosomal recessive spinal muscular atrophy

    Microsoft Academic Search

    G Matthijs; E Schollen; E Legius; K Devriendt; N Goemans; H Kayserili; M Y Apäk; J J Cassiman

    1996-01-01

    All three types of autosomal recessive spinal muscular atrophy map to chromosome 5q11.2-q13.3 and are associated with deletions or mutations of the SMN (survival motor neurone) gene. The availability of a test to distinguish between the SMN gene and its nearly identical centromeric copy cBCD541 allows molecular diagnosis. We have analysed patients from 24 Belgian and 34 Turkish families for

  2. Autosomal recessive renal proximal tubulopathy and hypercalciuria: a new syndrome

    Microsoft Academic Search

    Daniella Magen; Lior Adler; Hana Mandel; Edna Efrati; Israel Zelikovic

    2004-01-01

    Background: The best described primary inherited proximal tubulopathies include X-linked hypercalciuric nephrolithiasis (XLHN), caused by a mutation in the chloride channel gene CLCN5, and classic Fanconi’s syndrome, the genetic basis of which is unknown. The aim of this study is to examine the clinical, biochemical, and genetic characteristics of a highly consanguineous Druze family with autosomal recessive proximal tubulopathy and

  3. Characterization of large structural genetic mosaicism in human autosomes.

    PubMed

    Machiela, Mitchell J; Zhou, Weiyin; Sampson, Joshua N; Dean, Michael C; Jacobs, Kevin B; Black, Amanda; Brinton, Louise A; Chang, I-Shou; Chen, Chu; Chen, Constance; Chen, Kexin; Cook, Linda S; Crous Bou, Marta; De Vivo, Immaculata; Doherty, Jennifer; Friedenreich, Christine M; Gaudet, Mia M; Haiman, Christopher A; Hankinson, Susan E; Hartge, Patricia; Henderson, Brian E; Hong, Yun-Chul; Hosgood, H Dean; Hsiung, Chao A; Hu, Wei; Hunter, David J; Jessop, Lea; Kim, Hee Nam; Kim, Yeul Hong; Kim, Young Tae; Klein, Robert; Kraft, Peter; Lan, Qing; Lin, Dongxin; Liu, Jianjun; Le Marchand, Loic; Liang, Xiaolin; Lissowska, Jolanta; Lu, Lingeng; Magliocco, Anthony M; Matsuo, Keitaro; Olson, Sara H; Orlow, Irene; Park, Jae Yong; Pooler, Loreall; Prescott, Jennifer; Rastogi, Radhai; Risch, Harvey A; Schumacher, Fredrick; Seow, Adeline; Setiawan, Veronica Wendy; Shen, Hongbing; Sheng, Xin; Shin, Min-Ho; Shu, Xiao-Ou; VanDen Berg, David; Wang, Jiu-Cun; Wentzensen, Nicolas; Wong, Maria Pik; Wu, Chen; Wu, Tangchun; Wu, Yi-Long; Xia, Lucy; Yang, Hannah P; Yang, Pan-Chyr; Zheng, Wei; Zhou, Baosen; Abnet, Christian C; Albanes, Demetrius; Aldrich, Melinda C; Amos, Christopher; Amundadottir, Laufey T; Berndt, Sonja I; Blot, William J; Bock, Cathryn H; Bracci, Paige M; Burdett, Laurie; Buring, Julie E; Butler, Mary A; Carreón, Tania; Chatterjee, Nilanjan; Chung, Charles C; Cook, Michael B; Cullen, Michael; Davis, Faith G; Ding, Ti; Duell, Eric J; Epstein, Caroline G; Fan, Jin-Hu; Figueroa, Jonine D; Fraumeni, Joseph F; Freedman, Neal D; Fuchs, Charles S; Gao, Yu-Tang; Gapstur, Susan M; Patiño-Garcia, Ana; Garcia-Closas, Montserrat; Gaziano, J Michael; Giles, Graham G; Gillanders, Elizabeth M; Giovannucci, Edward L; Goldin, Lynn; Goldstein, Alisa M; Greene, Mark H; Hallmans, Goran; Harris, Curtis C; Henriksson, Roger; Holly, Elizabeth A; Hoover, Robert N; Hu, Nan; Hutchinson, Amy; Jenab, Mazda; Johansen, Christoffer; Khaw, Kay-Tee; Koh, Woon-Puay; Kolonel, Laurence N; Kooperberg, Charles; Krogh, Vittorio; Kurtz, Robert C; LaCroix, Andrea; Landgren, Annelie; Landi, Maria Teresa; Li, Donghui; Liao, Linda M; Malats, Nuria; McGlynn, Katherine A; McNeill, Lorna H; McWilliams, Robert R; Melin, Beatrice S; Mirabello, Lisa; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M; Prokunina-Olsson, Ludmila; Purdue, Mark; Qiao, You-Lin; Rabe, Kari G; Rajaraman, Preetha; Real, Francisco X; Riboli, Elio; Rodríguez-Santiago, Benjamín; Rothman, Nathaniel; Ruder, Avima M; Savage, Sharon A; Schwartz, Ann G; Schwartz, Kendra L; Sesso, Howard D; Severi, Gianluca; Silverman, Debra T; Spitz, Margaret R; Stevens, Victoria L; Stolzenberg-Solomon, Rachael; Stram, Daniel; Tang, Ze-Zhong; Taylor, Philip R; Teras, Lauren R; Tobias, Geoffrey S; Viswanathan, Kala; Wacholder, Sholom; Wang, Zhaoming; Weinstein, Stephanie J; Wheeler, William; White, Emily; Wiencke, John K; Wolpin, Brian M; Wu, Xifeng; Wunder, Jay S; Yu, Kai; Zanetti, Krista A; Zeleniuch-Jacquotte, Anne; Ziegler, Regina G; de Andrade, Mariza; Barnes, Kathleen C; Beaty, Terri H; Bierut, Laura J; Desch, Karl C; Doheny, Kimberly F; Feenstra, Bjarke; Ginsburg, David; Heit, John A; Kang, Jae H; Laurie, Cecilia A; Li, Jun Z; Lowe, William L; Marazita, Mary L; Melbye, Mads; Mirel, Daniel B; Murray, Jeffrey C; Nelson, Sarah C; Pasquale, Louis R; Rice, Kenneth; Wiggs, Janey L; Wise, Anastasia; Tucker, Margaret; Pérez-Jurado, Luis A; Laurie, Cathy C; Caporaso, Neil E; Yeager, Meredith; Chanock, Stephen J

    2015-03-01

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. PMID:25748358

  4. A Homozygous Nonsense Mutation within the Dystonin Gene Coding for the Coiled-Coil Domain of the Epithelial Isoform of BPAG1 Underlies a New Subtype of Autosomal Recessive Epidermolysis Bullosa Simplex

    Microsoft Academic Search

    Richard W Groves; Lu Liu; Patricia J Dopping-Hepenstal; Hugh S Markus; Patricia A Lovell; Linda Ozoemena; Joey E Lai-Cheong; Jeffrey Gawler; Katsushi Owaribe; Takashi Hashimoto; Jemima E Mellerio; John B Mee; John A McGrath

    2010-01-01

    Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell–matrix or cell–cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the

  5. Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency

    Microsoft Academic Search

    M. R. Baumgartner

    2005-01-01

    Most enzyme deficiencies in humans are inherited as autosomal recessive traits. The term dominant negative is applied to mutant alleles in which a mutant protein interferes in one way or another with the function of the normal protein being produced from the wild-type allele in a heterozygote. Such a dominant negative effect usually involves homomeric or heteromeric proteins. 3-Methylcrotonyl-CoA carboxylase

  6. Broadcast Domination Daniel Lokshtanov

    E-print Network

    Fomin, Fedor V.

    Introduction The Dominating Set [2, 16] problem is probably one of the most studied problems in graph. The Dominating Set problem can be stated as follows: Color the vertices of a graph G black or white so that every N P and N P-completeness . . . . . . . . . . . . . . . . . . . 7 3 Dominating Set and some of its

  7. Unusual autosomal recessive lymphatic anomalies in two unrelated Amish families.

    PubMed

    Williams, M S; Josephson, K D

    1997-12-19

    We report on two unrelated Amish families with familial occurrence of unusual lymphatic anomalies. The first family had two children, a boy and a girl, with congenital chylothorax both of whom died as a consequence of this condition (one prenatally and one neonatally). The second family has two brothers with isolated cystic hygroma. Neither family has any other individuals affected with any type of lymphatic anomaly. Differential diagnosis and presumed autosomal recessive inheritance pattern will be discussed. Familial cystic hygroma not associated with hydrops fetalis and neonatal death has not been reported previously. PMID:9415686

  8. Autosomal recessive polymicrogyria with infantile spasms and limb deformities.

    PubMed

    Ciardo, F; Zamponi, N; Specchio, N; Parmeggiani, L; Guerrini, R

    2001-12-01

    We describe two siblings, a girl and a boy, aged 4 and 2 years and 10 months respectively, born from non-consanguineous parents,with diffuse polymicrogyria, lower limb deformities, infantile spasms and developmental delay. Spasms had a good outcome under antiepileptic drug treatment. Clinical and imaging features were of identical severity in both siblings. Muscle biopsy,creatine kinase, metabolic investigations and chromosomal analysis were normal. This combination of anatomo-clinical features and their occurrence in siblings of both sexes suggests an autosomal recessive malformation syndrome. PMID:11870589

  9. Autosomal STR genetic variation in negroid Chocó and Bogotá populations

    Microsoft Academic Search

    M. L. Bravo; M. A. Moreno; J. J. Builes; A. Salas; M. V. Lareu; A. Carracedo

    2001-01-01

    Genetic data for eight autosomal STRs were obtained from two different population samples from Colombia: the European Mestizo\\u000a population of Bogotá and the African descent population of the Chocó region. The STRs were analysed in a multiplex system\\u000a that includes the STR markers CSF1PO, TPOX, TH01, VWA, D13S317, D7S820, D16S539 and D5S818. Separation of the fragments and\\u000a fluorescent detection was

  10. The Distribution of Human Genetic Diversity: A Comparison of Mitochondrial, Autosomal, and Y-Chromosome Data

    Microsoft Academic Search

    L. B. Jorde; W. S. Watkins; M. J. Bamshad; M. E. Dixon; C. E. Ricker; M. T. Seielstad; M. A. Batzer

    2000-01-01

    We report a comparison of worldwide genetic variation among 255 individuals by using autosomal, mitochondrial, and Y-chromosome polymorphisms. Variation is assessed by use of 30 autosomal restriction-site polymorphisms (RSPs), 60 autosomal short-tandem-repeat polymorphisms (STRPs), 13 Alu-insertion polymorphisms and one LINE- 1 element, 611 bp of mitochondrial control-region sequence, and 10 Y-chromosome polymorphisms. Analysis of these data reveals substantial congruity among

  11. Genetic Dominance & Cellular Processes

    ERIC Educational Resources Information Center

    Seager, Robert D.

    2014-01-01

    In learning genetics, many students misunderstand and misinterpret what "dominance" means. Understanding is easier if students realize that dominance is not a mechanism, but rather a consequence of underlying cellular processes. For example, metabolic pathways are often little affected by changes in enzyme concentration. This means that…

  12. An autosomal genetic linkage map of the sheep genome

    SciTech Connect

    Crawford, A.M.; Ede, A.J.; Pierson, C.A. [Univ. of Otago, Dunedin (New Zealand)] [and others

    1995-06-01

    We report the first extensive ovine genetic linkage map covering 2070 cM of the sheep genome. The map was generated from the linkage analysis of 246 polymorphic markers, in nine three-generation full-sib pedigrees, which make up the AgResearch International Mapping Flock. We have exploited many markers from cattle so that valuable comparisons between these two ruminant linkage maps can be made. The markers, used in the segregation analyses, comprised 86 anonymous microsatellite markers derived from the sheep genome, 126 anonymous microsatellites from cattle, one from deer, and 33 polymorphic markers of various types associated with known genes. The maximum number of informative meioses within the mapping flock was 22. The average number of informative meioses per marker was 140 (range 18-209). Linkage groups have been assigned to all 26 sheep autosomes. 102 refs., 8 figs., 5 tabs.

  13. Reduction in fitness of flea beetles which are homozygous for an autosomal gene conferring resistance to defences in Barbarea vulgaris.

    PubMed

    De Jong, P W; Nielsen, J K

    2000-01-01

    Major resistance genes are present in Danish flea beetle (Phyllotreta nemorum) populations, enabling the beetles to utilize a defended plant, Barbarea vulgaris ssp. arcuata, as a host plant, whereas this plant is unsuitable for beetles lacking the resistance genes. Two lines of beetles carrying a resistance gene have been established which are near-isogenic with a susceptible line. Larval survival of offspring from crosses between flea beetles carrying resistance genes and susceptible beetles, tested in bioassays on the defended B. vulgaris, and sex ratios of the survivors, were consistent with the presence of a dominant, autosomal resistance gene in each of the lines. An attempt to produce pure-breeding lines for the autosomal genes revealed that beetles that are homozygous for the resistance gene suffer a high mortality. This result was repeatable for both lines, and when both resistant males and females were used in the crosses. The high mortality was also independent of the plant (defended B. vulgaris or suitable radish) on which the beetles were reared. The results suggest that the time of death of homozygous resistant beetles is variable. The spread and maintenance of resistance genes in flea beetle populations are discussed. PMID:10692007

  14. Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over sexually

    E-print Network

    Crespi, Bernard J.

    Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over extreme, pathological expression. In this regard, pathology reveals hidden evolutionary design. We first and the autosomes may be associated with various pathologies caused by extreme expression along the male­female axis

  15. ORIGINAL INVESTIGATION Further characterization of ATP6V0A2-related autosomal

    E-print Network

    ORIGINAL INVESTIGATION Further characterization of ATP6V0A2-related autosomal recessive cutis laxa heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debre´ type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2

  16. Mutations in SOX9, the gene responsible for campomelic dysplasia and autosomal sex reversal

    SciTech Connect

    Kwok, C.; Weller, P.A.; Guioli, S. [St. George`s Hospital Medical School, London (United Kingdom)] [and others

    1995-11-01

    Campomelic dysplasia (CD) is a skeletal malformation syndrome frequently accompanied by 46,XY sex reversal. A mutation-screening strategy using SSCP was employed to identify mutations in SOX9, the chromosome 17q24 gene responsible for CD and autosomal sex reversal in man. We have screened seven CD patients with no cytologically detectable chromosomal aberrations and two CD patients with chromosome 17 rearrangements for mutations in the entire open reading frame of SOX9. Five different mutations have been identified in six CD patients: two missense mutations in the SOX9 putative DNA binding domain (high mobility group, or HMG, box); three frameshift mutations and a splice-acceptor mutation. An identical frameshift mutation is found in two unrelated 46,XY patients, one exhibiting a male phenotype and the other displaying a female phenotype (XY sex reversal). All mutations found affect a single allele, which is consistent with a dominant mode of inheritance. No mutations were found in the SOX9 open reading frame of two patients with chromosome 17q rearrangements, suggesting that the translocations affect SOX9 expression. These findings are consistent with the hypothesis that CD results from haploinsufficiency of SOX9. 27 refs., 3 figs., 3 tabs.

  17. An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p

    SciTech Connect

    Kaukonen, J.A.; Suomalainen, A.; Peltonen, L. [National Public Health Inst., Helsinki (Finland); Amati, P.; Zeviani, M. [Univ. of Milano, Milan (Italy)] [and others

    1996-04-01

    Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more respiratory-chain enzymes carrying mtDNA-encoded subunits. The pattern of inheritance indicates a nuclear gene defect predisposing to secondary mtDNA deletions. Recently, in one Finnish family, we assigned an adPEO locus to chromosome 10q23.3-24.3 but also excluded linkage to this same locus in two Italian adPEO families with a phenotype closely resembling the Finnish one. We applied a random mapping approach to informative non-10q-linked Italian families to assign the second locus for adPEO and found strong evidence for linkage on chromosome 3p14.1-21.2 in three Italian families, with a maximum two-point lod score of 4.62 at a recombination fraction of .0. However, in three additional families, linkage to the same chromosomal region was clearly absent, indicating further genetic complexity of the adPEO trait. 19 refs., 3 figs., 2 tabs.

  18. Genetic heterogeneity and exclusion of a modifying locus at 2q in a family with autosomal dominant primary erythermalgia

    Microsoft Academic Search

    T. M. Burns; R. H. M. te Morsche; J. B. M. J. Jansen; J. P. H. Drenth

    2005-01-01

    BACKGROUND: Primary erythermalgia is a rare disorder characterized by recurrent attacks of red, warm and painful hands and\\/or feet. In a previous study we reported localization of a gene for primary erythermalgia to a 7.94-cM region on chromosome 2q. A recent study reported voltage-gated sodium channel gene SCN9a sequence variants in a family and a single individual with primary erythermalgia.

  19. An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa

    Microsoft Academic Search

    Mayada Tassabehji; Kay Metcalfe; Jane Hurst; Gillian S. Ashcroft; Cay Kielty; Carrie Wilmot; Dian Donnai; Andrew P. Read; Carolyn J. P. Jones

    1998-01-01

    Elastin is the protein responsible for the characteristic elastic properties of many tissues including the skin, lungs and large blood vessels. Loss-of-function muta- tions in the elastin gene are known to cause the heart defect supravalvular aortic stenosis (SVAS). We and others have identified deletions, nonsense mutations and splice site mutations in SVAS patients that abolish the function of one

  20. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L

    Microsoft Academic Search

    Bei-sha Tang; Guo-hua Zhao; Wei Luo; Kun Xia; Fang Cai; Qian Pan; Ru-xu Zhang; Fu-feng Zhang; Xiao-min Liu; Biao Chen; Cheng Zhang; Lu Shen; Hong Jiang; Zhi-gao Long; He-ping Dai

    2005-01-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. We have previously described a large Chinese CMT family and assigned the locus underlying the disease (CMT2L; OMIM 608673) to chromosome 12q24. Here, we report a novel c.423G?T (Lys141Asn) missense mutation of small heat-shock protein 22-kDa protein 8 (encoded by HSPB8), which is also responsible for distal hereditary

  1. Frequency Analysis of Autosomal Dominant Cerebellar Ataxias in Taiwanese Patients and Clinical and Molecular Characterization of Spinocerebellar Ataxia Type 6

    Microsoft Academic Search

    Bing-wen Soong; Yi-chun Lu; Kong-bung Choo; Hsiang-ying Lee

    2001-01-01

    Background: Spinocerebellar ataxia (SCA) is a heter- ogeneous group of neurodegenerative disorders. The mu- tational basis for most of these disorders is an expanded CAG repeat sequence within the coding regions of the genes involved. The prevalence of SCA in the ethnic Chinese on Taiwan remains unclear. Moreover, there has been no report of SCA type 6 (SCA6) among Chinese

  2. Am. J. Hum. Genet. 70:10441048, 2002 A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer

    E-print Network

    Kruglyak, Leonid

    Pancreatic Cancer Maps to Chromosome 4q32-34 Michael A. Eberle,1,* Roland Pfu¨tzer,5,*, Kay L. Pogue-Geile,5 of Pittsburgh, and 6 Veterans Administration Pittsburgh Health Care System, Pittsburgh Pancreatic cancer cancer will die from it, usually in !6 mo. Familial clustering of pancreatic cancers is commonly

  3. A Novel Point Mutation in the KCNJ5 Gene Causing Primary Hyperaldosteronism and Early-Onset Autosomal Dominant Hypertension

    PubMed Central

    Sertedaki, Amalia; Kino, Tomoshige; Merakou, Christina; Hoffman, Dax A.; Hatch, Michael M.; Hurt, Darrell E.; Lin, Lin; Xekouki, Paraskevi; Stratakis, Constantine A.; Chrousos, George P.

    2012-01-01

    Context: Aldosterone production in the adrenal zona glomerulosa is mainly regulated by angiotensin II, [K+], and ACTH. Genetic deletion of subunits of K+-selective leak (KCNK) channels TWIK-related acid sensitive K+-1 and/or TWIK-related acid sensitive K+-3 in mice results in primary hyperaldosteronism, whereas mutations in the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene are implicated in primary hyperaldosteronism and, in certain cases, in autonomous glomerulosa cell proliferation in humans. Objective: The objective of the study was to investigate the role of KCNK3, KCNK5, KCNK9, and KCNJ5 genes in a family with primary hyperaldosteronism and early-onset hypertension. Patients and Methods: Two patients, a mother and a daughter, presented with severe primary hyperaldosteronism, bilateral massive adrenal hyperplasia, and early-onset hypertension refractory to medical treatment. Genomic DNA was isolated and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials. Results: Sequencing of the KCNJ5 gene revealed a single, heterozygous guanine to thymine (G ? T) substitution at nucleotide position 470 (n.G470T), resulting in isoleucine (I) to serine (S) substitution at amino acid 157 (p.I157S). This mutation results in loss of ion selectivity, cell membrane depolarization, increased Ca2+ entry in adrenal glomerulosa cells, and increased aldosterone synthesis. Sequencing of the KCNK3, KCNK5, and KCNK9 genes revealed no mutations in our patients. Conclusions: These findings explain the pathogenesis in a subset of patients with severe hypertension and implicate loss of K+ channel selectivity in constitutive aldosterone production. PMID:22628607

  4. Genetic linkage of autosomal dominant juvenile glaucoma to 1q21-q31 in three affected pedigrees

    Microsoft Academic Search

    J. L. Wiggs; C. Paglinauan; A. Fine; C. Sporn; D. Lou; J. L. Haines

    1994-01-01

    Glaucoma is a common disorder that results in irreversible damage to the optic nerve, causing absolute blindness. In most cases, the optic nerve is damaged by an elevation of the intraocular pressure that is the result of an abnormality in the normal drainage function of the trabecular meshwork. A family history of glaucoma is an important risk factor for the

  5. Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery–Dreifuss muscular dystrophy

    Microsoft Academic Search

    Maggie C. Walter; Thomas N. Witt; Beate Schlotter Weigel; Peter Reilich; Pascale Richard; Dieter Pongratz; Gisèle Bonne; Manfred S. Wehnert; Hanns Lochmüller

    2005-01-01

    Mutations in the LMNA gene encoding the nuclear envelope protein, lamins A and C, have been associated with at least nine distinct disorders now called laminopathies, including Emery–Dreifuss muscular dystrophy and Charcot–Marie–Tooth type 2 disease. We identified a novel mutation in the 5? region of the LMNA gene ?3del15, resulting in the loss of 15 nucleotides from ?3 to +12,

  6. Novel mutation in FBN1 causes ectopia lentis and varicose great saphenous vein in one Chinese autosomal dominant family

    PubMed Central

    Fu, Qing; Liu, Peng; Lu, Qingsheng; Wang, Feng; Wang, Hui; Shen, Wei; Xu, Fei; Liu, Lin; Sergeev, Yuri V.

    2014-01-01

    Purpose To identify genetic defects in a Chinese family with ectopia lentis (EL) and varicose great saphenous vein (GSV) and to analyze the correlations between phenotype and genotype. Methods Twenty-two (12 affected subjects and ten unaffected subjects) among 53 members of a Chinese family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from the leukocytes in the subjects’ peripheral blood. A minimum interval was achieved with linkage study and haplotype analysis. All 65 exons and the flanking intronic regions of fibrillin-1 (FBN1) were amplified with PCR and screened for mutations with direct Sanger sequencing. Molecular modeling was analyzed in an in silico study. Results The linkage study showed a strong cosegregation signal on chromosome 15. The non-parametric linkage analysis yielded a maximum score of 29.1(p<0.00001), and the parametric logarithm of the odds (LOD) score was 3.6. The minimum interval of the shared haplotype was rs1565863-rs877228. The best candidate gene in this region was FBN1. A novel mutation, c.3928G>A, p.1310G>S in exon 31, was identified in FBN1 and cosegregated well in the family. We applied molecular modeling to show the effect of this mutation on the fibrillin-1 structure. The mutation significantly distorts the calcium coordination, decreases the binding of the calcium ion in that motif, and affects the local calcium-binding epidermal growth factor (cbEGF) interface that depends on Ca binding. Conclusions FBN1-associated fibrillinopathies are a group of diseases with dynamic phenotype changes. Novel mutation p.1310G>S was first reported to cause Marfan syndrome (MFS). Our results expand the mutation spectrum in FBN1 and enhance our knowledge of genotype–phenotype correlations underlying FBN1 mutations. PMID:24940037

  7. PERFECT DOMINATING SETS

    Microsoft Academic Search

    Marilynn Livingston; Quentin F. Stout

    A dominating set of a graph is perfect if each vertex of is dominated by exactly one vertex in . We study the existence and construction of PDSs in families of graphs arising from the interconnection networks of parallel computers. These include trees, dags, series-parallel graphs, meshes, tori, hypercubes, cube-connected cycles, cube-connected paths, and de Bruijn graphs. For trees, dags,

  8. Genetic Analysis of the Proximal Region of Chromosome 2 of DROSOPHILA MELANOGASTER. I. Detachment Products of Compound Autosomes

    PubMed Central

    Hilliker, A. J.; Holm, D. G.

    1975-01-01

    To examine the genetic composition of proximal heterochromain in chromosome 2, the detachment of compound second autosomes, for generating proximal deficiencies, appeared a promising method. Compound seconds were detached by gamma radiation. A fraction of the detachment products were recessive lethals owing to proximal deficiencies. Analysis by inter se complementation, pseudo-dominance tests with proximal mutations and allelism tests with known deficiencies provided evidence for at least two loci between the centromere and the light locus in 2L and one locus in 2R between the rolled locus and the centromere. The data further demonstrate that rolled, and probably light, are located within the proximal heterochromatin. Thus, functional genetic loci are found in heterochromatin, albeit at low density. PMID:814038

  9. Viability of X-autosome translocations in mammals: an epigenomic hypothesis from a rodent case-study

    Microsoft Academic Search

    G. Dobigny; C. Ozouf-Costaz; C. Bonillo; V. Volobouev

    2004-01-01

    X-autosome translocations are highly deleterious chromosomal rearrangements due to meiotic disruption, the effects of X-inactivation on the autosome, and the necessity of maintaining different replication timing patterns between the two segments. In spite of this, X-autosome translocations are not uncommon. We here focus on the genus Taterillus (Rodentia, Gerbillinae) which provides two sister lineages differing by two autosome–gonosome translocations. Despite

  10. Toward a Gene Therapy for Dominant Disease: Validation of an RNA Interference-Based Mutation-Independent Approach

    Microsoft Academic Search

    Anna-Sophia Kiang; Arpad Palfi; Marius Ader; Paul F. Kenna; Sophia Millington-Ward; Gerry Clark; Avril Kennan; Mary O'Reilly; Lawrence C. T. Tam; Aileen Aherne; Niamh McNally; Pete Humphries; G. Jane Farrar

    2005-01-01

    The intragenic heterogeneity encountered in many dominant disease-causing genes represents a significant challenge with respect to development of economically viable therapeutics. For example, 25% of autosomal dominant retinitis pigmentosa is caused by over 100 different mutations within the gene encoding rhodopsin, each of which could require a unique gene therapy. We describe here an RNA interference (RNAi)-based mutation-independent approach, targeting

  11. Evidence for the existence of a fourth dominantly inherited spinocerebellar ataxia locus

    SciTech Connect

    Lopes-Cendes, I. (Montreal General Hospital Research Institute, Quebec (Canada) Montreal Neurological Institute and Hospital, Quebec (Canada) McGill Univ., Quebec (Canada)); Andermann, E. (Montreal Neurological Institute and Hospital, Quebec (Canada) McGill Univ., Quebec (Canada)); Rouleau, G.A. (Montreal General Hospital Research Institute, Quebec (Canada) Montreal Neurological Institute and Hospital, Quebec (Canada))

    1994-05-01

    The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of disorders. To date, three loci have been identified: The SCA1 locus (on chr 6p), the SCA2 locus (on chr 12q), and more recently a Machado-Joseph disease (MJD) locus (on chr 14q). The authors have studied one large French-Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers that flank the three previously described loci significantly exclude the French-Canadian kindred from the SCA1, SCA2, and MJD loci. Therefore, a fourth, still unmapped SCA locus remains to be identified. In addition, the unique clinical phenotype present in all affected individuals of the French-Canadian kindred might be characteristic of this still unmapped SCA locus. 34 refs., 2 figs., 2 tabs.

  12. Evidence for genetic homogeneity in autosomal recessive generalised myotonia (Becker).

    PubMed Central

    Koch, M C; Ricker, K; Otto, M; Wolf, F; Zoll, B; Lorenz, C; Steinmeyer, K; Jentsch, T J

    1993-01-01

    Generalised myotonia Becker (GM) is an autosomal recessively inherited muscle disorder. Affected subjects exhibit myotonic muscle stiffness in all skeletal muscles with marked hypertrophy in the legs. A transient muscle weakness is particularly pronounced in the arms and hands and is a typical symptom of the disorder. Recently, we showed complete linkage of the disorder GM to the gene (CLCN1) coding for the skeletal muscle chloride channel CLC-1 and the TCRB gene on chromosome 7 in German families. In the study presented here we performed linkage analysis on 14 new GM families. The GM locus was again completely linked to both the CLCN1 and the TCRB gene in all families with a combined lod score of Z = 9.26 at a recombination fraction of theta = 0.00. This confirms our previous data and supports the hypothesis that GM is a genetically homogeneous disorder. The previously detected T to G missense mutation is found on 15% of the 66 GM chromosomes counted so far. PMID:8301644

  13. SLC7A14 linked to autosomal recessive retinitis pigmentosa

    PubMed Central

    Jin, Zi-Bing; Huang, Xiu-Feng; Lv, Ji-Neng; Xiang, Lue; Li, Dong-Qing; Chen, Jiangfei; Huang, Changjiang; Wu, Jinyu; Lu, Fan; Qu, Jia

    2014-01-01

    Retinitis pigmentosa (RP) is characterized by degeneration of the retinal photoreceptors and is the leading cause of inherited blindness worldwide. Although few genes are known to cause autosomal recessive RP (arRP), a large proportion of disease-causing genes remain to be revealed. Here we report the identification of SLC7A14, a potential cationic transporter, as a novel gene linked to arRP. Using exome sequencing and direct screening of 248 unrelated patients with arRP, we find that mutations in the SLC7A14 gene account for 2% of cases of arRP. We further demonstrate that SLC7A14 is specifically expressed in the photoreceptor layer of the mammalian retina and its expression increases during postnatal retinal development. In zebrafish, downregulation of slc7a14 expression leads to an abnormal eye phenotype and defective light-induced locomotor response. Furthermore, targeted knockout of Slc7a14 in mice results in retinal degeneration with abnormal ERG response. This suggests that SLC7A14 has an important role in retinal development and visual function. PMID:24670872

  14. Bilateral Orientations and Domination

    Microsoft Academic Search

    Fedor V. Fomin; Martín Matamala; Erich Prisner; Ivan Rapaport

    2001-01-01

    AbstractWe consider the problem of finding the minimum diameter among all strong orientations of a given connected, bridgeless, undirected graph. We obtain some bounds for the smallest diameter for different classes of AT-free graphs and show that these bounds are sharp up to additive constants. Dominating sets and their properties are the main tools in our research.

  15. Mutations in SLC6A17 cause autosomal-recessive intellectual disability.

    PubMed

    Waltl, S

    2015-08-01

    Homozygous SLC6A17-mutations cause autosomal-recessive intellectual disability with progressive tremor, speech impairment, and behavioral problems Iqbal Z et al. (2015) American Journal of Human Genetics 96(3): 386-396. PMID:25970702

  16. Close genetic relationships in vast territories: autosomal and X chromosome Alu diversity in Yakuts from Siberia.

    PubMed

    Rocañín-Arjó, Ares; Rodríguez-Botigué, Laura; Esteban, Esther; Theves, Catherine; Evdokimova, Larissa E; Fedorova, Sardana A; Gibert, Morgane; Crubezy, Eric; Moral, Pedro

    2013-01-01

    Twelve autosomal and 8 X chromosome Alu markers were genotyped for the first time in 161 Central and West Yakuts to test their ability to reconstruct the genetic history of these populations, the northernmost Turkic-speaker ethnic group living in Siberia. Autosomal data revealed that both groups showed extremely close genetic distances to other populations of Siberian origins that occupied areas from Lake Baikal, the ancestral place of origin of Yakuts, to North Siberia, their current territories. Autosomal and X chromosome data revealed some discrepancies on the genetic differentiation and the effective sizes of Central and West Yakuts. Such discrepancies could be related to the patrilineal and occasionally polygamous structure of these populations. Autosomal and X Alu markers are informative markers to reconstruct population past demography and history, but their utility is limited by the available data. This study represents a contribution for further investigations on these populations. PMID:24466640

  17. The somatic autosomal mutation matrix in cancer genomes.

    PubMed

    Temiz, Nuri A; Donohue, Duncan E; Bacolla, Albino; Vasquez, Karen M; Cooper, David N; Mudunuri, Uma; Ivanic, Joseph; Cer, Regina Z; Yi, Ming; Stephens, Robert M; Collins, Jack R; Luke, Brian T

    2015-08-01

    DNA damage in somatic cells originates from both environmental and endogenous sources, giving rise to mutations through multiple mechanisms. When these mutations affect the function of critical genes, cancer may ensue. Although identifying genomic subsets of mutated genes may inform therapeutic options, a systematic survey of tumor mutational spectra is required to improve our understanding of the underlying mechanisms of mutagenesis involved in cancer etiology. Recent studies have presented genome-wide sets of somatic mutations as a 96-element vector, a procedure that only captures the immediate neighbors of the mutated nucleotide. Herein, we present a 32 × 12 mutation matrix that captures the nucleotide pattern two nucleotides upstream and downstream of the mutation. A somatic autosomal mutation matrix (SAMM) was constructed from tumor-specific mutations derived from each of 909 individual cancer genomes harboring a total of 10,681,843 single-base substitutions. In addition, mechanistic template mutation matrices (MTMMs) representing oxidative DNA damage, ultraviolet-induced DNA damage, (5m)CpG deamination, and APOBEC-mediated cytosine mutation, are presented. MTMMs were mapped to the individual tumor SAMMs to determine the maximum contribution of each mutational mechanism to the overall mutation pattern. A Manhattan distance across all SAMM elements between any two tumor genomes was used to determine their relative distance. Employing this metric, 89.5 % of all tumor genomes were found to have a nearest neighbor from the same tissue of origin. When a distance-dependent 6-nearest neighbor classifier was used, 86.9 % of all SAMMs were assigned to the correct tissue of origin. Thus, although tumors from different tissues may have similar mutation patterns, their SAMMs often display signatures that are characteristic of specific tissues. PMID:26001532

  18. Rapid detection of autosomal aneuploidy using microsatellite markers

    SciTech Connect

    Ray, P.N.; Teshima, I.E. [Hospital for Sick Children, Ontario (Canada); Winsor, E.J.T. [Toronto Hospital, Ontario (Canada)] [and others

    1994-09-01

    Trisomy occurs in at least 4% of all clinically recognized pregnancies, making it the most common type of chromosome abnormality in humans. The most commonly occurring trisomies are those of chromosomes 13, 18, 21 and aneuploidy of X and Y, accounting for about 0.3% of all newborns and a much higher percentage of conceptuses. In Canada, prenatal chromosome analysis by amniocentesis is offered to those women {ge} 35 years of age at the time of delivery or equivalent risk by maternal serum screen. We are developing a rapid molecular diagnostic test to detect the most common autosomal aneuploidies in prenatal and neonatal samples. The tests makes use of highly polymorphic short tandem repeat markers labeled with fluorescent tags which allow analysis on a GENESCANNER automated fragment analyzer (ABI). Multiple polymorphic markers have been selected on each of chromosomes 13, 18 and 21. At a given locus, trisomic fetuses/neonates will have either three alleles or two alleles with one allele having twice the intensity of the other. Unaffected individuals have two equal intensity alleles. We are conducting a blind study that will compare the detection efficiencies of FISH analysis on uncultured cells and the molecular method on confirmation amniotic fluid samples collected at the time of termination of affected fetuses. Results on cultured amniocytes from one such patient confirmed that trisomy 21 can be detected. FISH was not done on this sample. In addition, detection efficiency of the molecular method in whole blood samples from affected neonates is also being studied. To date, two such samples have been tested, one with trisomy 13 and one with trisomy 18, and both samples were diagnosed correctly. Preliminary results suggest that this method may provide a valuable tool for the rapid diagnosis of aneuploidy.

  19. An exome sequencing strategy to diagnose lethal autosomal recessive disorders.

    PubMed

    Ellard, Sian; Kivuva, Emma; Turnpenny, Peter; Stals, Karen; Johnson, Matthew; Xie, Weijia; Caswell, Richard; Lango Allen, Hana

    2015-03-01

    Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies. PMID:24961629

  20. Mutations in NSUN2 cause autosomal-recessive intellectual disability.

    PubMed

    Abbasi-Moheb, Lia; Mertel, Sara; Gonsior, Melanie; Nouri-Vahid, Leyla; Kahrizi, Kimia; Cirak, Sebahattin; Wieczorek, Dagmar; Motazacker, M Mahdi; Esmaeeli-Nieh, Sahar; Cremer, Kirsten; Weißmann, Robert; Tzschach, Andreas; Garshasbi, Masoud; Abedini, Seyedeh S; Najmabadi, Hossein; Ropers, H Hilger; Sigrist, Stephan J; Kuss, Andreas W

    2012-05-01

    With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(?)] and c.1114C>T [p.Gln372(?)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(?)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development. PMID:22541559

  1. Autosomal recessive inheritance of hereditary motor and sensory neuropathy with optic atrophy.

    PubMed Central

    Chalmers, R M; Riordan-Eva, P; Wood, N W

    1997-01-01

    Three siblings are reported with childhood onset hereditary motor and sensory neuropathy (HMSN) and adult onset optic atrophy. Electrophysiological studies showed an axonal neuropathy and dysfunction of the retinal ganglion cells or optic nerve. The presumed mode of inheritance is autosomal recessive. This is the second family in which autosomal recessive inheritance of HMSN and optic atrophy (HMSN type VI) has been described, and the first in which electrophysiological studies have been reported. PMID:9120454

  2. A new autosomal STR nineplex for canine identification and parentage testing.

    PubMed

    van Asch, Barbara; Alves, Cíntia; Gusmão, Leonor; Pereira, Vânia; Pereira, Filipe; Amorim, António

    2009-01-01

    A single multiplex PCR assay capable of simultaneously amplifying nine canine-specific autosomal STR markers (FH3210, FH3241, FH2004, FH2658, FH4012, REN214L11, FH2010, FH2361 and the newly described C38) was developed for individual identification and parentage testing in domestic dogs. In order to increase genotyping efficiency, amplicon sizes were optimized for a 90-350 bp range, with fluorescently labelled primers for use in Applied Biosystems, Inc., platforms. The performance of this new multiplex system was tested in 113 individuals from a case-study population and 12 random dogs from mixed-breed origin. Co-dominant inheritance of STR alleles was investigated in 101 father, mother and son trios. Expected heterozygosity values vary between 0.5648 for REN214L11 and 0.9050 for C38. The high level of genetic diversity observed for most markers provides this multiplex with a very high discriminating power (matching probability=1.63/10(10) and matching probability among siblings=4.9/10(3)). Allele sequences and a proposal for standardized nomenclature are also herein presented, aiming at implementing the use of this system in forensic DNA typing and population genetic studies. This approach resulted in an optimized and well-characterized canine DNA genotyping system that is highly performing and straightforward to integrate and employ routinely. Although this STR multiplex was developed for use and tested in a case-study population, the Portuguese breed Cão de Gado Transmontano, it proved to be useful for general identification purposes or parentage testing. PMID:19204943

  3. Tourist Town: Dominating Sets

    NSDL National Science Digital Library

    Tim Bell

    1998-01-01

    In this activity, learners use a fictitious map of "Tourist Town" and counters to problem solve how to place ice-cream vans on street intersections so that every other intersection is connected to one that has a van on it. Use this activity to introduce learners to computer science themes including nodes, dominating sets, exponential-time algorithms, polynomial-time algorithms, and NP-complete problems. Variations, extensions, background information, and solutions are included in the PDF.

  4. Disjoint dominating and total dominating sets in graphs

    Microsoft Academic Search

    Michael A. Henning; Christian Löwenstein; Dieter Rautenbach; Justin Southey

    2010-01-01

    It has been shown [M.A. Henning, J. Southey, A note on graphs with disjoint dominating and total dominating sets, Ars Combin. 89 (2008) 159–162] that every connected graph with minimum degree at least two that is not a cycle on five vertices has a dominating set D and a total dominating set T which are disjoint. We characterize such graphs

  5. Dominating Sets for Outerplanar Graphs

    Microsoft Academic Search

    VAL PINCIU

    We provide lower and upper bounds for the domination numbers and the connected domination numbers for outerplanar graphs. We also provide a recursive algorithm that finds a connected domination set for an outerplanar graph. Finally, we show that for outerplanar graphs where all bounded faces are 3-cycles, the problem of determining the connected domination number is equivalent to an art

  6. Weighted Domination of Cocomparability Graphs

    Microsoft Academic Search

    Maw-shang Chang

    1997-01-01

    It is shown in this paper that the weighted domination problem and its three variants, the weighted connected domination, total domination, and dominating clique problems are NP-complete on cobipartite graphs when arbitrary integer vertex weights are allowed and all of them can be solved in polynomial time on cocomparability graphs if vertex weights are integers and less than or equal

  7. Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy.

    PubMed Central

    Votruba, M; Moore, A T; Bhattacharya, S S

    1998-01-01

    Inherited optic neuropathies are a significant cause of childhood and adult blindness and dominant optic atrophy (DOA) is the most common form of autosomally inherited (non-glaucomatous) optic neuropathy. Patients with DOA present with an insidious onset of bilateral visual loss and they characteristically have temporal optic nerve pallor, centrocaecal visual field scotoma, and a colour vision deficit, which is frequently blue-yellow. Evidence from histological and electrophysiological studies suggests that the pathology is confined to the retinal ganglion cell. A gene for dominant optic atrophy (OPA1) has been mapped to chromosome 3q28-qter, and studies are under way to refine the genetic interval in which the gene lies, to map the region physically, and hence to clone the gene. A second locus for dominant optic atrophy has recently been shown to map to chromosome 18q12.2-12.3 near the Kidd blood group locus. The cloning of genes for dominant optic atrophy will provide important insights into the pathophysiology of the retinal ganglion cell in health and disease. These insights may prove to be of great value in the understanding of other primary ganglion cell diseases, such as the mitochondrially inherited Leber's hereditary optic neuropathy and other diseases associated with ganglion cell loss, such as glaucoma. Images PMID:9783700

  8. Graphs with disjoint dominating and paired-dominating sets

    Microsoft Academic Search

    Justin Southey; Michael A. Henning

    2010-01-01

    A dominating set of a graph is a set of vertices such that every vertex not in the set is adjacent to a vertex in the set,\\u000a while a paired-dominating set of a graph is a dominating set such that the subgraph induced by the dominating set contains\\u000a a perfect matching. In this paper, we show that no minimum degree

  9. Consanguineous marriages in Morocco and the consequence for the incidence of autosomal recessive disorders.

    PubMed

    Jaouad, I Cherkaoui; Elalaoui, S Chafaï; Sbiti, A; Elkerh, F; Belmahi, L; Sefiani, A

    2009-09-01

    Consanguineous marriage is traditionally common throughout Arab countries. This leads to an increased birth prevalence of infants with recessive disorders, congenital malformations, morbidity and mortality. The aim of this study was to evaluate the rate of consanguineous marriage in families with autosomal recessive diseases, and to compare it with the average rate of consanguinity in the Moroccan population. The study was conducted in the Department of Medical Genetics in Rabat on 176 families with autosomal recessive diseases diagnosed and confirmed by clinical, radiological, enzymatic or molecular investigations. The rate of consanguinity was also studied in 852 families who had infants with trisomy 21 confirmed by karyotyping. These families were chosen because: (i) there is no association between trisomy 21 and consanguinity, (ii) these cases are referred from different regions of Morocco and (iii) they concern all social statuses. Among 176 families with autosomal recessive disorders, consanguineous marriages comprised 59.09% of all marriages. The prevalence of consanguinity in Morocco was found to be 15.25% with a mean inbreeding coefficient of 0.0065. The differences in the rates of consanguineous marriages were highly significant when comparing the general population and couples with offspring affected by autosomal recessive conditions. These results place Morocco among the countries in the world with high rates of consanguinity. Autosomal recessive disorders are strongly associated with consanguinity. This study better defines the health risks associated with consanguinity for the development of genetic educational guidelines targeted at the public and the health sector. PMID:19433002

  10. Maternal uniparental isodisomy causing autosomal recessive GM1 gangliosidosis: a clinical report.

    PubMed

    King, Jessica E; Dexter, Amy; Gadi, Inder; Zvereff, Val; Martin, Meaghan; Bloom, Miriam; Vanderver, Adeline; Pizzino, Amy; Schmidt, Johanna L

    2014-10-01

    Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship. PMID:24777551

  11. Dominance Constraints with Set Operators

    Microsoft Academic Search

    Denys Duchier; Joachim Niehren

    2000-01-01

    Dominance constraints are widely used in computational linguisticsas a language for talking and reasoning about trees. In this paper,we extend dominance constraints by admitting set operators. We presenta solver for dominance constraints with set operators, which is based onpropagation and distribution rules, and prove its soundness and completeness.

  12. Parameterized Domination in Circle Graphs

    E-print Network

    Bousquet, Nicolas; Mertzios, George B; Paul, Christophe; Sau, Ignasi; Thomassé, Stéphan

    2012-01-01

    A circle graph is the intersection graph of a set of chords in a circle. Keil [Discrete Applied Mathematics, 42(1):51-63, 1993] proved that Dominating Set, Connected Dominating Set, and Total Dominating Set are NP-complete in circle graphs. To the best of our knowledge, nothing was known about the parameterized complexity of these problems in circle graphs. In this paper we prove the following results, which contribute in this direction: - Dominating Set, Independent Dominating Set, Connected Dominating Set, Total Dominating Set, and Acyclic Dominating Set are W[1]-hard in circle graphs, parameterized by the size of the solution. - Whereas both Connected Dominating Set and Acyclic Dominating Set are W[1]-hard in circle graphs, it turns out that Connected Acyclic Dominating Set is polynomial-time solvable in circle graphs. - If T is a given tree, deciding whether a circle graph has a dominating set isomorphic to T is NP-complete when T is in the input, and FPT when parameterized by |V(T)|. We prove that the FP...

  13. Dominating sets in directed graphs

    Microsoft Academic Search

    Chaoyi Pang; Rui Zhang; Qing Zhang; Junhu Wang

    2010-01-01

    We consider the problem of incrementally computing a minimal dominating set of a directed graph after the insertion or deletion of a set of arcs. Earlier results have either focused on the study of the properties that minimum (not minimal) dominating sets preserved or lacked to investigate which update affects a minimal dominating set and in what ways. In this

  14. Weighted Domination on Cocomparability Graphs

    Microsoft Academic Search

    Maw-shang Chang

    1995-01-01

    It is shown in this paper that the weighted domination problem and its two variants, the weighted connected domination and weighted total domination problems are NP-complete on cocomparability graphs when arbitrary integer vertex weights are allowed and all of them can be solved in polynomial time if vertex weights are integers and less than or equal to a constant c.

  15. Sex-linked and autosomal microsatellites provide new insights into island populations of the tammar wallaby

    PubMed Central

    MacDonald, A J; FitzSimmons, N N; Chambers, B; Renfree, M B; Sarre, S D

    2014-01-01

    The emerging availability of microsatellite markers from mammalian sex chromosomes provides opportunities to investigate both male- and female-mediated gene flow in wild populations, identifying patterns not apparent from the analysis of autosomal markers alone. Tammar wallabies (Macropus eugenii), once spread over the southern mainland, have been isolated on several islands off the Western Australian and South Australian coastlines for between 10?000 and 13?000 years. Here, we combine analyses of autosomal, Y-linked and X-linked microsatellite loci to investigate genetic variation in populations of this species on two islands (Kangaroo Island, South Australia and Garden Island, Western Australia). All measures of diversity were higher for the larger Kangaroo Island population, in which genetic variation was lowest at Y-linked markers and highest at autosomal markers (?=3.291, 1.208 and 0.627 for autosomal, X-linked and Y-linked data, respectively). Greater relatedness among females than males provides evidence for male-biased dispersal in this population, while sex-linked markers identified genetic lineages not apparent from autosomal data alone. Overall genetic diversity in the Garden Island population was low, especially on the Y chromosome where most males shared a common haplotype, and we observed high levels of inbreeding and relatedness among individuals. Our findings highlight the utility of this approach for management actions, such as the selection of animals for translocation or captive breeding, and the ecological insights that may be gained by combining analyses of microsatellite markers on sex chromosomes with those derived from autosomes. PMID:24169646

  16. Homozygosity for dominant mutations increases severity of muscle channelopathies.

    PubMed

    Arzel-Hézode, Marianne; Sternberg, Damien; Tabti, Nacira; Vicart, Savine; Goizet, Cyril; Eymard, Bruno; Fontaine, Bertrand; Fournier, Emmanuel

    2010-04-01

    Muscle channelopathies caused by mutations in the SCN4A gene that encodes the muscle sodium channel are transmitted by autosomal-dominant inheritance. We report herein the first cases of homozygous patients for sodium channel mutations responsible for paramyotonia congenita (I1393T) or hypokalemic periodic paralysis (R1132Q). A parallel was drawn between this unprecedented situation and that of myotonia congenita by including patients homozygous or heterozygous for the CLCN1 I556N channel mutation, which is known for incomplete dominance and penetrance. Standardized electromyographic (EMG) protocols combining exercise and cold served as provocative tests to compare homozygotes with heterozygotes for each of the three mutations. Surface-recorded compound muscle action potentials (CMAPs) were used to monitor muscle electrical activity, and myotonic discharges were evaluated by needle EMG. In heterozygous patients, exercise tests disclosed abnormal patterns of CMAP changes, which matched those previously described for similar dominant sodium and chloride channel mutations. Homozygotes showed much more severe clinical features and CMAP changes. We hypothesized that the presence of 100% defective ion channels in the homozygotes could account for the most severe phenotype. This suggests that the severity of muscle channelopathies depends both on the degree of channel impairment caused by the mutation and on the number of mutant channels engaged in the pathophysiological process. Overall, this study has practical consequences for the diagnosis of muscle channelopathies and raises new questions about their pathophysiology. PMID:19882638

  17. On the relative roles of faster-X evolution and dominance in the establishment of intrinsic postzygotic isolating barriers.

    PubMed

    Naveira, Horacio F

    2003-05-01

    The modern theory of speciation assigns a prominent role to the recessivity of genetic incompatibilities in the two rules of speciation, namely Haldane's rule and the 'large X effect', and considers that the contribution of faster evolution of the X versus the autosomes to those patterns is generally of relatively minor importance. By extending Turelli and Orr's previous analysis of the model of two-locus Dobzhansky-Muller incompatibilities, I first show that when the X and the autosomes evolve at the same rate, the two dominance parameters involved in that model are not equally important for the declaration of a large X effect, but that the degree of recessivity of homozygous-homozygous incompatibilities is the major determinant for such a declaration. When the X evolves faster than the autosomes, the model obviously predicts that the importance of both dominance parameters will progressively vanish. It is then of importance to obtain estimates of the relative evolutionary rate of X-linked incompatibility loci. Several different procedures to obtain such estimates from the perspective of the large X effect are suggested. The application of the appropriate test to the only suitable data from Drosophila hybridizations so far available leads to the conclusion that the X actually evolves at least 2.5 times faster than the autosomes, as far as hybrid male sterility determinants are concerned, thus making dominance considerations absolutely irrelevant. Notwithstanding the necessity of further tests, the relative roles currently assigned to faster-X evolution and dominance in the theory of speciation should be revised, giving due prominence to faster-X evolution, at least for hybrid male sterility in the genus Drosophila. PMID:12733663

  18. Finger Enslaving in the Dominant and Non-Dominant Hand

    PubMed Central

    Wilhelm, Luke A.; Martin, Joel R.; Latash, Mark L.; Zatsiorsky, Vladimir M.

    2014-01-01

    During single-finger force production, the non-instructed fingers unintentionally produce force (finger enslaving). In this study, enslaving effects were compared between the dominant and non-dominant hands. The test consisted of a series of maximum voluntary contractions with different finger combinations. Enslaving matrices were calculated by means of training an artificial neural network. The dominant hand was found to be stronger, but there was found to be no difference between the overall enslaving effects in the dominant and non-dominant hands. There was no correlation between the magnitude of finger enslaving and the performance in such tests as the Edinburgh Handedness Inventory, the Grooved Pegboard test, and the Jebsen-Taylor Hand Function test. Each one of those three tests showed a significant difference between the dominant and non-dominant hand performances. Eleven subjects were retested after two months, and it was found that enslaving effects did not fluctuate significantly between the two testing sessions. While the dominant and non-dominant hands are involved differently in everyday tasks, e.g. in writing or eating, this practice does not cause significant differences in enslaving between the hands. PMID:24360253

  19. Finger enslaving in the dominant and non-dominant hand.

    PubMed

    Wilhelm, Luke A; Martin, Joel R; Latash, Mark L; Zatsiorsky, Vladimir M

    2014-02-01

    During single-finger force production, the non-instructed fingers unintentionally produce force (finger enslaving). In this study, enslaving effects were compared between the dominant and non-dominant hands. The test consisted of a series of maximum voluntary contractions with different finger combinations. Enslaving matrices were calculated by means of training an artificial neural network. The dominant hand was found to be stronger, but there was found to be no difference between the overall enslaving effects in the dominant and non-dominant hands. There was no correlation between the magnitude of finger enslaving and the performance in such tests as the Edinburgh Handedness Inventory, the Grooved Pegboard test, and the Jebsen-Taylor Hand Function test. Each one of those three tests showed a significant difference between the dominant and non-dominant hand performances. Eleven subjects were retested after two months, and it was found that enslaving effects did not fluctuate significantly between the two testing sessions. While the dominant and non-dominant hands are involved differently in everyday tasks, e.g. in writing or eating, this practice does not cause significant differences in enslaving between the hands. PMID:24360253

  20. Clinical Features: Warburg Micro syndrome [OMIM #600118] is a rare autosomal recessive condition characterized by ocular and

    E-print Network

    Gilad, Yoav

    Micro syndrome is inherited in an autosomal recessive pattern. Parents of an affected child are most8/12 Clinical Features: Warburg Micro syndrome [OMIM #600118] is a rare autosomal recessive with Warburg Micro syndrome. RAB3GAP1 encodes the catalytic subunit of the Rab3 GTPase-activating protein

  1. Autosomal polymorphism due to pericentric inversions in the deer mouse (peromyscus maniculatus), and some evidence of somatic segregation

    Microsoft Academic Search

    S. Ohno; C. Weiler; J. Poole; L. Christian; C. Stenius

    1966-01-01

    The existence of extensive autosomal polymorphism due to pericentric inversions in a colony of deer mice, Peromyscus maniculatus, has been reported (Arakaki and Sparkes, personal communication). A background of intersubspecific hybridization was suspected to have contributed to the observed polymorphism. The present study describes findings on two separate subspecies, P. m. hollisteri and P. m. bairdii. Autosomal polymorphism existed within

  2. Simple Y-Autosomal Incompatibilities Cause Hybrid Male Sterility in Reciprocal Crosses Between Drosophila virilis and D. americana

    PubMed Central

    Sweigart, Andrea L.

    2010-01-01

    Postzygotic reproductive isolation evolves when hybrid incompatibilities accumulate between diverging populations. Here, I examine the genetic basis of hybrid male sterility between two species of Drosophila, Drosophila virilis and D. americana. From these analyses, I reach several conclusions. First, neither species carries any autosomal dominant hybrid male sterility alleles: reciprocal F1 hybrid males are perfectly fertile. Second, later generation (backcross and F2) hybrid male sterility between D. virilis and D. americana is not polygenic. In fact, I identified only three genetically independent incompatibilities that cause hybrid male sterility. Remarkably, each of these incompatibilities involves the Y chromosome. In one direction of the cross, the D. americana Y is incompatible with recessive D. virilis alleles at loci on chromosomes 2 and 5. In the other direction, the D. virilis Y chromosome causes hybrid male sterility in combination with recessive D. americana alleles at a single QTL on chromosome 5. Finally, in contrast with findings from other Drosophila species pairs, the X chromosome has only a modest effect on hybrid male sterility between D. virilis and D. americana. PMID:20048051

  3. Introduction The Chediak-Higashi syndrome (CHS) is a human autosomal

    E-print Network

    De Lozanne, Arturo

    Introduction The Chediak-Higashi syndrome (CHS) is a human autosomal disorder, which leads cell types but is implicated in a number of specialized functions, such as the killing of virally to kill target cells (Baetz et al., 1995). Thus the protein responsible for CHS seems to be directly

  4. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations.

    PubMed

    Depondt, Chantal; Donatello, Simona; Simonis, Nicolas; Rai, Myriam; van Heurck, Roxane; Abramowicz, Marc; D'Hooghe, Marc; Pandolfo, Massimo

    2014-05-13

    Autosomal recessive ataxias affect about 1 person in 20,000. Friedreich ataxia accounts for one-third of the cases in Caucasians; the others are due to a growing list of very rare molecular defects, including mild forms of metabolic diseases. In nearly 50%, the genetic cause remains undetermined. PMID:24719489

  5. Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish

    Microsoft Academic Search

    E. A. Streeten; T. J. Beck; J. R. O'Connell; Evadnie Rampersand; D. J. McBride; S. L. Takala; T. I. Pollin; K. Uusi-Rasi; B. D. Mitchell; A. R. Shuldiner

    2008-01-01

    IntroductionFracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric

  6. Absence of ?-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12

    Microsoft Academic Search

    Daniel Jung; Yoshihide Sunada; Franck Duclos; Fernando M. S. Tomé; Carolyn Moomaw; Luciano Merlini; Kemal Azibi; Malika Chaouch; Clive Slaughter; Michel Fardeau; Jean-Claude Kaplan; Kevin P. Campbell

    1996-01-01

    We have partially sequenced rabbit skeletal muscle ?-sarcoglycan an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a ?-sarcoglycan peptide and used to examine the expression of ?-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these

  7. Abnormal X : autosome ratio, but normal X chromosome inactivation in human triploid cultures

    Microsoft Academic Search

    Kartik R Varadarajan; Ping Luo; Thomas H Norwood; Theresa K Canfield; R Scott Hansen

    2006-01-01

    BACKGROUND: X chromosome inactivation (XCI) is that aspect of mammalian dosage compensation that brings about equivalence of X-linked gene expression between females and males by inactivating one of the two X chromosomes (Xi) in normal female cells, leaving them with a single active X (Xa) as in male cells. In cells with more than two X's, but a diploid autosomal

  8. J. theor. Biol. (1987) 124, 317-334 The Coevolution of Autosomal and Cytoplasmic Sex Ratio

    E-print Network

    Werren, John H.

    1987-01-01

    ). Cytoplasmically inherited factors which either distort the primary sex ratio, alter sex determination, or cause affect the sex ratio of a species. Two distinct categories are sex ratio genes and sex determinationJ. theor. Biol. (1987) 124, 317-334 The Coevolution of Autosomal and Cytoplasmic Sex Ratio Factors

  9. Dominant multi-state systems

    Microsoft Academic Search

    Jinsheng Huang; Ming J. Zuo

    2004-01-01

    In this paper, we propose a definition of the dominant multi-state system. Under the proposed definition, multi-state systems are divided into two groups without reference to component relevancy conditions: dominant systems, and nondominant systems. Dominant systems can be further divided into two groups: with binary image, and without binary image. A multi-state system with binary image implies that its structure

  10. Two cases of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P).

    PubMed

    Mori, Chiaki; Saito, Tomoko; Saito, Toshio; Fujimura, Harutoshi; Sakoda, Saburo

    2015-01-01

    We, herein, report two independent cases with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) inherited in an autosomal dominant fashion. Their common clinical features are slowly progressive proximal dominant muscular atrophy, fasciculations and mild to moderate distal sensory disturbance with areflexia. Nerve conduction study revealed an absence of sensory nerve action potentials, in contrast to almost normal compound muscle action potentials. Gene analysis in both patients elucidated heterozygous mutation (c.854C>T, p.Pro285Leu) in the TFG, which is an identical mutation, already described by Ishiura et al. Okinawa and Shiga are two foci of HMSN-P in Japan. Eventually, one patient is from Okinawa and the other is from a mountain village in Shiga prefecture. When we see a patient who has symptoms suggestive of motor neuron disease with sensory neuropathy, HMSN-P should be considered as a differential diagnosis despite the patient's actual resident place. PMID:26103812

  11. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH.

    PubMed

    Gouya, Laurent; Puy, Herve; Robreau, Anne-Marie; Bourgeois, Monique; Lamoril, Jerôme; Da Silva, Vasco; Grandchamp, Bernard; Deybach, Jean-Charles

    2002-01-01

    Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by a partial deficiency of ferrochelatase (FECH, EC 4.99.1.1). EPP is transmitted as an autosomal dominant disorder with an incomplete penetrance. Using haplotype segregation analysis, we have identified an intronic single nucleotide polymorphism (SNP), IVS3-48T/C, that modulates the use of a constitutive aberrant acceptor splice site. The aberrantly spliced mRNA is degraded by a nonsense-mediated decay mechanism (NMD), producing a decreased steady-state level of mRNA and the additional FECH enzyme deficiency necessary for EPP phenotypic expression. PMID:11753383

  12. Should females prefer dominant males?

    Microsoft Academic Search

    Anna Qvarnström; Elisabet Forsgren

    1998-01-01

    It is generally believed that success in male–male competition genuinely reflects high quality and that female preference for dominant males should therefore be widespread. However, recent studies suggest that male dominance is not always attractive and that it does not necessarily predict superior parental quality, better genes or other forms of benefit to females. In fact, the costs of choosing

  13. Economic Man'' Dominate Social Behavior?

    E-print Network

    Greer, Julia R.

    When Does `` Economic Man'' Dominate Social Behavior? Colin F. Camerer1 * and Ernst Fehr2,3 The canonical model in economics considers people to be rational and self-regarding. However, much evidence challenges this view, raising the question of when `` Economic Man'' dominates the outcome of social

  14. Dominant Leadership Style in Schools

    ERIC Educational Resources Information Center

    Rajbhandari, Mani Man Singh

    2006-01-01

    The dominant leadership style is defined by the situation and the kind of organizational environment and climate. This, however, does not sufficiently define the leadership qualities in school organizations. There are other factors which also determine the dominant leadership style, which are the traits and style, teachers commitments, pass out…

  15. Brain Dominance & Self-Actualization.

    ERIC Educational Resources Information Center

    Bernhoft, Franklin O.

    Numerous areas associated with brain dominance have been researched since Bogen and Sperry's work with split-brain patients in the 1960s, but only slight attention has been given to the connection between brain dominance and personality. No study appears in the literature seeking to understand optimal mental health as defined by Maslow's…

  16. Dominating Sets in Web Graphs

    Microsoft Academic Search

    Colin Cooper; Ralf Klasing; Michele Zito

    2004-01-01

    In this paper we study the size of generalised dominating sets in two graph processes which are widely used to model aspects of the world-wide web. On the one hand, we show that graphs gener- ated this way have fairly large dominating sets (i.e. linear in the size of the graph). On the other hand, we present efficient strategies to

  17. Solving Domination Problems with Mathematical Programming

    E-print Network

    van der Torre, Leon

    of optimization problems 4 Why these problems? Dominating Sets (DS) and its variants Connected Dominating Sets, they are often used to create virtual backbones Why this approach? #12;Definition: Dominating Set 5 A Dominating one member of D by some edge. Dominators Dominatees #12;Definition: Dominating Set 5 A Dominating Set

  18. Testosterone and dominance in men.

    PubMed

    Mazur, A; Booth, A

    1998-06-01

    In men, high levels of endogenous testosterone (T) seem to encourage behavior intended to dominate--to enhance one's status over--other people. Sometimes dominant behavior is aggressive, its apparent intent being to inflict harm on another person, but often dominance is expressed nonaggressively. Sometimes dominant behavior takes the form of antisocial behavior, including rebellion against authority and low breaking. Measurement of T at a single point in time, presumably indicative of a man's basal T level, predicts many of these dominant or antisocial behaviors. T not only affects behavior but also responds to it. The act of competing for dominant status affects male T levels in two ways. First, T rises in the face of a challenge, as if it were an anticipatory response to impending competition. Second, after the competition, T rises in winners and declines in losers. Thus, there is a reciprocity between T and dominance behavior, each affecting the other. We contrast a reciprocal model, in which T level is variable, acting as both a cause and effect of behavior, with a basal model, in which T level is assumed to be a persistent trait that influences behavior. An unusual data set on Air Force veterans, in which data were collected four times over a decade, enables us to compare the basal and reciprocal models as explanations for the relationship between T and divorce. We discuss sociological implications of these models. PMID:10097017

  19. LOXL3, encoding lysyl oxidase-like 3, is mutated in a family with autosomal recessive Stickler syndrome.

    PubMed

    Alzahrani, Fatema; Al Hazzaa, Selwa A; Tayeb, Hamsa; Alkuraya, Fowzan S

    2015-04-01

    Stickler syndrome (SS) is a collagenopathy characterized by arthropathy and vitreoretinopathy with high myopia and cleft palate as common features. In a family with an autosomal recessive SS that does not map to genes known to cause autosomal recessive forms of SS, we combined autozygome and exome analysis to identify a novel missense variant in LOXL3 as the likely candidate cause. LOXL3 cross-links collagen II and its morphants phenocopy the craniofacial defects characteristic of collagen XI deficiency. We propose LOXL3 as a novel candidate gene for autosomal recessive SS. PMID:25663169

  20. The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism.

    PubMed

    Oetting, William S; Pietsch, Jacy; Brott, Marcia J; Savage, Sarah; Fryer, James P; Summers, C Gail; King, Richard A

    2009-03-01

    Mutations in the gene for tyrosinase, the key enzyme in melanin synthesis, are responsible for oculocutaneous albinism type 1, and more than 100 mutations of this gene have been identified. The c.1205G > A variant of the tyrosinase gene (rs1126809) predicts p.R402Q and expression studies show thermolabile enzyme activity for the variant protein. The Q402 allele has been associated with autosomal recessive ocular albinism when it is in trans with a tyrosinase gene mutation associated with oculocutaneous albinism type 1. We have identified 12 families with oculocutaneous albinism type 1 that exhibit segregation of the c.1205G > A variant with a known pathologic mutation on the homologous chromosome, and demonstrate no genetic association between autosomal recessive oculocutaneous albinism and the Q402 variant. We conclude that the codon 402 variant of the tyrosinase gene is not associated with albinism. PMID:19208379

  1. Two families with autosomal recessive spastic paraplegia, pigmented maculopathy, and dementia

    PubMed Central

    Webb, S.; Patterson, V.; Hutchinson, M.

    1997-01-01

    OBJECTIVE—Two families with autosomal recessive hereditary spastic paraplegia and pigmented maculopathy are described.?METHODS—All family members were examined by two neurologists. An assessment of cognitive function in affected members was made using the mini mental state examination (MMSE) or Cambridge cognitive examination (CAMCOG).?RESULTS—Six patients from two families presented with a slowly progressive, autosomal recessive, spastic tetraplegia. Although they were always considered to be intellectually slower than their peers, further intellectual deterioration was noted during the second decade. Five had a pigmented maculopathy with mild decrease in visual acuity and all had distal amyotrophy, mild cerebellar signs, and developed faecal and urinary incontinence late in the course of the disease.?CONCLUSION—The association of hereditary spastic paraplegia and pigmented maculopathy has rarely been described; only 11 families with 32 affected members have been reported, showing considerable heterogeneity in presentation. These described conditions may be allelic or more probably reflect mutations at different genetic loci.?? PMID:9408105

  2. Analysis of Autosomal Dosage Compensation Involving the Alcohol Dehydrogenase Locus in Drosophila Melanogaster

    PubMed Central

    Birchler, J. A.; Hiebert, J. C.; Paigen, K.

    1990-01-01

    An example of autosomal dosage compensation involving the expression of the alcohol dehydrogenase (Adh) locus is described. Flies trisomic for a quarter of the length of the left arm of chromosome two, including Adh, have diploid levels of enzyme activity and alcohol dehydrogenase messenger RNA. Subdivision of the compensating trisomic into smaller ones revealed a region that exerts an inverse regulatory effect on alcohol dehydrogenase activity and messenger RNA levels and a smaller region surrounding the structural gene that exhibits a direct gene dosage response. The two opposing effects are of sufficient magnitude that they cancel when simultaneously present resulting in the observed compensation in the larger aneuploid. An Adh promoter-white structural gene fusion construct is affected by the inverse regulatory region indicating that the effect is mediated through the Adh promoter sequences. The role of autosomal dosage compensation in understanding aneuploid syndromes and karyotype evolution in Drosophila species is discussed. PMID:2107122

  3. Population data of 15 autosomal STR markers from Afro-Bolivians of Nor Yungas Province (Bolivia).

    PubMed

    Parolin, María Laura; Iudica, Celia Estela; Lancelotti, Julio Lucio; Sambuco, Lorena Andrea; Jaureguiberry, Stella Maris; Avena, Sergio Alejandro; Carnese, Francisco Raúl

    2015-05-01

    Allele frequencies and forensic parameters for 15 autosomal loci included in the AmpFlSTR® Identifiler kit were estimated in a sample of 57 unrelated Afro-descendants from Nor Yungas (Bolivia). Buccal swabs samples were obtained from voluntary donors, after consent was given. All loci were in Hardy-Weinberg equilibrium after Bonferroni correction. D21S11 was the most informative locus, while the least discriminating locus was D3S1358. The combined power of discrimination and the combined probability of exclusion were >0.99999999 and >0.99997, respectively. The multidimensional scaling (MDS) plot generated by Rst matrix supported that Afro-Bolivians of Nor Yungas preserved a stronger African descent compared to other admixed Latin American populations. These results amplified the Bolivian databases of autosomal STR loci and may provide a useful tool for human identification tests and population genetic studies. PMID:25217341

  4. Infantile variant of Bartter syndrome and sensorineural deafness: A new autosomal recessive disorder

    SciTech Connect

    Landau, D.; Shalev, H.; Carmi, Rivka; Ohaly, M. [Univ. of the Negev, Ashkelon (Israel)

    1995-12-04

    The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting either coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 35 refs., 2 figs., 2 tabs.

  5. Mediation of Drosophila autosomal dosage effects and compensation by network interactions

    PubMed Central

    2012-01-01

    Background Gene dosage change is a mild perturbation that is a valuable tool for pathway reconstruction in Drosophila. While it is often assumed that reducing gene dose by half leads to two-fold less expression, there is partial autosomal dosage compensation in Drosophila, which may be mediated by feedback or buffering in expression networks. Results We profiled expression in engineered flies where gene dose was reduced from two to one. While expression of most one-dose genes was reduced, the gene-specific dose responses were heterogeneous. Expression of two-dose genes that are first-degree neighbors of one-dose genes in novel network models also changed, and the directionality of change depended on the response of one-dose genes. Conclusions Our data indicate that expression perturbation propagates in network space. Autosomal compensation, or the lack thereof, is a gene-specific response, largely mediated by interactions with the rest of the transcriptome. PMID:22531030

  6. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): A phenotypic comparison

    Microsoft Academic Search

    Livia Pisciotta; Claudio Priore Oliva; Giovanni Mario Pes; Lilla Di Scala; Antonella Bellocchio; Raffaele Fresa; Alfredo Cantafora; Marcello Arca; Sebastiano Calandra; Stefano Bertolini

    2006-01-01

    Autosomal recessive hypercholesterolemia (ARH) is a rare disorder, due to complete loss of function of an adaptor protein (ARH protein) required for receptor-mediated hepatic uptake of LDL. ARH is a phenocopy of homozygous familial hypercholesterolemia (HoFH) due to mutations in LDL receptor (LDLR) gene; however, previous studies suggested that ARH phenotype is less severe than that of HoFH. To test

  7. A New Multiplex Assay of 17 Autosomal STRs and Amelogenin for Forensic Application

    PubMed Central

    Zhang, Suhua; Tian, Huaizhou; Wu, Jun; Zhao, Shumin; Li, Chengtao

    2013-01-01

    This paper describes a newly devised autosomal short tandem repeat (STR) multiplex polymerase chain reaction (PCR) systems for 17 autosomal loci (D1S1656, D2S441, D3S1358, D3S3045, D6S477, D7S3048, D8S1132, D10S1435, D10S1248, D11S2368, D13S325, D14S608, D15S659, D17S1290, D18S535, D19S253 and D22-GATA198B05) and Amelogenin. Primers for the loci were designed and optimized so that all of the amplicons were distributed from 50 base pairs (bp) to less than 500 bp within a five-dye chemistry design with the fifth dye reserved for the sizing standard. Strategies were developed to overcome challenges that encountered in creating the final assay. The limits of the multiplex were tested, resulting in the successful amplification of genomic DNA range from 0.25–4 ng with 30 PCR cycles. A total of 681 individuals from the Chinese Han population were studied and forensic genetic data were present. No significant deviations from Hardy–Weinberg equilibrium were observed. A total of 180 alleles were detected for the 17 autosomal STRs. The cumulative mean exclusion chance in duos (CMECD) was 0.999967, and cumulative mean exclusion chance in trios (CMECT) was 0.99999995. We conclude that the present 17plex autosomal STRs assay provides an additional powerful tool for forensic applications. PMID:23451235

  8. Horse domestication and conservation genetics of Przewalski's horse inferred from sex chromosomal and autosomal sequences.

    PubMed

    Lau, Allison N; Peng, Lei; Goto, Hiroki; Chemnick, Leona; Ryder, Oliver A; Makova, Kateryna D

    2009-01-01

    Despite their ability to interbreed and produce fertile offspring, there is continued disagreement about the genetic relationship of the domestic horse (Equus caballus) to its endangered wild relative, Przewalski's horse (Equus przewalskii). Analyses have differed as to whether or not Przewalski's horse is placed phylogenetically as a separate sister group to domestic horses. Because Przewalski's horse and domestic horse are so closely related, genetic data can also be used to infer domestication-specific differences between the two. To investigate the genetic relationship of Przewalski's horse to the domestic horse and to address whether evolution of the domestic horse is driven by males or females, five homologous introns (a total of approximately 3 kb) were sequenced on the X and Y chromosomes in two Przewalski's horses and three breeds of domestic horses: Arabian horse, Mongolian domestic horse, and Dartmoor pony. Five autosomal introns (a total of approximately 6 kb) were sequenced for these horses as well. The sequences of sex chromosomal and autosomal introns were used to determine nucleotide diversity and the forces driving evolution in these species. As a result, X chromosomal and autosomal data do not place Przewalski's horses in a separate clade within phylogenetic trees for horses, suggesting a close relationship between domestic and Przewalski's horses. It was also found that there was a lack of nucleotide diversity on the Y chromosome and higher nucleotide diversity than expected on the X chromosome in domestic horses as compared with the Y chromosome and autosomes. This supports the hypothesis that very few male horses along with numerous female horses founded the various domestic horse breeds. Patterns of nucleotide diversity among different types of chromosomes were distinct for Przewalski's in contrast to domestic horses, supporting unique evolutionary histories of the two species. PMID:18931383

  9. A Novel Mutation in the Transglutaminase-1 Gene in an Autosomal Recessive Congenital Ichthyosis Patient

    PubMed Central

    Vaigundan, D.; Kalmankar, Neha V.; Krishnappa, J.; Gowda, N. Yellappa; Kutty, A. V. M.; Krishnaswamy, Patnam R.

    2014-01-01

    Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1) observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated. PMID:25180191

  10. A novel mutation in the transglutaminase-1 gene in an autosomal recessive congenital ichthyosis patient.

    PubMed

    Vaigundan, D; Kalmankar, Neha V; Krishnappa, J; Gowda, N Yellappa; Kutty, A V M; Krishnaswamy, Patnam R

    2014-01-01

    Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1) observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated. PMID:25180191

  11. A new multiplex assay of 17 autosomal STRs and Amelogenin for forensic application.

    PubMed

    Zhang, Suhua; Tian, Huaizhou; Wu, Jun; Zhao, Shumin; Li, Chengtao

    2013-01-01

    This paper describes a newly devised autosomal short tandem repeat (STR) multiplex polymerase chain reaction (PCR) systems for 17 autosomal loci (D1S1656, D2S441, D3S1358, D3S3045, D6S477, D7S3048, D8S1132, D10S1435, D10S1248, D11S2368, D13S325, D14S608, D15S659, D17S1290, D18S535, D19S253 and D22-GATA198B05) and Amelogenin. Primers for the loci were designed and optimized so that all of the amplicons were distributed from 50 base pairs (bp) to less than 500 bp within a five-dye chemistry design with the fifth dye reserved for the sizing standard. Strategies were developed to overcome challenges that encountered in creating the final assay. The limits of the multiplex were tested, resulting in the successful amplification of genomic DNA range from 0.25-4 ng with 30 PCR cycles. A total of 681 individuals from the Chinese Han population were studied and forensic genetic data were present. No significant deviations from Hardy-Weinberg equilibrium were observed. A total of 180 alleles were detected for the 17 autosomal STRs. The cumulative mean exclusion chance in duos (CMECD) was 0.999967, and cumulative mean exclusion chance in trios (CMECT) was 0.99999995. We conclude that the present 17plex autosomal STRs assay provides an additional powerful tool for forensic applications. PMID:23451235

  12. Recombinant human growth hormone therapy in autosomal recessive polycystic kidney disease

    Microsoft Academic Search

    Marusia Lilova; Bernard S. Kaplan; Kevin E. C. Meyers

    2003-01-01

    Patients with autosomal recessive polycystic kidney disease (ARPKD) may have growth retardation that is disproportionate to the degree of renal dysfunction. We treated growth-retarded ARPKD patients with recombinant growth hormone (rhGH) and document the response to therapy and effect of rhGH on the rate of progression of renal failure. The diagnosis of ARPKD and congenital hepatic fibrosis was made on

  13. Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy

    Microsoft Academic Search

    P. K. Thomas; D. Claus; R. H. M. King

    1999-01-01

    A family is described with presumed autosomal recessive inheritance in which three siblings developed a progressive neuropathy\\u000a that combined limb weakness and severe distal sensory loss leading to prominent mutilating changes. Electrophysiological and\\u000a nerve biopsy findings indicated an axonopathy. The disorder is therefore classifiable as type II hereditary motor and sensory\\u000a neuropathy (HMSN II). The clinical features differ from those

  14. Private SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) families from Turkey.

    PubMed

    Richter, Andrea M; Ozgul, Riza Koksal; Poisson, Virginie C; Topaloglu, Haluk

    2004-09-01

    We studied five families with pediatric-onset recessive spastic ataxia from Turkey. The clinical characteristics and linkage studies are compatible with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). SACS mutations are responsible for ARSACS in Québec families. In four of the five families tested we detected new disease-causing mutations using automated sequencing of SACS. Our study raises to 12 the number of SACS mutations detected in ARSACS patients with origins around the Mediterranean basin. PMID:15156359

  15. Autosomal recessive Duchenne-like muscular dystrophy: molecular and histochemical results.

    PubMed

    McGuire, S A; Fischbeck, K H

    1991-12-01

    An autosomal recessive disorder which mimics Duchenne muscular dystrophy has long been suspected as a cause of muscular dystrophy in karyotypically normal girls and in both boys and girls with consanguineous parents. Analysis of dystrophin now allows confirmation of the existence of this disorder. We report the results of this analysis in a brother and sister who have the typical clinical features of Duchenne muscular dystrophy, but no demonstrable abnormality in dystrophin or its gene. PMID:1766451

  16. Two Forms of Autosomal Chronic Granulomatous Disease Lack Distinct Neutrophil Cytosol Factors

    Microsoft Academic Search

    Hiroyuki Nunoi; Daniel Rotrosen; John I. Gallin; Harry L. Malech

    1988-01-01

    Chronic granulomatous diseases of childhood (CGD) are a group of disorders of phagocytic cell superoxide (O2\\\\cdot -) production (respiratory burst). Anion exchange chromatography separated from normal neutrophil cytosol a 47-kilodalton neutrophil cytosol factor, NCF-1, that restored activity to defective neutrophil cytosol from most patients with autosomally inherited CGD in a cell-free O2\\\\cdot --generating system. A 65-kilodalton factor, NCF-2, restored activity

  17. Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum

    Microsoft Academic Search

    Saqib Mahmood; Wasim Ahmad; Muhammad J Hassan

    2011-01-01

    Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference\\u000a at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original\\u000a volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci\\u000a (MCPH1-7) for this condition have

  18. Comparative chromosome painting of chicken autosomal paints 1–9 in nine different bird species

    Microsoft Academic Search

    M. Guttenbach; I. Nanda; W. Feichtinger; J. S. Masabanda; D. K. Griffin; M. Schmid

    2003-01-01

    In a Zoo-FISH study chicken autosomal chromosome paints 1 to 9 (GGA1–GGA9) were hybridized to metaphase spreads of nine diverse birds belonging to primitive and modern orders. This comparative approach allows tracing of chromosomal rearrangements that occurred during bird evolution. Striking homologies in the chromosomes of the different species were noted, indicating a high degree of evolutionary conservation in avian

  19. Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD)

    Microsoft Academic Search

    William E. Sweeney Jr; Ellis D. Avner

    2006-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes characterized by dual renal and hepatic involvement of variable severity. Despite the wide clinical spectrum of ARPKD (MIM 263200), genetic linkage studies indicate that mutations at a single locus, PKHD1 (polycystic kidney and hepatic disease 1), located on human chromosome region 6p21.1–p12, are responsible for

  20. A Human Autosomal Phosphoglycerate Kinase Locus Maps near the HLA Cluster

    Microsoft Academic Search

    Paul Szabo; Karl-Heinz Grzeschik; Marcello Siniscalco

    1984-01-01

    The human cDNA probe pPGK824, of Singer-Sam et al. [Singer-Sam, J., Simmer, R. L., Keith, D. H., Shively, L., Teplitz, M., Itakura, K., Gartler, S. M. & Riggs, A. D. (1983) Proc. Natl. Acad. Sci. USA 80, 802-806] was used to isolate a genomic clone lambda PGK-1 containing a portion of an autosomal locus for phosphoglycerate kinase (PGK). A unique

  1. A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation.

    PubMed

    Kabzi?ska, Dagmara; Kotruchow, Katarzyna; Cegielska, Joanna; Hausmanowa-Petrusewicz, Irena; Kocha?ski, Andrzej

    2014-01-01

    Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations. PMID:25337607

  2. Dominating Sets in Planar Graphs

    Microsoft Academic Search

    Lesley R. Matheson; Robert Endre Tarjan

    1996-01-01

    Motivated by an application to unstructured multigrid calculations, we consider the problem of asymptotically minimizing the size of dominating sets in triangulated planar graphs. Specifically, we wish to find the smallest?such that, fornsufficiently large, everyn-vertex planar graph contains a dominating set of size at most?n.We prove that 1\\/4

  3. Neural mechanisms of social dominance

    PubMed Central

    Watanabe, Noriya; Yamamoto, Miyuki

    2015-01-01

    In a group setting, individuals' perceptions of their own level of dominance or of the dominance level of others, and the ability to adequately control their behavior based on these perceptions are crucial for living within a social environment. Recent advances in neural imaging and molecular technology have enabled researchers to investigate the neural substrates that support the perception of social dominance and the formation of a social hierarchy in humans. At the systems' level, recent studies showed that dominance perception is represented in broad brain regions which include the amygdala, hippocampus, striatum, and various cortical networks such as the prefrontal, and parietal cortices. Additionally, neurotransmitter systems such as the dopaminergic and serotonergic systems, modulate and are modulated by the formation of the social hierarchy in a group. While these monoamine systems have a wide distribution and multiple functions, it was recently found that the Neuropeptide B/W contributes to the perception of dominance and is present in neurons that have a limited projection primarily to the amygdala. The present review discusses the specific roles of these neural regions and neurotransmitter systems in the perception of dominance and in hierarchy formation.

  4. Reversal of an ancient sex chromosome to an autosome in Drosophila.

    PubMed

    Vicoso, Beatriz; Bachtrog, Doris

    2013-07-18

    Although transitions of sex-determination mechanisms are frequent in species with homomorphic sex chromosomes, heteromorphic sex chromosomes are thought to represent a terminal evolutionary stage owing to chromosome-specific adaptations such as dosage compensation or an accumulation of sex-specific mutations. Here we show that an autosome of Drosophila, the dot chromosome, was ancestrally a differentiated X chromosome. We analyse the whole genome of true fruitflies (Tephritidae), flesh flies (Sarcophagidae) and soldier flies (Stratiomyidae) to show that genes located on the dot chromosome of Drosophila are X-linked in outgroup species, whereas Drosophila X-linked genes are autosomal. We date this chromosomal transition to early drosophilid evolution by sequencing the genome of other Drosophilidae. Our results reveal several puzzling aspects of Drosophila dot chromosome biology to be possible remnants of its former life as a sex chromosome, such as its minor feminizing role in sex determination or its targeting by a chromosome-specific regulatory mechanism. We also show that patterns of biased gene expression of the dot chromosome during early embryogenesis, oogenesis and spermatogenesis resemble that of the current X chromosome. Thus, although sex chromosomes are not necessarily evolutionary end points and can revert back to an autosomal inheritance, the highly specialized genome architecture of this former X chromosome suggests that severe fitness costs must be overcome for such a turnover to occur. PMID:23792562

  5. The Evolving Puzzle of Autosomal Versus Y-linked Male Determination in Musca domestica

    PubMed Central

    Hamm, Ronda L.; Meisel, Richard P.; Scott, Jeffrey G.

    2014-01-01

    Sex determination is one of the most rapidly evolving developmental pathways, but the factors responsible for this fast evolution are not well resolved. The house fly, Musca domestica, is an ideal model for studying sex determination because house fly sex determination is polygenic and varies considerably between populations. Male house flies possess a male-determining locus, the M factor, which can be located on the Y or X chromosome or any of the five autosomes. There can be a single M or multiple M factors present in an individual male, in heterozygous or homozygous condition. Males with multiple copies of M skew the sex ratio toward the production of males. Potentially in response to these male-biased sex ratios, an allele of the gene transformer, Md-traD, promotes female development in the presence of one or multiple M factors. There have been many studies to determine the linkage and frequency of these male determining factors and the frequency of Md-traD chromosomes in populations from around the world. This review provides a summary of the information available to date regarding the patterns of distribution of autosomal, X-linked and Y-linked M factors, the relative frequencies of the linkage of M, the changes in frequencies found in field populations, and the fitness of males with autosomal M factors vs. Y-linked M. We evaluate this natural variation in the house fly sex determination pathway in light of models of the evolution of sex determination. PMID:25552607

  6. Allele frequencies of 23 autosomal short tandem repeat loci in the Philippine population.

    PubMed

    Rodriguez, Jae Joseph Russell Beltran; Salvador, Jazelyn M; Calacal, Gayvelline C; Laude, Rita P; De Ungria, Maria Corazon A

    2015-07-01

    We characterized diversity and forensic descriptive parameters of 23 autosomal STR loci (CSF1PO, D13S317, D16S539, D5S818, D7S820, TPOX, D18S51, D21S11, D3S1358, D8S1179, FGA, TH01, vWA, D1S1656, D10S1248, D12S391, D2S441, D22S1045, D19S433, D2S1338, D6S1043, Penta D and Penta E) among 167 unrelated Filipinos. The most variable autosomal STR loci observed is Penta E (observed heterozygosity: 0.9222, match probability: 0.0167). Results reveal matching probability of 8.21×10(-28) for 23 autosomal STR loci. This dataset for the Philippine population may now be used in evaluating the weight of DNA evidence for forensic applications such as in human identification, parentage/kinship testing, and interpretation of DNA mixtures. PMID:25804725

  7. Genetic data provided by 21 autosomal STR loci from Chinese Tujia ethnic group.

    PubMed

    Yuan, Guo-Lian; Shen, Chun-Mei; Wang, Hong-Dan; Liu, Wen-Juan; Yang, Guang; Yan, Jiang-Wei; Qin, Hai-Xia; Xie, Tong; Ran, Hangyan; Yuan, Jie; Liu, Zuochun; Zhu, Bofeng

    2012-12-01

    The aim of this study was to investigate allelic frequency distribution and forensic genetic parameters of autosomal short tandem repeats (STR) loci of the population samples from 107 Tujia individuals from Chinese Hubei Province. Twenty-one autosomal STR genetic markers (D9S1122, D6S474, D6S1017, D5S2500, D4S2408, D3S4529, D2S441, D2S1776, D22S1045, D20S482, D1S1677, D1S1627, D1GATA113, D19S433, D18S853, D17S1301, D11S4463, D12ATA63, D10S1248, D10S1435 and D14S1434) were simultaneously amplified in a new multiplex polymerase chain reaction system. 155 alleles for all the STR loci from the Tujia population were observed and the corresponding allelic frequencies ranged from 0.005 to 0.589. Expected heterozygosity, polymorphic information content, power of discrimination and power of exclusion of the 21 STR loci in the Tujia population were from 0.579 to 0.824, from 0.525 to 0.802, from 0.773 to 0.945 and from 0.257 to 0.641, respectively. Our results indicate that the autosomal STRs multiplex system provides highly informative STR data and could be useful in forensic individual identification and parentage testing in this region. PMID:23065199

  8. Genetic Architecture of Autosome-Mediated Hybrid Male Sterility in Drosophila

    PubMed Central

    Marin, I.

    1996-01-01

    Several estimators have been developed for assesing the number of sterility factors in a chromosome based on the sizes of fertile and sterile introgressed fragments. Assuming that two factors are required for producing sterility, simulations show that one of these, twice the inverse of the relative size of the largest fertile fragment, provides good average approximations when as few as five fertile fragments are analyzed. The estimators have been used for deducing the number of factors from previous data on several pairs of species. A particular result contrasts with the authors' interpretations: instead of the high number of sterility factors suggested, only a few per autosome are estimated in both reciprocal crosses involving Drosophila buzzatii and D. koepferae. It has been possible to map these factors, between three and six per chromosome, in the autosomes 3 and 4 of these species. Out of 203 introgressions of different fragments or combinations of fragments, the outcome of at least 192 is explained by the mapped zones. These results suggest that autosome-mediated sterility in the male hybrids of these species is mediated by a few epistatic factors, similarly to X-mediated sterility in the hybrids of other Drosophila species. PMID:8846896

  9. Identification of CHIP as a Novel Causative Gene for Autosomal Recessive Cerebellar Ataxia

    PubMed Central

    Shi, Yuting; Wang, Junling; Li, Jia-Da; Ren, Haigang; Guan, Wenjuan; He, Miao; Yan, Weiqian; Zhou, Ying; Hu, Zhengmao; Zhang, Jianguo; Xiao, Jingjing; Su, Zheng; Dai, Meizhi; Wang, Jun; Jiang, Hong; Guo, Jifeng; Zhou, Yafang; Zhang, Fufeng; Li, Nan; Du, Juan; Xu, Qian; Hu, Yacen; Pan, Qian; Shen, Lu; Wang, Guanghui; Xia, Kun; Zhang, Zhuohua; Tang, Beisha

    2013-01-01

    Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia. PMID:24312598

  10. Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy

    PubMed Central

    Kelly, K. J.; Zhang, Jizhong; Han, Ling; Kamocka, Malgorzata; Miller, Caroline; Dominguez, Jesus H.

    2015-01-01

    Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA. PMID:26136112

  11. Genetic architecture of autosome-mediated hybrid male sterility in Drosophila

    SciTech Connect

    Marin, I. [Stanford Univ., CA (United States)

    1996-04-01

    Several estimators have been developed for assesing the number of sterility factors in a chromosome based on the sizes of fertile and sterile introgressed fragments. Assuming that two factors are required for producing sterility, simulations show that one of these, twice the inverse of the relative size of the largest fertile fragment, provides good average approximations when as few as five fertile fragments are analyzed. The estimators have been used for deducing the number of factors from previous data on several pairs of species. A particular result contrasts with the authors` interpretations: instead of the high number of sterility factors suggested, only a few per autosome are estimated in both reciprocal crosses involving Drosophila buzzatii and D. koepferae. It has been possible to map these factors, between three and six per chromosome, in the autosomes 3 and 4 of these species. Out of 203 introgressions of different fragments or combinations of fragments, the outcome of at least 192 is explained by the mapped zones. These results suggest that autosome-mediated sterility in the male hybrids of these species is mediated by a few epistatic factors, similarly to X-mediated sterility in the hybrids of other Drosophila species. 48 refs., 5 tabs.

  12. Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots

    Microsoft Academic Search

    Andreas Walter Kuss; Masoud Garshasbi; Kimia Kahrizi; Andreas Tzschach; Farkhondeh Behjati; Hossein Darvish; Lia Abbasi-Moheb; Lucia Puettmann; Agnes Zecha; Robert Weißmann; Hao Hu; Marzieh Mohseni; Seyedeh Sedigheh Abedini; Anna Rajab; Christoph Hertzberg; Dagmar Wieczorek; Reinhard Ullmann; Saghar Ghasemi-Firouzabadi; Susan Banihashemi; Sanaz Arzhangi; Valeh Hadavi; Gholamreza Bahrami-Monajemi; Mahboubeh Kasiri; Masoumeh Falah; Pooneh Nikuei; Atefeh Dehghan; Masoumeh Sobhani; Payman Jamali; Hans Hilger Ropers; Hossein Najmabadi

    2011-01-01

    Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant\\u000a excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive\\u000a forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set

  13. Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype.

    PubMed

    Gurgel-Giannetti, Juliana; Senkevics, Adriano S; Zilbersztajn-Gotlieb, Dinorah; Yamamoto, Lydia U; Muniz, Viviane P; Pavanello, Rita C M; Oliveira, Acary B; Zatz, Mayana; Vainzof, Mariz

    2012-02-01

    We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia. PMID:22246887

  14. Genetic and molecular analysis of the autosomal component of the primary sex determination signal of Drosophila melanogaster

    SciTech Connect

    Barbash, D.A.; Cline, T.W. [Univ. of California, Berkeley, CA (United States)

    1995-12-01

    Drosophila sex is determined by the action of the X:A chromosome balance on transcription of Sex-lethal (Sxl), a feminizing switch gene. We obtained loss-of-function mutations in denominator elements of the X:A signal by selecting for dominant suppressors of a female-specific lethal mutation in the numerator element, sisterlessA (sisA). Ten suppressors were recovered in this extensive genome-wide selection. All were mutations in deadpan (dpn), a pleiotropic locus previously discovered to be a denominator element. Detailed genetic and molecular characterization is presented of this diverse set of new dpn alleles including their effects on Sxl. Although selected only for impairment of sex-specific functions, all were also impaired in nonsex-specific functions. Male-lethal effects were anticipated for mutations in a major denominator element, but we found that viability of males lacking dpn function was reduced no more than 50% relative to their dpn{sup -} sisters. Moreover, loss of dpn activity in males caused only a modest depression of the Sxl {open_quotes}establishment{close_quotes} promoter (Sxl{sub Pe}), the X:A target. By itself, dpn cannot account for the masculinizing effect of increased autosomal ploidy, the effect that gave rise to the concept of the X:A ratio; nevertheless, if there are other denominator elements, our results suggest that their individual contributions to the sex-determination signal are even less than that of dpn. The time course of expression of dpn and Sxl in dpn mutant backgrounds suggests that dpn is required for sex determination only during the later stages of X:A signaling in males to prevent inappropriate expression of Sxl{sub Pe} in the face of increasing sis gene product levels. 77 refs., 6 figs., 6 tabs.

  15. Zinc-finger-based transcriptional repression of rhodopsin in a model of dominant retinitis pigmentosa

    PubMed Central

    Mussolino, Claudio; Sanges, Daniela; Marrocco, Elena; Bonetti, Ciro; Di Vicino, Umberto; Marigo, Valeria; Auricchio, Alberto; Meroni, Germana; Surace, Enrico Maria

    2011-01-01

    Despite the recent success of gene-based complementation approaches for genetic recessive traits, the development of therapeutic strategies for gain-of-function mutations poses great challenges. General therapeutic principles to correct these genetic defects mostly rely on post-transcriptional gene regulation (RNA silencing). Engineered zinc-finger (ZF) protein-based repression of transcription may represent a novel approach for treating gain-of-function mutations, although proof-of-concept of this use is still lacking. Here, we generated a series of transcriptional repressors to silence human rhodopsin (hRHO), the gene most abundantly expressed in retinal photoreceptors. The strategy was designed to suppress both the mutated and the wild-type hRHO allele in a mutational-independent fashion, to overcome mutational heterogeneity of autosomal dominant retinitis pigmentosa due to hRHO mutations. Here we demonstrate that ZF proteins promote a robust transcriptional repression of hRHO in a transgenic mouse model of autosomal dominant retinitis pigmentosa. Furthermore, we show that specifically decreasing the mutated human RHO transcript in conjunction with unaltered expression of the endogenous murine Rho gene results in amelioration of disease progression, as demonstrated by significant improvements in retinal morphology and function. This zinc-finger-based mutation-independent approach paves the way towards a ‘repression–replacement’ strategy, which is expected to facilitate widespread applications in the development of novel therapeutics for a variety of disorders that are due to gain-of-function mutations. PMID:21268285

  16. Sighting versus sensory ocular dominance

    PubMed Central

    Pointer, Jonathan S.

    2012-01-01

    Purpose An indication of the laterality of ocular dominance (OD) informs the clinical decision making process when considering certain ophthalmic refractive and surgical interventions. Can predictive reliance be assured regardless of OD technique or is the indication of a dominant eye method-dependent? Methods Two alternative OD test formats were administered to a group of 72 emmetropic healthy young adult subjects: the ‘hole-in-card’ test for sighting dominance and the ‘+1.50D blur’ test for sensory dominance. Both techniques were chosen as being likely familiar to the majority of ophthalmic clinicians; to promote and expedite application during the examination routine neither test required specialist training nor equipment. Results Right eye dominance was indicated in 71% of cases by the sighting test but in only 54% of subjects using the sensory test. The laterality of OD indicated for the individual subject by each technique was in agreement on only 50% of occasions. Conclusions Reasons are considered for the poor intra-individual agreement between OD tests, along with an item of procedural advice for the clinician.

  17. AutoSOME: a clustering method for identifying gene expression modules without prior knowledge of cluster number

    PubMed Central

    2010-01-01

    Background Clustering the information content of large high-dimensional gene expression datasets has widespread application in "omics" biology. Unfortunately, the underlying structure of these natural datasets is often fuzzy, and the computational identification of data clusters generally requires knowledge about cluster number and geometry. Results We integrated strategies from machine learning, cartography, and graph theory into a new informatics method for automatically clustering self-organizing map ensembles of high-dimensional data. Our new method, called AutoSOME, readily identifies discrete and fuzzy data clusters without prior knowledge of cluster number or structure in diverse datasets including whole genome microarray data. Visualization of AutoSOME output using network diagrams and differential heat maps reveals unexpected variation among well-characterized cancer cell lines. Co-expression analysis of data from human embryonic and induced pluripotent stem cells using AutoSOME identifies >3400 up-regulated genes associated with pluripotency, and indicates that a recently identified protein-protein interaction network characterizing pluripotency was underestimated by a factor of four. Conclusions By effectively extracting important information from high-dimensional microarray data without prior knowledge or the need for data filtration, AutoSOME can yield systems-level insights from whole genome microarray expression studies. Due to its generality, this new method should also have practical utility for a variety of data-intensive applications, including the results of deep sequencing experiments. AutoSOME is available for download at http://jimcooperlab.mcdb.ucsb.edu/autosome. PMID:20202218

  18. Machado-Joseph disease is genetically different from Holguin dominant ataxia (SCA2)

    SciTech Connect

    Silveria, I.; Manaia, A. (Univ. Porto (Portugal) Hopital Necker-Enfants Malades, Paris (France)); Melki, J.; Burlet, P.; Rozet, J.M.; Munnich, A. (Hopital Necker-Enfants Malades, Paris (France)); Magarino, C.; Gispert, S. (Univ. Porto (Portugal) Centro Nacional Genetica Medica, Havana (Cuba)); Lunkes, A.; Auburger, G. (Univ. Hospital, Duesseldorf (Germany))

    1993-09-01

    Machado-Joseph disease (MJD) and Holguin ataxia (SCA2) are autosomal dominant multisystem degenerations with spinocerebellar involvement that are predominant among people of Portuguese-Azorean and of Cuban descent, respectively. Their clinical distinction may at times be difficult to make in individual patients, due to significant phenotypic overlapping (similar overall age-of-onset and duration of cerebellar ataxia, eye movement, and, often, other common problems). The recent mapping of SCA2 to chromosome 12q provided another candidate region for linkage studies of MJD. Original data on 10 families with Holguin ataxia show that the locus of phenylalanine hydroxylase (PAH) on chromosome 12q is linked to SCA2 at 4 cM and is thus far its closest marker. The exclusion of linkage 15 cM on each side of PAH in 16 families with MJD shows that these two forms of dominant ataxia are genetically distinct and at different chromosomal locations (nonallelic). 20 refs., 2 tabs.

  19. Dominant Sets and Pairwise Clustering

    Microsoft Academic Search

    Massimiliano Pavan; Marcello Pelillo

    2007-01-01

    Abstract—We developa,newgraph-theoretic approach,for pairwise data clustering which is motivated,by the analogies,between,the intuitive concept,of a cluster and that of a dominant set of vertices, a notion introduced here which generalizes that of a maximal,complete,subgraph,to edge-weighted,graphs. We establish a correspondence,between,dominant,sets and the extrema,of a quadratic form over the standard simplex, thereby allowing the use of straightforward and easily implementable,continuous,optimization techniques,from evolutionary game,theory.

  20. Dominant resistance against plant viruses

    PubMed Central

    de Ronde, Dryas; Butterbach, Patrick; Kormelink, Richard

    2014-01-01

    To establish a successful infection plant viruses have to overcome a defense system composed of several layers. This review will overview the various strategies plants employ to combat viral infections with main emphasis on the current status of single dominant resistance (R) genes identified against plant viruses and the corresponding avirulence (Avr) genes identified so far. The most common models to explain the mode of action of dominant R genes will be presented. Finally, in brief the hypersensitive response (HR) and extreme resistance (ER), and the functional and structural similarity of R genes to sensors of innate immunity in mammalian cell systems will be described. PMID:25018765

  1. Germline Mutations in the Extracellular Domains of the 55 kDa TNF Receptor, TNFR1, Define a Family of Dominantly Inherited Autoinflammatory Syndromes

    Microsoft Academic Search

    Michael F McDermott; Ivona Aksentijevich; Jérôme Galon; Elizabeth M McDermott; B. William Ogunkolade; Michael Centola; Elizabeth Mansfield; Massimo Gadina; Leena Karenko; Tom Pettersson; John McCarthy; David M Frucht; Martin Aringer; Yelizaveta Torosyan; Anna-Maija Teppo; Meredith Wilson; H. Mehmet Karaarslan; Ying Wan; Ian Todd; Geryl Wood; Ryan Schlimgen; Thisum R Kumarajeewa; Sheldon M Cooper; John P Vella; Christopher I Amos; John Mulley; Kathleen A Quane; Michael G Molloy; Annamari Ranki; Richard J Powell; Graham A Hitman; John J O’Shea; Daniel L Kastner

    1999-01-01

    Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased

  2. Targeted Proteolysis of Plectin Isoform 1a Accounts for Hemidesmosome Dysfunction in Mice Mimicking the Dominant Skin Blistering Disease EBS-Ogna

    Microsoft Academic Search

    Gernot Walko; Nevena Vukasinovic; Karin Gross; Irmgard Fischer; Sabrina Sibitz; Peter Fuchs; Siegfried Reipert; Ute Jungwirth; Walter Berger; Ulrich Salzer; Oliviero Carugo; Maria J. Castañón; Gerhard Wiche

    2011-01-01

    Autosomal recessive mutations in the cytolinker protein plectin account for the multisystem disorders epidermolysis bullosa simplex (EBS) associated with muscular dystrophy (EBS-MD), pyloric atresia (EBS-PA), and congenital myasthenia (EBS-CMS). In contrast, a dominant missense mutation leads to the disease EBS-Ogna, manifesting exclusively as skin fragility. We have exploited this trait to study the molecular basis of hemidesmosome failure in EBS-Ogna

  3. Quaternion Algebraic Geometry Dominic Widdows

    E-print Network

    Joyce, Dominic

    Quaternion Algebraic Geometry Dominic Widdows June 5, 2006 #12;Abstract QUATERNION ALGEBRAIC and quaternionic manifolds, focussing on two main areas. These are exterior forms and double complexes quaternionic algebra. A new double complex on quaternionic manifolds is presented, a quaternionic version

  4. Language Dominance Testing: Some Questions.

    ERIC Educational Resources Information Center

    Kuhlman, Natalie A.

    This paper examines the usage of testing instruments to identify the language and dialect dominance of children. In order not to misuse language assessment tests, a careful distinction must be made between the terms "language proficiency,""language preference," and "relative language proficiency." Differences in the several types of language…

  5. Ivan Stojmenovic 1 Broadcasting and dominating sets

    E-print Network

    Stojmenovic, Ivan

    1 Ivan Stojmenovic 1 Broadcasting and dominating sets in ad hoc and sensor networks Ivan neighbors Ivan Stojmenovic 5 Connected dominating sets Each node either in dominating set or has a neighbor from dominating set Flooding reduced if only nodes in connected dominating set nodes retransmit Ivan

  6. Dominating direct products of graphs Bostjan Bresar

    E-print Network

    Klavzar, Sandi

    with no isolated vertices. Let G = (V, E) be a graph. A set S V is a dominating set if each vertex in V, then S is called a total dominating set. Furthermore, as in [8], a dominating set S is called a paired-dominatingDominating direct products of graphs Bostjan Bresar Sandi Klavzar§ Douglas F. Rall ¶ Abstract

  7. Connected Domination of Regular Graphs W. Duckworth

    E-print Network

    Mans, Bernard

    , Sydney, NSW 2109, Australia. Abstract A dominating set D of a graph G is a subset of V (G sets of small cardinality are of interest. A connected dominating set C of a graph G is a dominating-connected dominating set W of a graph G is a dominating set of G such that the subgraph consisting of V (G) and all

  8. 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

  9. Fourteen non-CODIS autosomal short tandem repeat loci multiplex data from Taiwanese.

    PubMed

    Hwa, Hsiao-Lin; Chang, Yih-Yuan; Lee, James Chun-I; Yin, Hsiang-Yi; Tseng, Li-Hui; Su, Yi-Ning; Ko, Tsang-Ming

    2011-03-01

    Interest in the development of polymorphic short tandem repeat (STR) markers unlinked to the CODIS loci is growing among forensic practitioners. We developed a multiplex system in which14 autosomal STR (D3S1744, D4S2366, D8S1110, D12S1090, D13S765, D14S608, Penta E, D17S1294, D18S536, D18S1270, D20S470, D21S1437, Penta D, and D22S683) could be amplified in one single polymerase chain reaction. DNA samples from 572 unrelated Taiwanese Han subjects were analyzed using this 14 STR multiplex system. Thirty parent-child pairs of parentage testing cases with a combined paternity index (CPI) below 1,000 and 32 parent-child pairs with single-step mutations found in AmpF?STR Identifiler loci were also recruited for validation of the newly developed system. DNA sequencing was performed for novel STRs and novel alleles found in these subjects. The distributions of allelic frequencies for these autosomal STRs and sequence data, allele nomenclature for the STRs, and forensic parameters are presented. The discrimination power in our multiplex loci ranged from 0.6858 (D18S536) to 0.9168 (Penta E), with a combined discrimination power of 0.999999999. It provides additional power to distinguish the possible single-step mutations in parent-child pairs and improves the ability to prove parentage by increasing the CPI. The combined power of exclusion of these 14 loci in Taiwanese Han in this study was 0.9999995913. In conclusion, this 14-autosomal STRs multiplex system provides highly informative STR data and appears useful in forensic casework and parentage testing. PMID:20809099

  10. STR data for 15 autosomal STR markers from Paraná (Southern Brazil).

    PubMed

    Alves, Hemerson B; Leite, Fábio P N; Sotomaior, Vanessa S; Rueda, Fábio F; Silva, Rosane; Moura-Neto, Rodrigo S

    2014-03-01

    Allelic frequencies for 15 STR autosomal loci, using AmpF?STR® Identifiler™, forensic, and statistical parameters were calculated. All loci reached the Hardy-Weinberg equilibrium. The combined power of discrimination and mean power of exclusion were 0.999999999999999999 and 0.9999993, respectively. The MDS plot and NJ tree analysis, generated by FST matrix, corroborated the notion of the origins of the Paraná population as mainly European-derived. The combination of these 15 STR loci represents a powerful strategy for individual identification and parentage analyses for the Paraná population. PMID:23615678

  11. Genetic variation of 15 autosomal STR loci in a population sample from Poland

    Microsoft Academic Search

    Agnieszka Parys-Proszek; Tomasz Kupiec; Paulina Wola?ska-Nowak; Wojciech Branicki

    2010-01-01

    Fifteen autosomal STR loci included in AmpF?STR® NGM™ kit were analyzed in 154 unrelated individuals from Poland. This multiplex kit enables simultaneous amplification of 10 standard STR loci included in AmpF?STR® SGM Plus® kit (D3S1358, vWA, D16S539, D2S1338, D8S1179, D19S433, TH01, FGA, D21S11 and D18S51) and five new mini- and midi-STR loci (D10S1248, D22S1045, D2S441, D1S1656 and D12S391). Population study

  12. Successful twin pregnancy in a patient with parkin-associated autosomal recessive juvenile parkinsonism

    Microsoft Academic Search

    Takehiro Serikawa; Takayoshi Shimohata; Mami Akashi; Akio Yokoseki; Miwa Tsuchiya; Arika Hasegawa; Kazufumi Haino; Ryoko Koike; Koichi Takakuwa; Keiko Tanaka; Kenichi Tanaka; Masatoyo Nishizawa

    2011-01-01

    Background  Pregnancy in patients with Parkinson disease is a rare occurrence. To the best of our knowledge, the effect of pregnancy as\\u000a well as treatment in genetically confirmed autosomal recessive juvenile parkinsonism (ARJP) has never been reported. Here,\\u000a we report the first case of pregnancy in a patient with ARJP associated with a parkin gene mutation, ARJP\\/PARK2.\\u000a \\u000a \\u000a \\u000a \\u000a Case presentation  A 27-year-old woman

  13. Genetics of X-linked and autosomal recessive hereditary nephropathy in the domestic dog

    E-print Network

    Bell, Rebecca Jane

    2008-10-10

    disease in the domestic dog that is similar to Alport syndrome of the human. Both diseases are caused by mutations in the type IV collagens genes, and the disease has nearly identical pathology and clinical presentations in the dog and human. By studying...DNA to be used for gene therapy treatment of dogs with X-linked hereditary nephropathy, 4) the iv investigation of type IV collagen gene expression changes in normal dogs and those affected with X-linked and autosomal recessive hereditary nephropathy, and 5...

  14. Survival over 2 years of autosomal-recessive renal tubular dysgenesis

    PubMed Central

    Kim, Su Yeong; Kang, Hee Gyung; Kim, Ee Kyung; Choi, Jung Hwan; Choi, Yong

    2012-01-01

    Autosomal-recessive renal tubular dysgenesis (AR-RTD) is a rare disorder caused by a genetic defect in the renin–angiotensin system. Although AR-RTD has typically been known as a lethal disease due to refractory hypotension and renal failure immediately after birth, few cases have reported survival of the neonatal period. We report here an additional case of AR-RTD, who had novel ACE mutations and survived over 2 years and provide a review of the five previously reported surviving cases. In conclusion, AR-RTD is not a uniformly fatal disease, although factors affecting the survival remain unknown.

  15. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...2010-01-01 2010-01-01 false Dominant industry. 532.305 Section 532.305 Administrative...Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the...

  16. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...2014-01-01 2014-01-01 false Dominant industry. 532.305 Section 532.305 Administrative...Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the...

  17. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...2011-01-01 2011-01-01 false Dominant industry. 532.305 Section 532.305 Administrative...Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the...

  18. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...2013-01-01 2013-01-01 false Dominant industry. 532.305 Section 532.305 Administrative...Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the...

  19. 5 CFR 532.305 - Dominant industry.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...2012-01-01 2012-01-01 false Dominant industry. 532.305 Section 532.305 Administrative...Types of Positions § 532.305 Dominant industry. (a)(1) A specialized industry is a “dominant industry” if the...

  20. A novel GCAP1(N104K) mutation in EF-hand 3 (EF3) linked to autosomal dominant cone dystrophy

    E-print Network

    Palczewski, Krzysztof

    -negative effect that slows GC stimulation. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction cGMP synthesis roughly 8- and 10-fold. GCAPs are N-myristoylated neuronal Ca2+ sensors in which, Palczewski, & Sousa, 2007). A hall- mark of the GCAP