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1

A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B.  

PubMed

Brachydactyly type B1 (BDB1), an autosomal dominant condition characterized by terminal deficiency of the fingers and toes, results from mutations in the gene ROR2 encoding a receptor tyrosine kinase. In addition to BDB1, mutations in the gene ROR2 also cause a more severe form of skeletal dysplasia, autosomal recessive Robinow syndrome. The present study reports on a large Punjabi-speaking Pakistani family segregating autosomal dominant BDB1. In total, 34 individuals in this family showed features of BDB1. Sequence analysis of the gene ROR2 identified a previously reported nonsense mutation (c.2278C>T, p.Q760X) in all affected individuals of the family. PMID:23238279

Habib, Rabia; Amin-ud-din, Muhammad; Ahmad, Wasim

2013-04-01

2

Autosomal-Dominant Hypertension With Type E Brachydactyly Is Caused by Rearrangement on the Short Arm of Chromosome 12  

Microsoft Academic Search

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1,

Sylvia Bahring; Anita Rauch; Okan Toka; Christoph Schroeder; Christiane Hesse; Heike Siedler; Gabor Fesus; Walter E. Haefeli; Andreas Busjahn; Atakan Aydin; Yvette Neuenfeld; Astrid Muhl; Hakan R. Toka; Maik Gollasch; Jens Jordan; Friedrich C. Luft

2010-01-01

3

Autosomal dominant genes (image)  

MedlinePLUS

In the case of autosomal dominant genes, a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from either parent can cause the disease. One of the parents ...

4

Autosomal Dominant Spinocerebellar Ataxia  

PubMed Central

The autosomal dominant spinocerebellar ataxias (also known as the SCAs) are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging due to phenotypic overlap amongst numerous acquired, genetic, and idiopathic etiologies, and a stratified and systematic approach is essential. Molecular etiologies include DNA repeat expansions (both polyglutamine and non-coding repeats), ion-channel dysfunction, and disorders of signal transduction. Prompt recognition of acquired conditions or comorbidities is essential as treatment options for the genetic ataxias are currently limited. Recent advances in the field include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models which may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole exome sequencing, to improve diagnosis. PMID:24176420

Shakkottai, Vikram G.; Fogel, Brent L.

2013-01-01

5

Autosomal-dominant primary immunodeficiencies.  

PubMed

The vast majority of known primary immunodeficiencies (PIDs) are autosomal or X-linked recessive Mendelian traits. Only four classical primary immunodeficiencies are thought to be autosomal-dominant, three of which still lack a well-defined genetic etiology: isolated congenital asplenia, isolated chronic mucocutaneous candidiasis, and hyper IgE syndrome. The large deletions on chromosome 22q11.2 associated with Di George syndrome suggest that this disease may be dominant but not Mendelian, possibly involving several genes. The clinical and genetic features of six novel autosomal-dominant primary immunodeficiencies have however been described in recent years. These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency). These recent data suggest that many more autosomal-dominant PIDs are likely to be identified in the near future. PMID:15604887

Lawrence, Tatiana; Puel, Anne; Reichenbach, Janine; Ku, Cheng-Lung; Chapgier, Ariane; Renner, Ellen; Minard-Colin, Véronique; Ouachée, Marie; Casanova, Jean-Laurent

2005-01-01

6

Answering a century old riddle: brachydactyly type A1  

Microsoft Academic Search

In 1903, Farabee analyzed the heredity of the human digital malformation, brachydactyly, the first recorded disorder of the autosomal dominant Mendelian trait. In 1951, Bell classified this type of brachydactyly as type A1 (BDA1). Over 100 cases from different ethnic groups have so far been reported. However, the real breakthrough in identifying the cause of BDA1 has only taken place

Bo GAO; Lin HE; Lin HE

2004-01-01

7

Autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney disease. Enlarging cysts within the kidneys are the clinical hallmark of the disease. Renal manifestations include varying degrees of kidney injury, urinary tract infections, kidney stones, and hematuria. Extrarenal manifestations can include pain, hypertension, left ventricular hypertrophy, hepatic cysts, intracranial aneurysm, diverticulosis, and abdominal and inguinal hernias. The progression of ADPKD cannot be reversed with current treatment modalities; therefore, therapies target the resulting clinical manifestations. Early detection and management of hypertension are important to delay the progression of renal dysfunction and development of cardiovascular complications. Pain management includes evaluation of concomitant illnesses, use of analgesics, and adjuvant therapy. Fluoroquinolones may be the most useful class of antibiotics for the treatment of urinary tract infections because of their lipophilic properties and bactericidal action against gram-negative pathogens. Nephrolithiasis is twice as common in persons with ADPKD compared with the general population and is suggested by flank pain with or without hematuria. Cystic hemorrhages usually resolve within one week, although microscopic hematuria may still be present. Because of the proliferative effect of estrogen on hepatic cysts, oral contraceptives containing estrogen and menopausal estrogen therapy should be administered at the lowest effective dose or avoided in patients with ADPKD. Intracranial aneurysms are at least twice as common in patients with ADPKD than in the general population. Renal ultrasonography is the diagnostic modality of choice to screen at-risk individuals for ADPKD. PMID:25251090

Srivastava, Ajay; Patel, Neel

2014-09-01

8

Hypertension in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Hypertension in autosomal dominant polycystic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) has been shown to be associated with a greater than 50 percent incidence of hypertension prior to deterioration in renal function as assessed by glomerular filtration rate. The present study provides evidence for increased cardiac pre-load, as assessed by plasma atrial natriuretic factor (ANF) and cardiac index,

Patricia E Bell; Kenneth F Hossack; Patricia A Gabow; Jacques A Durr; Ann M Johnson; Robert W Schrier

1988-01-01

9

Brachydactyly Type C Gene Maps to Human Chromosome 12q24  

Microsoft Academic Search

Brachydactyly type C is an autosomal dominant disorder characterized by abnormal segmentation of the index and middle fingers segregating with a high degree of variable expression in members of the same family. We have followed up and studied members of the large kindred segregating with the brachydactyly type C phenotype described by Virgil Haws in 1963, and using genetic linkage

Mihael H. Polymeropoulos; Susan E. Ide; Trish Magyari; Clair A. Francomano

1996-01-01

10

Brachydactyly, distal symphalangism, scoliosis, tall stature, and club feet: a new syndrome  

Microsoft Academic Search

Five members of a kindred with brachydactyly and distal symphalangism, normal stature, pes cavus, and scoliosis were ascertained. The pedigree was consistent with autosomal dominant inheritance. The combination of clinical and radiological features is believed to be distinct from those previously reported in patients with brachydactyly\\/symphalangism.

D O Sillence

1978-01-01

11

Autosomal dominant transmission of familial laterality defects.  

PubMed

Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development. Most familial cases are thought to be autosomal recessive. We have identified a family in which 4 individuals from 3 generations manifest laterality defects. Twenty-five family members have been examined. Two have complete reversal of normal laterality (situs inversus) while 2 others have asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two additional obligate gene carriers are anatomically normal (situs solitus). Male-to-male transmission confirms autosomal inheritance. Identification of this family establishes an autosomal dominant form of laterality defect, suggesting that a portion of sporadic cases may be new-mutation dominant or unrecognized familial cases. The finding of all forms of laterality (solitus, ambiguus, and inversus) among obligate disease gene carriers within a single family may be relevant to genetic evaluation and counseling in apparently isolated patients with laterality disturbance. PMID:8834043

Casey, B; Cuneo, B F; Vitali, C; van Hecke, H; Barrish, J; Hicks, J; Ballabio, A; Hoo, J J

1996-02-01

12

Recurrence risks for Mendelian traits Autosomal Dominant  

E-print Network

Recurrence risks for Mendelian traits · Autosomal Dominant ­ Risk of next child being affected;· Definition ­ Multifactorial Trait · Trait determined by multiple genetic and environmental factors, which determine individual risk, age of onset, severity of disease and clinical symptoms #12;A trait is determined

Dellaire, Graham

13

Autosomal Dominant Stargardt-Like Macular Dystrophy  

Microsoft Academic Search

Autosomal dominant Stargardt-like macular dystrophy is one of the early onset macular dystrophies. It is characterized clinically in its early stages by visual loss and by the presence of atrophic macular changes with or without the presence of yellowish flecks. It is an important retinal dystrophy to study, not only because it has implications in the care and treatment of

Larry A Donoso; Albert O Edwards; Arcilee Frost; Tamara Vrabec; Edwin M Stone; Gregory S Hageman; Thomas Perski

2001-01-01

14

Autosomal dominant sensory ataxia: a neuroaxonal dystrophy  

Microsoft Academic Search

Autosomal dominant sensory ataxia (ADSA), a rare hereditary ataxia, is characterized by progressive dysfunction of central\\u000a sensory pathways. Its pathological features have not been previously documented. We report a case of a 61-year-old man with\\u000a ADSA who died of congestive heart failure. Autopsy specimens of brain, thoracolumbar spinal cord, peripheral nerve and skeletal\\u000a muscle were examined. There was no abnormality

Jeremy J. Moeller; Robert J. B. Macaulay; Paul N. Valdmanis; Lyle E. Weston; Guy A. Rouleau; Nicolas Dupré

2008-01-01

15

Autosomal dominant hereditary ataxia in Sri Lanka  

PubMed Central

Background Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. Methods Thirty four patients with autosomal dominant ataxia were recruited. For every patient the following was done: recording of clinical details and genotyping for SCA 1, 2, 3, 6, 7, 8, 12, and 17. Results Sixty one per cent of the subjects were identified as SCA1. One subject had SCA2, 12 remain unidentified. Mean age at onset was 34.8?±?10years for SCA1 and 32.7?±?9.8 for non SCA1. 76% of SCA1 patients and 50% of non SCA1 were using walking aids. Quantification of symptoms and signs were similar in the SCA1 and non SCA1 groups. Clinical depression was evidenced in 68.4% of SCA1 and 75% non SCA-1 patients. Mean CAG repeat length in SCA1 patients was 52.0?±?3.8, with greater anticipation seen with paternal inheritance. Conclusion SCA1 was the predominant subtype and showed similar phenotype to previous reports. However, disease severity was higher and depression more prevalent in this population than previously described. PMID:23634774

2013-01-01

16

Clinical neurogenetics: autosomal dominant spinocerebellar ataxia.  

PubMed

The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis. PMID:24176420

Shakkottai, Vikram G; Fogel, Brent L

2013-11-01

17

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 ...

18

Genetics Home Reference: Autosomal dominant nocturnal frontal lobe epilepsy  

MedlinePLUS

... disorder catalog Conditions > Autosomal dominant nocturnal frontal lobe epilepsy (often shortened to ADNFLE ) On this page: Description ... What is ADNFLE? Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon form of epilepsy that ...

19

Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease. Congenital hepatic fibrosis was found in four families with autosomal-dominant polycystic kidney disease. Congenital hepatic fibrosis is commonly thought to be characteristic for autosomal-recessive polycystic kidney disease, but the reported families show that it can also complicate autosomal-dominant polycystic kidney disease. In three families close linkage between the mutation causing the disease

Jan M Cobben; Martijn H Breuning; Coen Schoots; Leo P ten Kate; Klaus Zerres

1990-01-01

20

Mechanisms of Disease: autosomal dominant and recessive polycystic kidney diseases  

Microsoft Academic Search

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

Peter C Harris; Vicente E Torres

2006-01-01

21

Cleidocranial Dysplasia with Autosomal Dominant Inheritance Pattern  

PubMed Central

Cleidocranial dysplasia (CCD) is an autosomal dominant disease with a wide range of expression, characterized by clavicular hypoplasia, retarded cranial ossification, delayed bone and teeth development, supernumerary teeth, stomatognathic, craniofacial and skeletal abnormalities. This paper presents a case of CCD in a female with brachycephalic skull, depressed frontal bone and nasal bridge, hypoplastic middle one-third of face with mandibular prognathism and hyper mobility of both shoulders with associated radiographic features. Odontologist is often the first professional who patient of CCD approaches, since there is a delay in the eruption or absence of permanent teeth. The premature diagnosis allows a scope for proper treatment modalities, offering a better life quality for patient. PMID:25184084

Bhargava, P; Khan, S; Sharma, R; Bhargava, S

2014-01-01

22

Brachydactyly type C associated with shortening of the hallux  

Microsoft Academic Search

A four generation autosomal dominant pedigree of brachydactyly type C is presented with its radiological features. The hands and feet were similarly affected. All the subjects showing these changes had shortening of the big toes and, in addition, had cupped ears.

J M Rowe-Jones; A L Moss; M A Patton

1992-01-01

23

Pregnancy after preimplantation genetic diagnosis for brachydactyly type B  

Microsoft Academic Search

Brachydactyly type B (BDB) is an autosomal dominant disease caused by mutations in the ROR2 gene. Truncating mutations lead to the severe form of the disease, which is characterized by terminal deficiency of fingers and toes. Preimplantation genetic diagnosis (PGD) was carried out in a family suffering from severe BDB. The family was screened for mutations in exons 8 and

Ali Hellani; Khaled Abu-Amero; Joseph Azouri; Hadeel Al-Sharif; Hamish Barblet; Siham El-Akoum

2009-01-01

24

Renal structure and hypertension in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Renal structure and hypertension in autosomal dominant polycystic kidney disease. Hypertension has been reported to occur in 50 to 75 percent of subjects with autosomal dominant polycystic kidney disease (ADPKD) prior to the onset of marked renal insufficiency but concurrent with cystic deformation of the renal parenchyma. The present study was undertaken to examine whether the renal structural abnormalities are

Patricia A Gabow; Arlene B Chapman; Ann M Johnson; Douglas J Tangel; Irene T Duley; William D Kaehny; Michael Manco-Johnson; Robert W Schrier

1990-01-01

25

Cyst formation and growth in autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Cyst formation and growth in autosomal dominant polycystic kidney disease. Previous morphologic studies on kidneys from adult patients with autosomal dominant polycystic kidney disease (ADPKD) indicates that the cysts developed from nephrons and collecting ducts in association with hyperplasia of epithelial cells lining the cyst walls. In the present study, we systematically evaluated by scanning electron microscopy 387 cysts in

Jared J Grantham; James L Geiser; Andrew P Evan

1987-01-01

26

Familial meralgia paresthetica with an autosomal dominant trait  

Microsoft Academic Search

Familial occurrence of Meralgia paresthetica is uncommon. Only few familial case studies have been reported up to now. The author presents a family with Meralgia in four generations, suggesting a distinctly autosomal dominant trait.

J.-P. Malin

1979-01-01

27

INTRODUCTION Huntington's disease (HD) is an autosomal dominant, progressive  

E-print Network

INTRODUCTION Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative protein, huntingtin (Htt) (The Huntington's Disease Collaborative Research Group, 1993). The polyQ tract in HD (The Huntington's Disease Collaborative Research Group, 1993). Numerous studies have demonstrated

Perrimon, Norbert

28

Autosomal dominant polycystic kidney disease in childhood: A longitudinal study  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease in childhood: A longitudinal study. One hundred fifty–four children aged eighteen years or younger from 83 families with autosomal–dominant polycystic kidney disease were studied by ultrasonography or excretory urography. Twenty–three children had bilateral renal involvement with at least five cysts (ADPKD), 28 children were classified as suspicious (SADPKD), and 103 children had no renal involvement

Aileen Sedman; Patricia Bell; Robert Schrier; Bradley A Warady; Edward O Heard; Patricia Gabow

1987-01-01

29

In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome.  

PubMed

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies. PMID:12525539

Faivre, L; Gorlin, R J; Wirtz, M K; Godfrey, M; Dagoneau, N; Samples, J R; Le Merrer, M; Collod-Beroud, G; Boileau, C; Munnich, A; Cormier-Daire, V

2003-01-01

30

Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?  

Microsoft Academic Search

Mutations in ROR2, encoding a receptor tyrosine kinase, can cause autosomal recessive Robinow syndrome (RRS), a severe skeletal dysplasia with limb shortening, brachydactyly, and a dysmorphic facial appearance. Other mutations in ROR2 result in the autosomal dominant disease, brachydactyly type B (BDB1). No functional mechanisms have been delineated to effectively explain the association between mutations and different modes of inheritance

S. Ben-Shachar; M. Khajavi; M. A. Withers; C. A. Shaw; J. H. L. M. van Bokhoven; H. G. Brunner; J. R. Lupski

2009-01-01

31

Rapid publication: Clinical and locus heterogeneity in brachydactyly type C  

SciTech Connect

Brachydactyly type C is characterized by shortness of the second and fifth middle phalanges and the first metacarpal. It is inherited as an autosomal dominant trait, and is noted for its widely variable clinical phenotype both within and between families. In most families involvement is limited to the hands. However, in some families additional skeletal and nonskeletal findings have been reported. We report on 12 affected members from a 5 generation kindred that segregates a brachydactyly type C phenotype. All affected individuals had shortness principally affecting the second and fifth phalanges and first metacarpal. However, the metacarpal-phalangeal profile indicated that other digital elements were short as well. In addition, one affected individual had a bilateral Madelung deformity, but none had foot involvement. No other non-skeletal findings cosegregated with brachydactyly in this family. Recently, a gene for brachydactyly type C has been localized to 12q24. This was done by studying a large kindred first reported by Haws [1963], which manifests both hand and foot anomalies. Here we present linkage data which excludes the 12q24 locus in our kindred, indicating locus heterogeneity as one explanation for the interfamilial variability described in brachydactyly type C. 33 refs., 2 figs., 2 tabs.

Robin, N.H.; Gunay-Aygun, M.; Polinkovsky, A. [Univ. Hospitals of Cleveland, OH (United States)] [and others] [Univ. Hospitals of Cleveland, OH (United States); and others

1997-01-31

32

Perilipin Deficiency and Autosomal Dominant Partial Lipodystrophy  

PubMed Central

Summary Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue. PMID:21345103

Gandotra, Sheetal; Le Dour, Caroline; Bottomley, William; Cervera, Pascale; Giral, Philippe; Reznik, Yves; Charpentier, Guillaume; Auclair, Martine; Delepine, Marc; Barroso, Ines; Semple, Robert K.; Lathrop, Mark; Lascols, Olivier; Capeau, Jacqueline; O'Rahilly, Stephen; Magre, Jocelyne; Savage, David B.; Vigouroux, Corinne

2013-01-01

33

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

PubMed Central

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

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

2009-01-01

34

Autosomal dominant palmoplantar hyperkeratosis and sensorineural deafness in three generations  

Microsoft Academic Search

A family is presented with autosomal dominant progressive palmoplantar hyperkeratosis, which is invariably associated with a slowly progressive, bilateral, high frequency, sensorineural hearing loss. The family show no other ectodermal abnormality. The differential diagnosis and possible mechanisms are discussed. This family appears to represent a unique variant in the hyperkeratosis-deafness association.

M Sharland; N R Bleach; P D Goberdhan; M A Patton

1992-01-01

35

Autosomal dominant transmission of ureteral triplication and bilateral amastia.  

PubMed

We report a case of ureteral triplication as part of an autosomal dominant syndrome comprising bilateral amastia, pectus excavatum, umbilical hernia, patent ductus arteriosus, dysmorphic low set ears, ptosis, epicanthic folds with an antimongoloid slant to the eyes, hypertelorism, high arched palate, flat broad nasal bridge, tapered digits, cubitus valgus and syndactyly. PMID:3795344

Rich, M A; Heimler, A; Waber, L; Brock, W A

1987-01-01

36

Autosomal dominant polycystic kidney disease: the last 3 years  

Microsoft Academic Search

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

Vicente E Torres; Peter C Harris

2009-01-01

37

Hereditary brachydactyly with nail dysplasia  

Microsoft Academic Search

A family is described in which sometimes asymmetrical brachydactyly, with nail dysplasia of the involved fingers, has been transmitted through 6 generations affecting 6 males and 15 females. The thumbs and feet have been normal. This previously unreported condition is inherited as an autosomal disorder with full penetrance and variable expressivity, and causes only minor inconvenience.

G D Schott

1978-01-01

38

Gene therapy in animal models of autosomal dominant retinitis pigmentosa  

PubMed Central

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

Rossmiller, Brian; Mao, Haoyu

2012-01-01

39

Autosomal-dominant polycystic kidney disease in the rat  

Microsoft Academic Search

Autosomal-dominant polycystic kidney disease in the rat. Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements

Benjamin D Cowley; Seshagirirao Gudapaty; Amy L Kraybill; Brian D Barash; Michael A Harding; James P Calvet; Vincent H Gattone

1993-01-01

40

Predictors of autosomal dominant polycystic kidney disease progression.  

PubMed

Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments. PMID:24925719

Schrier, Robert W; Brosnahan, Godela; Cadnapaphornchai, Melissa A; Chonchol, Michel; Friend, Keith; Gitomer, Berenice; Rossetti, Sandro

2014-11-01

41

Nonallelic heterogeneity in autosomal dominant retinitis pigmentosa with incomplete penetrance  

SciTech Connect

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

Kim, S.K.; Berson, E.L.; Dryja, T.P. [Harvard Medical School, Boston, MA (United States)] [and others] [Harvard Medical School, Boston, MA (United States); and others

1994-08-01

42

A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved  

Microsoft Academic Search

Brachydactyly type A1 (BDA1) was the first disorder described in terms of autosomal dominant Mendelian inheritance. Early in the 1900s Farabee and Drinkwater described a number of families with BDA1. Examination of two of Drinkwater's families has revealed that, although they are not known to be related, both share a common mutation within the Indian hedgehog gene (IHH). This novel

Elizabeth M. McCready; Elizabeth Sweeney; Allan E. Fryer; Dian Donnai; Akeel Baig; Lemuel Racacho; Matthew L. Warman; Alasdair G. W. Hunter; Dennis E. Bulman

2002-01-01

43

Family study of inherited syndrome with multiple congenital deformities: symphalangism, carpal and tarsal fusion, brachydactyly, craniosynostosis, strabismus, hip osteochondritis  

Microsoft Academic Search

A syndrome of brachydactyly (absence of some middle or distal phalanges), aplastic or hypoplastic nails, symphalangism (ankylois of proximal interphalangeal joints), synostosis of some carpal and tarsal bones, craniosynostosis, and dysplastic hip joints is reported in five members of an Italian family. It may represent a previously undescribed autosomal dominant trait.

V Ventruto; R Di Girlamo; B Festa; A Romano; G Sebastio; L Sebastio

1976-01-01

44

Pregnancy outcome in women with autosomal dominant hypocalcaemic hypercalciuric nephrocalcinosis.  

PubMed

Abstract Autosomal dominant hypocalcaemic hypercalciuric nephrocalcinosis is an extremely rare clinical condition caused by an activating mutation of calcium-sensing receptor. Patients presenting with this condition are generally asymptomatic of hypocalcaemia inspite of significant lower serum calcium levels. Attempts at administering vitamin D to correct their hypocalcaemia tend to result in hypercalciuria with its attendant complications of nephrocalcinosis and renal impairment. To our knowledge there are no reports of pregnancy outcomes in women suffering with this ailment, hence this report of three pregnancies in two such women. In view of the rarity of this condition we hope it will assist professionals managing such cases. PMID:24428838

Adeniyi, Jacob Olusegun; Esen, Umo; Parr, John

2014-11-01

45

Autosomal dominant polycystic kidney disease: the last 3 years.  

PubMed

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

Torres, Vicente E; Harris, Peter C

2009-07-01

46

Autosomal dominant polycystic kidney disease: the last 3 years  

PubMed Central

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

Torres, Vicente E.; Harris, Peter C.

2010-01-01

47

Homozygotes for the autosomal dominant neoplasia syndrome (MEN1)  

SciTech Connect

Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, the authors had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked to the MEN1 locus, at 11q13, two of the siblings were found to be homozygotes, and one a heterozygote, for MEN1. With regard to the MEN1 syndrome, no phenotypic differences were observed between the two homozygotes and the heterozygotes. However, the two homozygotes showed unexplained infertility, which was not the case for any of the heterozygotes. Thus, MEN1 appears to be a disease with complete dominance, and the presence of two MEN1 alleles with mutations of the type that occur constitutionally may be insufficient for tumor development. 28 refs., 2 figs.

Brandi, M.L.; Falchetti, A.; Tonelli, F. (Univ. of Florence (Italy)); Weber, G.; Svensson, A.; Larsson, C. (Karolinska Hospital, Stockholm (Sweden)); Castello, R.; Furlani, L.; Scappaticci, S.; Fraccaro, M.

1993-12-01

48

Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa  

E-print Network

), autosomal- recessive, or X-linked manner.1,2 To date, 192 retinal disease loci have been mapped and 144ARTICLE Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p

Abecasis, Goncalo

49

Autosomal dominant distal myopathy: Linkage to chromosome 14  

SciTech Connect

We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64 - the family structure precludes a two-point LOD score {ge} 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity. 24 refs., 3 figs., 1 tab.

Laing, N.G.; Laing, B.A.; Wilton, S.D.; Dorosz, S.; Mastaglia, F.L.; Kakulas, B.A. [Australian Neuromuscular Research Institute, Perth (Australia); Robbins, P.; Meredith, C.; Honeyman, K.; Kozman, H.

1995-02-01

50

Autosomal dominant epidermodysplasia verruciformis: a clinicotherapeutic experience in two cases.  

PubMed

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by a unique susceptibility to cutaneous infection by a group of phylogenetically related human papilloma viruses (HPVs). These patients show a defect in cell-mediated immunity specific toward the causative HPVs that lead to lifelong disease. The defect is usually inherited as autosomal recessive trait and presents clinically with plane warts, pityriasis versicolor-like lesions and reddish verrucous plaques. Dysplastic and malignant changes in the form of actinic keratoses, Bowen's disease and squamous cell carcinoma (SCC) are common but metastasis occurs rarely. A totally effective treatment against EV is as yet highly desirable. Two siblings having autosomal dominant EV presented with multiple actinic keratoses in addition to classic lesions. One of them had also developed well-differentiated SCC over forehead with metastases to regional lymph nodes. They were treated with combination of excision of small malignant/premalignant lesions, topical 5-flurouracil and sun protection. Additionally, elective excision/grafting of large SCC was performed after chemotherapy/radiotherapy in patient with metastatic SCC. Oral acitretin (25 mg/day) was of benefit in the other patient. Overall clinicotherapeutic experience in both the patients is discussed here. PMID:20826999

Vohra, Surbhi; Sharma, Nand Lal; Shanker, Vinay; Mahajan, Vikram K; Jindal, Nidhi

2010-01-01

51

Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy.  

PubMed

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

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

2013-02-01

52

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.  

PubMed

Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically. PMID:15099544

Schöls, Ludger; Bauer, Peter; Schmidt, Thorsten; Schulte, Thorsten; Riess, Olaf

2004-05-01

53

Mutations of DEPDC5 cause autosomal dominant focal epilepsies.  

PubMed

The main familial focal epilepsies are autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy and familial focal epilepsy with variable foci. A frameshift mutation in the DEPDC5 gene (encoding DEP domain-containing protein 5) was identified in a family with focal epilepsy with variable foci by linkage analysis and exome sequencing. Subsequent pyrosequencing of DEPDC5 in a cohort of 15 additional families with focal epilepsies identified 4 nonsense mutations and 1 missense mutation. Our findings provided evidence of frequent (37%) loss-of-function mutations in DEPDC5 associated with a broad spectrum of focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain-containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research. PMID:23542701

Ishida, Saeko; Picard, Fabienne; Rudolf, Gabrielle; Noé, Eric; Achaz, Guillaume; Thomas, Pierre; Genton, Pierre; Mundwiller, Emeline; Wolff, Markus; Marescaux, Christian; Miles, Richard; Baulac, Michel; Hirsch, Edouard; Leguern, Eric; Baulac, Stéphanie

2013-05-01

54

From the Cover: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2  

Microsoft Academic Search

Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic

Katarina Lehmann; Petra Seemann; Sigmar Stricker; Marai Sammar; Birgit Meyer; Katrin Süring; Frank Majewski; Sigrid Tinschert; Karl-Heinz Grzeschik; Dietmar Müller; Petra Knaus; Peter Nürnberg; Stefan Mundlos

2003-01-01

55

Nephrocalcinosis in a child with autosomal dominant polycystic kidney disease and a prolapsing ectopic ureterocele.  

PubMed

Although autosomal dominant polycystic kidney disease commonly presents in adults, it can occur in children. Usually, renal calcification in patients with autosomal dominant polycystic kidney disease is manifested as calculi or as hemorrhage into a renal cyst. An ectopic ureterocele is a well-known finding in patients with renal duplication. To our knowledge, this is the first case report of a child who had combined findings of autosomal dominant polycystic kidney disease, nephrocalcinosis, and an obstructing ectopic ureterocele. PMID:7491203

Burton, E M; Hanna, J D; Mercado-Deane, M G

1995-01-01

56

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Autosomal-dominant polycystic kidney disease results in renal failure at a varying age from childhood to old age. We postulated that factors other than the culprit gene alone contribute to the course of progression of the renal failure. We studied 580 subjects with autosomal-dominant polycystic kidney disease and 194

Patricia A Gabow; Ann M Johnson; William D Kaehny; William J Kimberling; Dennis C Lezotte; Irene T Duley; Richard H Jones

1992-01-01

57

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

E-print Network

RP), autosomal recessive (arRP) and X-linked (xlRP). Many RP genes are expressed specifically or predominantlyIdentification of photoreceptor genes affected by PRPF31 mutations associated with autosomal been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8

Wu, Jane Y.

58

The evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease.  

PubMed

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

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

59

Renal transplantation in autosomal dominant polycystic kidney disease.  

PubMed

In patients with autosomal dominant polycystic kidney disease (ADPKD) evaluated for kidney transplantation, issues related to native nephrectomy, cystic liver involvement, screening for intracranial aneurysms and living-related kidney donation deserve special consideration. Prophylactic native nephrectomy is restricted to patients with a history of cyst infection or recurrent haemorrhage or to those in whom space must be made to implant the graft. Patients with liver involvement require pretransplant imaging. Selection of patients for pretransplant screening of intracranial aneurysms should follow the general recommendations for patients with ADPKD. In living related-donor candidates aged <30 years and at-risk of ADPKD, molecular genetic testing should be carried out when ultrasonography and MRI findings are normal or equivocal. After kidney transplantation, patient and graft survival rates are excellent and the volume of native kidneys decreases. However, liver cysts continue to grow and treatment with a somatostatin analogue should be considered in patients with massive cyst involvement. Cerebrovascular events have a marginal effect on post-transplant morbidity and mortality. An increased risk of new-onset diabetes mellitus and nonmelanoma skin cancers has been reported, but several studies have challenged these findings. Finally, no data currently support the preferential use of mammalian target of rapamycin inhibitors as immunosuppressive agents in transplant recipients with ADPKD. PMID:24935705

Kanaan, Nada; Devuyst, Olivier; Pirson, Yves

2014-08-01

60

New treatments for autosomal dominant polycystic kidney disease  

PubMed Central

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

Chang, Ming-Yang; Ong, Albert C M

2013-01-01

61

Developments in the management of autosomal dominant polycystic kidney disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life- threatening, hereditary disease. ADPKD is more common than sickle cell anemia, cystic fibrosis, muscular dystrophy, hemophilia, Down’s syndrome, and Huntington’s disease combined. ADPKD is a multisystemic disorder characterized by the progressive development of renal cysts and marked renal enlargement. Structural and functional renal deterioration occurs in ADPKD patients and is the fourth leading cause of end-stage renal disease (ESRD) in adults. Aside from the renal manifestations, extrarenal structural abnormalities, such as liver cysts, cardiovascular abnormalities, and intracranial aneurysms may lead to morbidity and mortality. Recent studies have identified prognostic factors for progressive renal impairment including gender, race, age, proteinuria, hematuria, hypertension and increased left ventricular mass index (LVMI). Early diagnosis and better understanding of the pathophysiology of the disease provides the opportunity to aggressivly treat hypertension with renin-angiotensin-aldosterone system inhibitors and thereby potentially reduce LVMI, prevent cardiovascular morbidity and mortality and slow progression of the renal disease. PMID:18728845

Masoumi, Amirali; Reed-Gitomer, Berenice; Kelleher, Catherine; Bekheirnia, Mir Reza; Schrier, Robert W

2008-01-01

62

Impaired default network functional connectivity in autosomal dominant Alzheimer disease  

PubMed Central

Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease. PMID:23884042

Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Benzinger, Tammie L.S.; Jack, Clifford; Ances, Beau M.; Sullivan, Caroline A.; Salloway, Stephen P.; Ringman, John M.; Koeppe, Robert A.; Marcus, Daniel S.; Thompson, Paul; Saykin, Andrew J.; Correia, Stephen; Schofield, Peter R.; Rowe, Christopher C.; Fox, Nick C.; Brickman, Adam M.; Mayeux, Richard; McDade, Eric; Bateman, Randall; Fagan, Anne M.; Goate, Allison M.; Xiong, Chengjie; Buckles, Virginia D.; Morris, John C.

2013-01-01

63

Bull terrier hereditary nephritis: A model for autosomal dominant Alport syndrome  

Microsoft Academic Search

Bull terrier hereditary nephritis: A model for autosomal dominant Alport syndrome. Bull terrier hereditary nephritis is inherited as an autosomal dominant disease and causes renal failure at variable ages in affected dogs. The aims of this study were to compare the clinical, ultrastructural and immunohistochemical features of bull terrier hereditary nephritis with the characteristics of the human forms of Alport

Jennifer C Hood; Judy Savige; Anne Hendtlass; Mary M Kleppel; Clive R Huxtable; Wayne F Robinson; Jennifer Hood BSc

1995-01-01

64

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease. We studied young adults with autosomal dominant polycystic kidney disease (ADPKD) to determine the characteristics that precede renal impairment. Nineteen affected (A) and 20 unaffected (U) offspring from families with ADPKD showed no significant differences in basal glomerular filtration rate (A: mean 97, SD 19; U:

Stephen B Harrap; David L Davies; Ann M Macnicol; Anna F Dominiczak; Robert Fraser; Alan F Wright; Michael L Watson; J Douglas Briggs

1991-01-01

65

Clinical and genetic heterogeneity in autosomal dominant cataract  

PubMed Central

AIMS—To determine the different morphologies of autosomal dominant cataract (ADC), assess the intra- and interfamilial variation in cataract morphology, and undertake a genetic linkage study to identify loci for genes causing ADC and detect the underlying mutation.?METHODS—Patients were recruited from the ocular genetic database at Moorfields Eye Hospital. All individuals underwent an eye examination with particular attention to the lens including anterior segment photography where possible. Blood samples were taken for DNA extraction and genetic linkage analysis was carried out using polymorphic microsatellite markers.?RESULTS—292 individuals from 16 large pedigrees with ADC were examined, of whom 161 were found to be affected. The cataract phenotypes could all be described as one of the eight following morphologies—anterior polar, posterior polar, nuclear, lamellar, coralliform, blue dot (cerulean), cortical, and pulverulent. The phenotypes varied in severity but the morphology was consistent within each pedigree, except in those affected by the pulverulent cataract, which showed considerable intrafamilial variation. Positive linkage was obtained in five families; in two families linkage was demonstrated to new loci and in three families linkage was demonstrated to previously described loci. In one of the families the underlying mutation was isolated. Exclusion data were obtained on five families.?CONCLUSIONS—Although there is considerable clinical heterogeneity in ADC, the phenotype is usually consistent within families. There is extensive genetic heterogeneity and specific cataract phenotypes appear to be associated with mutations at more than one chromosome locus. In cases where the genetic mutation has been identified the molecular biology and clinical phenotype are closely associated.?? PMID:10381667

Ionides, A.; Francis, P.; Berry, V.; Mackay, D.; Bhattacharya, S.; Shiels, A.; Moore, A.

1999-01-01

66

Connexin46 mutations in autosomal dominant congenital cataract.  

PubMed Central

Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q (CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Zmax]=>7.0; maximum recombination frequency [thetamax] =0). Haplotyping indicated that CZP3 probably lies in the genetic interval D13S1236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared approximately 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identifies GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens. PMID:10205266

Mackay, D; Ionides, A; Kibar, Z; Rouleau, G; Berry, V; Moore, A; Shiels, A; Bhattacharya, S

1999-01-01

67

Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity  

Microsoft Academic Search

BACKGROUND: Familial keloids have been reported, having either autosomal dominant or autosomal recessive inheritance. We wished to determine the inheritance pattern and phenotype of keloids among multigenerational families, as a prelude to a positional mapping strategy to identify candidate genes. METHODS: We studied three African American families, one Afro-Caribbean family and one Asian-American family. Phenotyping including assessing all patients for

Jason A Clark; Maria L Turner; Lillian Howard; Horia Stanescu; Robert Kleta; Jeffrey B Kopp

2009-01-01

68

Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Synthesis of renin by tubulocystic epithelium in autosomal-dominant polycystic kidney disease. Evidence suggests an important role for the renin-angiotensin system in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD). Therefore, we studied the presence of immunoreactive renin in renal biopsies and measured the concentrations of renin in cyst fluids. Normal kidneys and kidneys with renal artery stenosis were used for

Vicente E Torres; Kathleen A Donovan; Gloria Scicli; Keith E Holley; Stephen N Thibodeau; Oscar A Carretero; Tadashi Inagami; James A McAteer; Christopher M Johnson

1992-01-01

69

A gene for autosomal dominant congenital nystagmus localizes to 6p12  

SciTech Connect

Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.

Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K. [Johns Hopkins Hospital, Baltimore, MD (United States)] [and others] [Johns Hopkins Hospital, Baltimore, MD (United States); and others

1996-05-01

70

Bovine Polledness – An Autosomal Dominant Trait with Allelic Heterogeneity  

Microsoft Academic Search

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than

Ivica Medugorac; Doris Seichter; Alexander Graf; Ingolf Russ; Helmut Blum; Karl Heinrich Göpel; Sophie Rothammer; Stefan Krebs

2012-01-01

71

Genetic Factors Modifying Clinical Expression of Autosomal Dominant RP  

Microsoft Academic Search

Factors modifying clinical expression of inherited diseases are likely to be complex, involving genetic factors, environmental\\u000a factors and stochastic effects. One way to reduce the complexity is to focus on individuals who share a dominant mutation\\u000a identical by descent, thus eliminating variability in the underlying mutation and variation in cis to the mutation. A further simplification is to limit analysis

Stephen P. Daiger; Suma P. Shankar; Alice B. Schindler; Lori S. Sullivan; Sara J. Bowne; Terri M. King; E. Warick Daw; Edwin M. Stone; John R. Heckenlively

72

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

PubMed

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 respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions. PMID:12921794

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

2003-09-01

73

Bovine Polledness - An Autosomal Dominant Trait with Allelic Heterogeneity  

PubMed Central

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ?381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations. PMID:22737241

Medugorac, Ivica; Seichter, Doris; Graf, Alexander; Russ, Ingolf; Blum, Helmut; Gopel, Karl Heinrich; Rothammer, Sophie; Forster, Martin; Krebs, Stefan

2012-01-01

74

Bovine polledness--an autosomal dominant trait with allelic heterogeneity.  

PubMed

The persistent horns are an important trait of speciation for the family Bovidae with complex morphogenesis taking place briefly after birth. The polledness is highly favourable in modern cattle breeding systems but serious animal welfare issues urge for a solution in the production of hornless cattle other than dehorning. Although the dominant inhibition of horn morphogenesis was discovered more than 70 years ago, and the causative mutation was mapped almost 20 years ago, its molecular nature remained unknown. Here, we report allelic heterogeneity of the POLLED locus. First, we mapped the POLLED locus to a ?381-kb interval in a multi-breed case-control design. Targeted re-sequencing of an enlarged candidate interval (547 kb) in 16 sires with known POLLED genotype did not detect a common allele associated with polled status. In eight sires of Alpine and Scottish origin (four polled versus four horned), we identified a single candidate mutation, a complex 202 bp insertion-deletion event that showed perfect association to the polled phenotype in various European cattle breeds, except Holstein-Friesian. The analysis of the same candidate interval in eight Holsteins identified five candidate variants which segregate as a 260 kb haplotype also perfectly associated with the POLLED gene without recombination or interference with the 202 bp insertion-deletion. We further identified bulls which are progeny tested as homozygous polled but bearing both, 202 bp insertion-deletion and Friesian haplotype. The distribution of genotypes of the two putative POLLED alleles in large semi-random sample (1,261 animals) supports the hypothesis of two independent mutations. PMID:22737241

Medugorac, Ivica; Seichter, Doris; Graf, Alexander; Russ, Ingolf; Blum, Helmut; Göpel, Karl Heinrich; Rothammer, Sophie; Förster, Martin; Krebs, Stefan

2012-01-01

75

Palmoplantar keratoderma, nail dystrophy, and hereditary motor and sensory neuropathy: an autosomal dominant trait  

Microsoft Academic Search

Autosomal dominant inheritance of a syndrome comprising palmoplantar keratoderma, nail dystrophy, and hereditary motor and sensory neuropathy (HMSN) was observed in three generations of one family. Nail dystrophy affected the toe and fingernails; it was present at birth or developed during early childhood. Palmoplantar keratoderma became apparent in later childhood. Each subject with nail dystrophy and keratoderma also had clinical

J L Tolmie; D E Wilcox; R McWilliam; A Assindi; J B Stephenson

1988-01-01

76

Complex Segregation Analysis of Thyroid Autoantibodies: Are They Inherited as an Autosomal Dominant Trait?  

Microsoft Academic Search

The presence of circulating autoantibodies (Abs) to the thyroid antigens thyroid peroxidase (TPO) and thyroglobulin (Tg) is a marker for autoimmune thyroid disease. Recent studies have suggested that the tendency to produce these Abs is inherited as an autosomal dominant characteristic. In order to confirm or refute these observations, we have carried out a complex segregation analysis using POINTER on

D. I. W Phillips; D. C. Shields; J. M. Dugoujon; L. Prentice; P. McGuffin; Rees Smith

1993-01-01

77

Familial Cutaneous Malignant Melanoma: Autosomal Dominant Trait Possibly Linked to the Rh Locus  

Microsoft Academic Search

Segregation and linkage analyses were undertaken in families with multiple cases of cutaneous malignant melanoma (CMM) and a recently-described melanoma precursor, the dysplastic nevus syndrome (DNS). Clinical and laboratory data, including 23 genetic markers, were collected on 401 members of 14 high-risk kindreds. Pedigree analysis was compatible with an autosomal dominant mode of inheritance for the familial CMM trait. Although

Mark H. Greene; Lynn R. Goldin; Wallace H. Clark; Everett Lovrien; Kenneth H. Kraemer; Margaret A. Tucker; David E. Elder; Mary C. Fraser; Shirley Rowe

1983-01-01

78

Abstract Autosomal-dominant polycystic kidney dis-ease represents one of the most common monogenetic  

E-print Network

Abstract Autosomal-dominant polycystic kidney dis- ease represents one of the most common. In this review, we will highlight some of the characteristics of polycystic kidney disease, briefly touch kidney disease actually behaves re- cessively on a cellular level. Finally, a model will be pre- sented

Witzgall, Ralph - Naturwissenschaftliche Fakultät III

79

Contribution of Renal Innervation to Hypertension in Rat Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

The kidney has both afferent (sensory) and efferent (sympa- thetic) nerves that can influence renal function. Renal innerva- tion has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and

VINCENT H. GATTONE; TIBERIO M. SIQUEIRA JR.; CHARLES R. POWELL

80

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

Microsoft Academic Search

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

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

81

Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL  

Microsoft Academic Search

A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg,

C. Hagel; C. Groden; R. Niemeyer; D. Stavrou; H. J. Colmant

2004-01-01

82

Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease  

Microsoft Academic Search

In autosomal dominant polycystic kidney disease (ADPKD), abnormal proliferation of tubular cells drives cyst development and growth. Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD). We determined here the effect of sirolimus on renal cyst growth in

Iram Zafar; Kameswaran Ravichandran; Franck A Belibi; R Brian; Charles L Edelstein

2010-01-01

83

Evidence for a third genetic locus for autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disease with loci on chromosomes 16p and 4q. It has a moderately high spontaneous mutation rate, although the relative frequency of such mutations at each gene locus is unknown. In studying genetic heterogeneity in the French-Canadian population, we identified a family in which a classical clinical presentation of ADPKD resulted

Martin C. Daoust; David M. Reynolds; Daniel G. Bichet; Stefan Somlo

1995-01-01

84

Human Genome and Diseases: Review Molecular basis of autosomal-dominant polycystic  

E-print Network

Human Genome and Diseases: Review Molecular basis of autosomal-dominant polycystic kidney disease A and therapeutic strategies. Key words. PKD1; PKD2; polycystin-1; polycystin-2; ADPKD; polycystic kidney disease kidney dis- ease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery

Witzgall, Ralph - Naturwissenschaftliche Fakultät III

85

origiNal articlE Autosomal dominant polycystic kidney disease in hemodialysis  

E-print Network

origiNal articlE 18 Autosomal dominant polycystic kidney disease in hemodialysis patients and laboratory characteristics of patients with polycystic kidneys and relate disease manifestations by gender patients with polycystic kidneys, the primary cause of stage 5 CKD. Disease prevalence was one in 10

Paris-Sud XI, Université de

86

The Molecular Basis of Focal Cyst Formation in Human Autosomal Dominant Polycystic Kidney Disease Type I  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is a common disease and an important cause of renal failure. It is characterized by considerable intrafamilial phenotypic variation and focal cyst formation. To elucidate the molecular basis for these observations, we have developed a novel method for isolating renal cystic epithelia from single cysts and have used it to show that individual renal

Feng Qian; Terry J Watnick; Luiz F Onuchic; Gregory G Germino

1996-01-01

87

Laparoscopic nephrectomy in patients with end-stage renal disease and autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is often characterized by end-stage renal disease (ESRD) and problems including pain, hematuria, and infection. Open nephrectomy is curative; however, the morbidity of the procedure is considerable. Between 1995 and 1998, 11 laparoscopic nephrectomies were performed on nine symptomatic patients (five men and four women) with ESRD and ADPKD. Two patients underwent a staged

Matthew D. Dunn; Andrew J. Portis; Abdelhamid M. Elbahnasy; Arieh L. Shalhav; Marcos Rothstein; Elspeth M. McDougall; Ralph V. Clayman

2000-01-01

88

PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease  

Microsoft Academic Search

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. METHODS: We collected samples from 36 Slovene

Katja Vouk; Lana Strmecki; Jitka Stekrova; Jana Reiterova; Matjaz Bidovec; Petra Hudler; Anton Kenig; Simona Jereb; Irena Zupanic-Pajnic; Joze Balazic; Guido Haarpaintner; Bostjan Leskovar; Anton Adamlje; Antun Skoflic; Reina Dovc; Radovan Hojs; Radovan Komel

2006-01-01

89

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

E-print Network

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

Palmeri, Thomas

90

Hereditary Brachydactyly Associated with Hypertension  

Microsoft Academic Search

A family showing brachydactyly associated with hypertension is reported. The number and location of the involved bones are quite different from the other cases with brachydactyly reported in the literature. Additionally, all our patients have high blood pressure. We believe that the disorder reported here represents a hitherto undescribed entity. It is thought that both hypertension and brachydactyly are transmitted

N. Bilginturan; S. Zileli; S. Karacadag; T. Pirnar

1973-01-01

91

Autopsy Report with Clinical and Pathophysiologic Discussion of Autosomal Dominant Adult Polycystic Kidney Disease  

PubMed Central

The average weight of a kidney is approximately 135?gm, measuring on average 10?×?6?×?4?cm. In hereditary conditions, autosomal dominant and autosomal recessive polycystic kidney disease, the shape, size, and the weight can be significantly abnormal, causing progressive renal failure, often necessitating dialysis or renal transplant for survival. We report a case of adult polycystic kidney disease in a 50-year-old female without a family history, who died of complications of the disease which included accelerated hypertension, and renal and cardiac failure. PMID:25313343

Siderits, Richard; Rimmer, Cheryl

2014-01-01

92

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

Microsoft Academic Search

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

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

2006-01-01

93

Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology  

Microsoft Academic Search

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

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

94

Spontaneous intracranial hypotension syndrome in a patient with marfan syndrome and autosomal dominant polycystic kidney disease.  

PubMed

Intracranial hypotension is typically manifested by orthostatic headache. The most frequent underlying factor is cerebrospinal fluid leakage. It has been suggested that dural structural weakness in some connective tissue diseases may be responsible for dural tears and diverticula and consequently leakage. We present a case of spontaneous intracranial hypotension associated with Marfan syndrome and autosomal dominant polycystic kidney disease. The patient was treated successfully with epidural autologous blood patch. Dural involvements of these hereditary connective tissue diseases are also discussed. PMID:18194297

Albayram, Sait; Ba?, Ahmet; Ozer, Harun; Dikici, Suleyman; Gulertan, Serap Yavuz; Yuksel, Adnan

2008-04-01

95

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

Microsoft Academic Search

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

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

2007-01-01

96

Mutation Spectra in Autosomal Dominant and Recessive Retinitis Pigmentosa in Northern Sweden  

Microsoft Academic Search

\\u000a Retinal degenerations represent a heterogeneous group of disorders affecting the function of the retina. The frequency of\\u000a retinitis pigmentosa (RP) is 1\\/3500 worldwide, however, in northern Sweden it is 1\\/2000 due to limited migration and a ‘founder’\\u000a effect. In this study we identified genetic mechanisms underlying autosomal dominant and recessive RP present in northern\\u000a Sweden. Several novel mutations unique for

Irina Golovleva; Linda Köhn; Marie Burstedt; Stephen Daiger; Ola Sandgren

97

Genetic heterogeneity in autosomal dominant retinitis pigmentosa with low-frequency damped electroretinographic wavelets  

Microsoft Academic Search

PurposeTo define molecular and ophthalmic features of a rare phenotype in autosomal dominant (ad) retinitis pigmentosa (RP)MethodsA 32-year-old woman (proband) with adRP and the low-frequency damped electroretinographic (ERG) wavelet phenotype and her mother were studied with optical coherence tomography (OCT), chromatic perimetry and ERG. A previously reported adRP patient with this ERG phenotype (Lam et al) was also studied with

T S Aleman; B L Lam; A V Cideciyan; A Sumaroka; E A M Windsor; A J Roman; S B Schwartz; E M Stone; S G Jacobson

2009-01-01

98

Mutations in Known Genes Account for 58% of Autosomal Dominant Retinitis Pigmentosa (adRP)  

Microsoft Academic Search

Inherited retinal diseases such as autosomal dominant retinitis pigmentosa (adRP) are strikingly complex, with mutations in\\u000a many different genes causing the same disease, with many different mutations in each gene, and with different clinical consequences\\u000a resulting from the same mutation, even within the same family. for example, mutations in sixteen genes are known to cause\\u000a adRP and an additional two

Stephen P. Daiger; Lori S. Sullivan; Anisa I. Gire; David G. Birch; John R. Heckenlively; Sara J. Bowne

99

An autosomal dominant syndrome with 'acromegaloid' features and thickened oral mucosa.  

PubMed Central

A previously undescribed autosomal dominant syndrome has been observed in a large kindred with affected relatives spanning at least five generations. The phenotype is highly variable and appears to show complete penetrance. Affected persons have a progressively coarse, acromegaloid-like facial appearance and thickening of the lips and intraoral mucosa. The differences are discussed between this syndrome and three rather similar syndromes, pachydermoperiostosis, the Ascher syndrome, and multiple neuroma syndrome. Images PMID:3989825

Hughes, H E; McAlpine, P J; Cox, D W; Philipps, S

1985-01-01

100

Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease.BackgroundThe fluid filling renal cysts in human polycystic kidneys is secreted chiefly by the tubular epithelium lining the cysts via secondary chloride transport. Inhibiting this process by somatostatin therapy should induce shrinking of renal cysts.MethodsIn this randomized, cross-over, placebo-controlled trial we compared the risk\\/benefit profile of 6-month treatment with

PIERO RUGGENENTI; ANDREA REMUZZI; PATRIZIA ONDEI; GIORGIO FASOLINI; LUCA ANTIGA; BOGDAN ENE-IORDACHE; GIUSEPPE REMUZZI; FRANKLIN H EPSTEIN

2005-01-01

101

The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52

Jared J. Grantham

1996-01-01

102

MRI of the intraorbital optic nerve in patients with autosomal dominant optic atrophy  

Microsoft Academic Search

Measurements of the intraorbital optic nerve were made using high-resolution coronal MRI in 10 adults with autosomal dominant\\u000a optic atrophy. Comparisons were made with previous studies of 10 normal adult subjects. The cross-sectional diameters of the\\u000a optic nerve and the perineural subarachnoid space were measured and a ratio of there diameters at anterior, mid and posterior\\u000a positions along the optic

M. Votruba; S. Leary; N. Losseff; S. S. Bhattacharya; A. T. Moore; D. H. Miller; I. F. Moseley

2000-01-01

103

Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course.  

PubMed

Autosomal dominant brachyolmia (Type 3, OMIM #113500) belongs to a group of skeletal dysplasias caused by mutations in the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) gene, encoding a Ca++-permeable, non-selective cation channel. The disorder is characterized by disproportionate short stature with short trunk, scoliosis and platyspondyly. The phenotypic variability and long-term natural course remain inadequately characterized. The purpose of this study was to describe a large Swedish family with brachyolmia type 3 due to a heterozygous TRPV4 mutation c.1847G>A (p.R616Q) in 11 individuals. The mutation has previously been detected in another family with autosomal dominant brachyolmia [Rock et al., 2008]. Review of hospital records and patient assessments indicated that clinical symptoms of brachyolmia became evident by school age with chronic pain in the spine and hips; radiographic changes were evident earlier. Growth was not affected during early childhood but deteriorated with age in some patients due to increasing spinal involvement. Affected individuals had a wide range of subjective symptoms with chronic pain in the extremities and the spine, and paresthesias. Our findings indicate that autosomal dominant brachyolmia may be associated with significant long-term morbidity, as seen in this family. PMID:24677493

Grigelioniene, Giedre; Geiberger, Stefan; Horemuzova, Eva; Moström, Eva; Jäntti, Nina; Neumeyer, Lo; Åström, Eva; Nordenskjöld, Magnus; Nordgren, Ann; Mäkitie, Outi

2014-07-01

104

Fine mapping and genetic heterogeneity in the pure form of autosomal dominant familial spastic paraplegia.  

PubMed

We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod = 3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several cross-overs in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus. PMID:11354831

Ashley-Koch, A; Bonner, E R; Gaskell, P C; West, S G; Tim, R; Wolpert, C M; Jones, R; Farrell, C D; Nance, M; Svenson, I K; Marchuk, D A; Boustany, R M; Vance, J M; Scott, W K; Pericak-Vance, M A

2001-03-01

105

Autosomal dominant polycystic kidney disease: risk factor for nonmelanoma skin cancer following kidney transplantation.  

PubMed

Nonmelanoma skin cancers (NMSC) are the most common malignant tumors following solid organ transplantation. Risk factors for NMSC mainly include immunosuppression, age, sun exposure and patient phototype. Recent findings have suggested that autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of developing NMSC. We performed a monocenter retrospective study including all kidney recipients between 1985 and 2006 (n = 1019). We studied the incidence of NMSC, solid cancers and post-transplantation lymphoproliferative disease (PTLD), and analyzed the following parameters: age, gender, phototype, time on dialysis, graft rank, immunosuppressive regimen, history of cancer and kidney disease (ADPKD versus others). Median follow-up was 5.5 years (range: 0.02-20.6; 79 838 patient-years). The cumulated incidence of NMSC 10 years after transplantation was 12.7% (9.3% for solid cancers and 3.5% for PTLD). Autosomal dominant polycystic kidney disease and age were risk factors for NMSC (HR 2.63; P < 0.0001 and HR 2.21; P < 0.001, respectively) using univariate analysis. The association between ADPKD and NMSC remained significant after adjustments for age, gender and phototype using multivariate analysis (HR 1.71; P = 0.0145) and for immunosuppressive regimens (P < 0.0001). Autosomal dominant polycystic kidney disease was not a risk factor for the occurrence of solid cancers after transplantation (HR 0.96; P = 0.89). Our findings suggest that ADPKD is an independent risk factor for developing NMSC after kidney transplantation. PMID:20230542

Bretagnol, Anne; Halimi, Jean Michel; Roland, Mélanie; Barbet, Christelle; Machet, Laurent; Al Najjar, Azmi; Marlière, Jean Frédéric; Badin, Julie; Nivet, Hubert; Lebranchu, Yvon; Büchler, Matthias

2010-09-01

106

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

Microsoft Academic Search

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

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

1997-01-01

107

Bilateral hand-assisted laparoscopic nephrectomy for autosomal dominant polycystic kidney disease using a single midline handport incision  

Microsoft Academic Search

Objectives. To present one of the first known series of bilateral, transperitoneal laparoscopic nephrectomy for autosomal dominant polycystic kidney disease using a hand-assisted technique by way of a single, midline HandPort incision. Synchronous, bilateral nephrectomy for autosomal dominant polycystic kidney disease is an infrequently performed procedure, with only a few reports using laparoscopy.Methods. We retrospectively reviewed the charts of 4

Michael A Jenkins; J. Jason Crane; Larry C Munch

2002-01-01

108

A novel approach to bilateral hand-assisted laparoscopic nephrectomy for autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Purpose  Laparoscopic nephrectomy in patients with autosomal dominant polycystic kidney disease (ADPKD) is technically challenging.\\u000a We describe our technique and present our experience with a transperitoneal hand-assisted laparoscopic (HAL) technique using\\u000a a standard vacuum curettage system to reduce the size of the kidneys thereby facilitating nephrectomy.\\u000a \\u000a \\u000a \\u000a Materials and methods  A retrospective review was completed of 10 consecutive patients undergoing bilateral HAL nephrectomy

M. G. Whitten; W. Van der Werf; L. Belnap

2006-01-01

109

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

PubMed

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

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

110

Multiple Cardiovascular Manifestations in a Patient with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder associated with various extrarenal complications. The major cardiovascular complications of ADPKD include valvulopathies and vascular ectasia. A 64-year-old man who was diagnosed with ADPKD seven years previously was admitted to our hospital for heart failure. Pelvic computed tomography revealed multiple variable-sized cysts in both kidneys. Transthoracic echocardiography showed enlargement of the left ventricle and left atrium. Severe mitral regurgitation and moderate aortic regurgitation with annuloaortic ectasia were observed. The left main coronary artery was dilated. The patient had various cardiovascular features associated with ADPKD.

Kang, Young Ran; Ahn, Jong-Hwa; Kim, Kye Hwan; Choi, Young Min; Choi, Jungwoo

2014-01-01

111

Nephrectomy in Autosomal Dominant Polycystic Kidney Disease: A Patient with Exceptionally Large, Still Functioning Kidneys  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is characterized by progressive cyst formation in both kidneys, often leading to end-stage kidney disease. Indications for surgical removal of an ADPKD kidney include intractable pain, hematuria, infection, or exceptional enlargement and small abdominal cavity hampering implantation of a donor kidney. We report the case of an extraordinarily large ADPKD kidney weighing 8.7 kg (19.3 lb) with a maximal length of 48 cm (19 inch), and with cysts filled with both clear and bloody fluid. PMID:25028584

Spithoven, Edwin M.; Casteleijn, Niek F.; Berger, Paul; Goldschmeding, Roel

2014-01-01

112

Evidence for a third genetic locus for autosomal dominant polycystic kidney disease  

SciTech Connect

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disease with loci on chromosomes 16p and 4q. It has a moderately high spontaneous mutation rate, although the relative frequency of such mutations at each gene locus is unknown. In studying genetic heterogeneity in the French-Canadian population, we identified a family in which a classical clinical presentation of ADPKD resulted from a mutation at a locus genetically distinct from either of the previously described loci for this disease. This suggests the existence of a third genetic locus for ADPKD. 21 refs., 1 fig., 1 tab.

Daoust, M.C.; Bichet, D.G. [Universite de Montreal, Quebec (Canada)] [Universite de Montreal, Quebec (Canada); Reynolds, D.M. [Albert Einstein College of Medicine, Bronx, NY (United States)] [and others] [Albert Einstein College of Medicine, Bronx, NY (United States); and others

1995-02-10

113

A transducin-like gene maps to the autosomal dominant polycystic kidney disease gene region  

SciTech Connect

A novel human gene (sazD) that maps to the autosomal dominant polycystic kidney disease region shares sequence similarity with members of the [beta]-transducin superfamily. The cDNA sazD-c predicts an [approximately]58-kDa protein (sazD) with seven internal repeats, similar to the WD-40 motif of the transducin family. The size of this protein family has been expanding rapidly; however, neither the structure nor the function of this repeated motif is known. Preliminary data do not suggest that sazD is mutated in patients with polycystic kidney disease. 13 refs., 2 figs.

Weinstat-Saslow, D.L.; Reeders, S.T.; Germino, G.G.; Somlo, S. (Yale Univ. School of Medicine, New Haven, CT (United States))

1993-12-01

114

Mechanisms and management of hypertension in autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, characterized by progressive cyst growth and renal enlargement, resulting in renal failure. Hypertension is common and occurs early, prior to loss of kidney function. Whether hypertension in ADPKD is a primary vasculopathy secondary to mutations in the polycystin genes or secondary to activation of the renin-angiotensin-aldosterone system by cyst expansion and intrarenal ischemia is unclear. Dysregulation of the primary cilium causing endothelial and vascular smooth muscle cell dysfunction is a component of ADPKD. In this article, we review the epidemiology, pathophysiology and clinical characteristics of hypertension in ADPKD and give specific recommendations for its treatment. PMID:24463189

Rahbari-Oskoui, Frederic; Williams, Olubunmi; Chapman, Arlene

2014-12-01

115

COL4A3\\/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome  

Microsoft Academic Search

COL4A3\\/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome.BackgroundMutations of the type IV collagen COL4A5 gene cause X-linked Alport syndrome (ATS). Mutations of COL4A3 and COL4A4 have been reported both in autosomal-recessive and autosomal-dominant ATS, as well as in benign familial hematuria (BFH). In the latter conditions, however, clinical features are less defined, few mutations have been reported,

Ilaria Longo; Paola Porcedda; Francesca Mari; Daniela Giachino; Ilaria Meloni; Carla Deplano; Alfredo Brusco; Maurizio Bosio; Laura Massella; Giancarlo Lavoratti; Dario Roccatello; Giovanni Frascá; Gianna Mazzucco; Andrea Onetti Muda; Maura Conti; Federica Fasciolo; Christelle Arrondel; Laurence Heidet; Alessandra Renieri; Mario De Marchi

2002-01-01

116

Mutation spectra in autosomal dominant and recessive retinitis pigmentosa in northern Sweden.  

PubMed

Retinal degenerations represent a heterogeneous group of disorders affecting the function of the retina. The frequency of retinitis pigmentosa (RP) is 1/3500 worldwide, however, in northern Sweden it is 1/2000 due to limited migration and a 'founder' effect. In this study we identified genetic mechanisms underlying autosomal dominant and recessive RP present in northern Sweden. Several novel mutations unique for this region were found. In an autosomal recessive form of RP, Bothnia dystrophy caused by mutations in the RLBP1 gene, bi-allelic mutations R234W, M226K and compound heterozygosity, M226K+R234W was detected.In dominant form of RP mapped to 19q13.42 a 59 kb genomic deletion including the PRPF31 and three other genes was found.These data provide additional information on the molecular mechanisms of RP evolvement and in the future might be useful in development of therapeutic strategies. Identification of the disease-causing mutations allowed introducing molecular genetic testing of the patients and their families into the clinical practice. PMID:20238024

Golovleva, Irina; Köhn, Linda; Burstedt, Marie; Daiger, Stephen; Sandgren, Ola

2010-01-01

117

Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts  

PubMed Central

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

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

2014-01-01

118

An Autosomal Dominant Thrombocytopenia Gene Maps to Chromosomal Region 10p  

PubMed Central

Summary The increasing number of diagnosed cases of inherited thrombocytopenias, owing to the routine practice of including platelet counts in blood tests, suggests that this condition is not so rare as expected. In the majority of cases, the molecular basis of the disease is unknown, although the defect is likely to affect thrombocytopoiesis and regulation of the normal platelet count. Here we report a genomewide search in a large Italian family affected by autosomal dominant thrombocytopenia. Patients showed a moderate thrombocytopenia with minimal symptoms characterized by normocellular bone marrow, normal medium platelet volume, and positive aggregation tests. Microsatellite analysis demonstrated that the disease locus (THC2) is linked to chromosome 10p11.1-12, within a candidate region of 6 cM between markers D10S586 and D19S1639. A maximum LOD score of 8.12 at recombination fraction .00 was obtained with the microsatellite D10S588. These data localized the first locus of an autosomal dominant thrombocytopenia, and the subsequent identification of the gene will provide new insight into the basic mechanism of megakaryocytopoiesis disorders. PMID:10521306

Savoia, Anna; Del Vecchio, Maria; Totaro, Antonio; Perrotta, Silverio; Amendola, Giovanni; Moretti, Arcangela; Zelante, Leopoldo; Iolascon, Achille

1999-01-01

119

Genetics and pathogenesis of autosomal dominant polycystic kidney disease: 20 years on.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is characterized by the progressive development and expansion of bilateral fluid-filled cysts derived from the renal tubule epithelial cells. Although typically leading to end-stage renal disease in late middle age, ADPKD represents a continuum, from neonates with hugely enlarged cystic kidneys to cases with adequate kidney function into old age. Since the identification of the first causative gene (i.e., PKD1, encoding polycystin 1) 20 years ago, genetic studies have uncovered a large part of the key factors that underlie the phenotype variability. Here, we provide a comprehensive review of these significant advances as well as those related to disease pathogenesis models, including mutation analysis of PKD1 and PKD2 (encoding polycystin 2), current mutation detection rate, allelic heterogeneity, genotype and phenotype relationships (in terms of three different inheritance patterns: classical autosomal dominant inheritance, complex inheritance, and somatic and germline mosaicism), modifier genes, the role of second somatic mutation hit in renal cystogenesis, and findings from mouse models of polycystic kidney disease. Based upon a combined consideration of the current knowledge, we attempted to propose a unifying framework for explaining the phenotype variability in ADPKD. PMID:25263802

Cornec-Le Gall, Emilie; Audrézet, Marie-Pierre; Meur, Yannick Le; Chen, Jian-Min; Férec, Claude

2014-12-01

120

Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation.  

PubMed Central

Split hand/split foot (SHSF; also known as ectrodactyly) is a human developmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogenetically visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this location, and the locus has been designated SHFD1. In the present study, marker loci were localized to the SHFD1 critical region through the analysis of somatic cell hybrids derived from individuals with SHSF and cytogenetic abnormalities involving the 7q21-q22 region. Combined genetic and physical data suggest that the order of markers in the SHFD1 critical region is cen-D7S492-D7S527-(D7S479-D7S491)-SHFD1-++ +D7S554-D7S518-qter. Dinucleotide repeat polymorphisms at three of these loci were used to test for linkage of SHSF to this region in a large pedigree that demonstrates autosomal dominant SHSF. Evidence against linkage of the SHSF gene to 7q21-q22 was obtained in this pedigree. Therefore, combined molecular and genetic data provide evidence for locus heterogeneity in autosomal dominant SHSF. We propose the name SHSF2 for this second locus. Images Figure 1 Figure 3 PMID:7912888

Palmer, S. E.; Scherer, S. W.; Kukolich, M.; Wijsman, E. M.; Tsui, L. C.; Stephens, K.; Evans, J. P.

1994-01-01

121

Linkage of the late onset autosomal dominant familial spastic paraplegia (DFSPII) to chromosome 2p markers  

SciTech Connect

Pure familial spastic paraplegias (FSP) is a neurodegenerative disease characterized by spasticity of lower limbs. FSP in inherited as an autosomal dominant (DFSP) or an autosomal recessive (RFSP) trait. DFSP has been classified into early onset (DFSPI) and late onset (DFSPII) based on the mean age of onset in families. A locus for RFSP has been mapped to chromosome 8, while a locus for DFSPI has been mapped to chromosome 14q. Genetic locus heterogeneity was observed in both of these forms. The location of DFSPII locus (or loci) is unknown. We collected DNA samples from 81 individuals including 26 affecteds from three DFSPII families (9998, 840, 581). The mean age of onset of systems was 26.5, 42.5, and 35.2 years, respectively. We first tested 156 DNA markers distributed throughout the human 22 autosomes with family 9998 and positive lod scores were obtained with chromosome 2p markers D2S174 (Z({theta})=2.93 at {theta}=0.00), D2S146 (Z({theta})=1.03 at {theta}=0.00) and D2S177 (Z({theta})=1.04 at {theta}=0.00). Analysis of the 2 additional families confirmed the linkage with a peak lod score of Z({theta})=4.62 at {theta}=0.105 with D2S174. The multipoint linkage analysis using the map D2S175-10cM-D2S174-14cM-D2DS177 suggested that the DFSPII locus most likely maps between D2S174 and D2S177 with Z({theta})=6.11. There was no evidence in our data supporting genetic locus heterogeneity for the DFSPII.

Hentati, A.; Wasserman, B.; Siddique, T. [Northwestern Univ. Medical School, Chicago, IL (United States)] [and others

1994-09-01

122

Autosomal dominant familial spastic paraplegia; Linkage analysis and evidence for linkage to chromosome 2p  

SciTech Connect

Familial spastic paraplegia (FSP) is a degenerative disorder of the motor system characterized by progressive weakness and spasticity of the lower limbs. Little is known about the pathophysiology of this disorder. FSP can be inherited as an autosomal dominant (AD), autosomal recessive, or X-linked trait. We have undertaken linkage analysis for a group of 36 AD FSP families from which we have collected blood samples from 427 individuals, including 148 affected individuals. Typing of polymorphic markers has allowed us to exclude more than 50% of the genome. Recently, linkage for AD FSP to a locus on chromosome 14q was reported. Our AD FSP kindreds were tested for linkage to markers spanning the 20 cM region between D14S69 and D14S66; however, we were not able to establish linkage for any of our families to chromosome 14. Lod scores suggestive of linkage for some AD FSP kindreds have been obtained for markers on chromosome 2p. We have tested seven polymorphic markers spanning the region between D2S405 and D2S177. Our highest aggregate lod score, including all families tested, was obtained at the locus D2S352: 2.4 at 20 cM. Results from HOMOG analysis for linkage heterogeneity will be reported.

Figlewicz, D.A. [Univ. of Rochester, NY (United States); Dube, M.P.; Rouleau, G.A. [McGill Univ., Montreal (Canada)] [and others

1994-09-01

123

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

PubMed Central

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

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

124

An Aquaporin2 Water Channel Mutant Which Causes Autosomal Dominant Nephrogenic Diabetes Insipidus Is Retained in the Golgi Complex  

Microsoft Academic Search

Mutations in the aquaporin-2 ( AQP2 ) water channel gene cause autosomal recessive nephrogenic diabetes insipidus (NDI). Here we report the first patient with an autosomal dominant form of NDI, which is caused by a G866A transi- tion in the AQP2 gene of one allele, resulting in a E258K substitution in the C-tail of AQP2. To define the molecular cause

Sabine M. Mulders; Daniel G. Bichet; Johan P. L. Rijss; Erik-Jan Kamsteeg; Marie-Françoise Arthus; Michele Lonergan; Mary Fujiwara; Kenneth Morgan; Richtje Leijendekker; Peter van der Sluijs; Carel H. van Os; Peter M. T. Deen

125

Am. J. Hum. Genet. 70:10441048, 2002 A New Susceptibility Locus for Autosomal Dominant Pancreatic Cancer  

E-print Network

. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early cancer is relatively com- mon, very few dominant genetic or environmental risk factors have been of Human Genetics. All rights reserved. 0002-9297/2002/7004-0025$15.00 inherited pancreatic cancer

Kruglyak, Leonid

126

Recurrent Acute Pancreatitis and Cholangitis in a Patient with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder associated with multiple cyst formation in the different organs. Development of pancreatic cyst in ADPKD is often asymptomatic and is associated with no complication. A 38-year-old man with ADPKD was presented with six episodes of acute pancreatitis and two episodes of cholangitis in a period of 12 months. Various imaging studies revealed multiple renal, hepatic and pancreatic cysts, mild ectasia of pancreatic duct, dilation of biliary system and absence of biliary stone. He was managed with conservative treatment for each attack. ADPKD should be considered as a potential risk factor for recurrent acute and/or chronic pancreatitis and cholangitis. PMID:23543834

Yazdanpanah, Kambiz; Manouchehri, Navid; Hosseinzadeh, Elinaz; Emami, Mohammad Hassan; Karami, Mehdi; Sarrami, Amir Hossein

2013-01-01

127

Novel mutation in the ATL1 with autosomal dominant hereditary spastic paraplegia presented as dysautonomia.  

PubMed

SPG3A, which is the second most common type of autosomal dominant hereditary spastic paraplegia (HSP), is caused by mutations in the atlastin GTPase 1 gene, ATL1. We report a case of a patient who presented as dysautonomia and had a novel splicing mutation c.35-3C>T in exon 2 of the ATL1. Orthostatic intolerance, urinary symptoms, hyperreflexia in the biceps and knee jerk, and decreased proprioception in both limbs were observed on neurological examinations. We tested the autonomic function and performed genetic tests for the SPG4 and SPG3A forms of HSP. This case is a genetically confirmed HSP with a novel mutation in SPG3A, and extends the phenotype of SPG3A. PMID:24969372

Shin, Jung-Won; Jung, Keun-Hwa; Lee, Soon-Tae; Moon, Jangsup; Seong, Moon-Woo; Park, Sung Sup; Lee, Sang Kun; Chu, Kon

2014-10-01

128

Autosomal Dominant Cataract: Intrafamilial Phenotypic Variability, Interocular Asymmetry, and Variable Progression in Four Chilean Families  

PubMed Central

PURPOSE To document intrafamilial and interocular phenotypic variability of autosomal dominant cataract (ADC). DESIGN Prospective observational case series. METHODS We performed ophthalmologic examination in four Chilean ADC families. RESULTS The families exhibited variability with respect to morphology, location with the lens, color and density of cataracts among affected members. We documented asymmetry between eyes in the morphology, location within the lens, color and density of cataracts, and a variable rate of progression. CONCLUSIONS The cataracts in these families exhibit wide intrafamilial and interocular phenotypic variability, supporting the premise that the mutated genes are expressed differentially in individuals and between eyes; other genes or environmental factors may be the bases for this variability. Marked progression among some family members underscores the variable clinical course of a common mutation within a family. Like retinitis pigmentosa, classification of ADC will be most useful if based on the gene and specific mutation. PMID:16564818

Shafie, Suraiya M.; Barria von-Bischhoffshausen, Fernando R.; Bateman, J. Bronwyn

2006-01-01

129

Novel Single-Base Deletional Mutation in Major Intrinsic Protein (MIP) in Autosomal Dominant Cataract  

PubMed Central

PURPOSE To further elucidate the cataract phenotype, and identify the gene and mutation for autosomal dominant cataract (ADC) in an American family of European descent (ADC2) by sequencing the major intrinsic protein gene (MIP), a candidate based on linkage to chromosome 12q13. DESIGN Observational case series and laboratory experimental study. METHODS We examined two at-risk individuals in ADC2. We PCR-amplified and sequenced all four exons and all intron-exon boundaries of the MIP gene from genomic and cloned DNA in affected members to confirm one variant as the putative mutation. RESULTS We found a novel single deletion of nucleotide (nt) 3223 (within codon 235) in exon four, causing a frameshift that alters 41 of 45 subsequent amino acids and creates a premature stop codon. CONCLUSIONS We identified a novel single base pair deletion in the MIP gene and conclude that it is a pathogenic sequence alteration. PMID:16564824

Geyer, David D.; Spence, M. Anne; Johannes, Meriam; Flodman, Pamela; Clancy, Kevin P.; Berry, Rebecca; Sparkes, Robert S.; Jonsen, Matthew D.; Isenberg, Sherwin J.; Bateman, J. Bronwyn

2006-01-01

130

Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12  

SciTech Connect

Congenital cataracts constitute a morphologically and genetically heterogeneous group of diseases that are a major cause of childhood blindness. Different loci for hereditary congenital cataracts have been mapped to chromosomes 1, 2, 16, and 17q24. We report linkage of a gene causing a unique form of autosomal dominant zonular cataracts with Y-sutural opacities to chromosome 17q11-12 in a three-generation family exhibiting a maximum lod score of 3.9 at D17S805. Multipoint analysis gave a Mod confidence interval of 17 cM. This interval is bounded by the markers D17S799 and D17S798, a region that would encompass a number of candidate genes including that coding for {Beta}A3/A1-crystallin. 30 refs., 2 figs., 1 tab.

Padma, T.; Ayyagari, R.; Murty, J.S. [and others

1995-10-01

131

A stepwise approach for effective management of chronic pain in autosomal-dominant polycystic kidney disease.  

PubMed

Chronic pain, defined as pain existing for >4-6 weeks, affects >60% of patients with autosomal-dominant polycystic disease (ADPKD). It can have various causes, indirectly or directly related to the increase in kidney and liver volume in these patients. Chronic pain in ADPKD patients is often severe, impacting physical activity and social relationships, and frequently difficult to manage. This review provides an overview of pathophysiological mechanisms that can lead to pain and discusses the sensory innervation of the kidneys and the upper abdominal organs, including the liver. In addition, the results of a systematic literature search of ADPKD-specific treatment options are presented. Based on pathophysiological knowledge and evidence derived from the literature an argumentative stepwise approach for effective management of chronic pain in ADPKD is proposed. PMID:25165181

Casteleijn, Niek F; Visser, Folkert W; Drenth, Joost P H; Gevers, Tom J G; Groen, Gerbrand J; Hogan, Marie C; Gansevoort, Ron T

2014-09-01

132

Linkage disequilibrium in the region of the autosomal dominant polycystic kidney disease gene (PKD1)  

SciTech Connect

The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 and D16S125 (26.6 prox). This region is 750 kb long and has been cloned. The authors have looked at the association of 10 polymorphic markers from the region, with the disease and with each other. This was done in a set of Scottish families that had previously shown association with D16S94, a marker proximal to the PKD1 region. They report significant association between two CA repeat markers and the disease but have not found evidence for a single founder haplotype in these families, indicating the presence of several mutations in this population. Their results favor a location of the PKD1 gene in the proximal part of the candidate region. 25 refs., 1 fig., 4 tabs.

Snarey, A. (Imperial Cancer Research Fund, London (United Kingdom)); Thomas, S.; Harris, P.C. (Institute of Molecular Medicine, Oxford (United Kingdom)); Schneider, M.C. (Brigham and Women's Hospital, Boston, MA (United States)); Pound, S.E.; Wright, A.F. (Western General Hospital, Edinburgh (United Kingdom)); Barton, N.; Somlo, S.; Germino, G.G.; Reeders, S.T. (and others)

1994-08-01

133

Refined localisation of the second gene for autosomal dominant polycystic kidney disease  

SciTech Connect

The PKD1-gene responsible for autosomal dominant polycystic kidney disease in 85% of the families maps to chromosome 16q13. Last year the PKD2-gene was localized on chromosome 4q21-23 between the markers D4S231 and D4S231 and D4S423, an interval of about 8cM. In a collaborative effort to narrow down the PKD2-region, families with recombinants have been analyzed with several markers within the interval. First, an integrated map had to be constructed which contains previously published markers of different sources. To construct this map, cosmids and/or YACs isolated with the markers have been mapped by two-color FISH and were screened with the other markers. Affected recombinants localize the disease between D4S1534 and D4S1544.

Peters, D.J.M.; Saris, J.J.; Spruit, L. [Wassenaaseweg, Leiden (Netherlands)] [and others

1994-09-01

134

High-density renal cysts in autosomal dominant polycystic kidney disease demonstrated by CT  

SciTech Connect

Unenhanced abdominal CT scans of 35 patients with autosomal dominant polycystic kidney disease (ADPKD) showed multiple high-density (58-84 HU) renal cysts in 42.9% of patients, occasional high-density cysts in 25.7%, and no high-density cysts in 31.4%. These high-density cysts were usually subcapsular and were more frequent in patients with markedly enlarged kidneys and flank pain at the time of CT. Follow-up CT often showed a reduction in cyst densities, although some cysts developed mural calcification and calcification of their contents. Renal carcinomas occur rarely in ADPKD and may occasionally be hyperdense. However, high-density cysts may usually be distinguished from carcinomas on CT by their smooth contours, sharp interfaces with renal parenchyma, homogeneity, and lack of contrast enhancement.

Levine, E.; Grantham, J.J.

1985-02-01

135

Autosomal dominant zonular cataract with sutural opacities localized to chromosome 17q11-12.  

PubMed Central

Congenital cataracts constitute a morphologically and genetically heterogeneous group of diseases that are a major cause of childhood blindness. Different loci for hereditary congenital cataracts have been mapped to chromosomes 1, 2, 16, and 17q24. We report linkage of a gene causing a unique form of autosomal dominant zonular cataracts with Y-sutural opacities to chromosome 17q11-12 in a three-generation family exhibiting a maximum lod score of 3.9 at D17S805. Multipoint analysis gave a 1-lod confidence interval of 17 cM. This interval is bounded by the markers D17S799 and D17S798, a region that would encompass a number of candidate genes including that coding for beta A3/A1-crystallin. Images Figure 2 PMID:7573044

Padma, T; Ayyagari, R; Murty, J S; Basti, S; Fletcher, T; Rao, G N; Kaiser-Kupfer, M; Hejtmancik, J F

1995-01-01

136

A novel nonsense mutation in CRYBB1 associated with autosomal dominant congenital cataract  

PubMed Central

Purpose To identify the molecular defect underlying an autosomal dominant congenital nuclear cataract in a Chinese family. Methods Twenty-two members of a three-generation pedigree were recruited, clinical examinations were performed, and genomic DNA was extracted from peripheral blood leukocytes. All members were genotyped with polymorphic microsatellite markers adjacent to each of the known cataract-related genes. Linkage analysis was performed after genotyping. Candidate genes were screened for mutation using direct sequencing. Individuals were screened for presence of a mutation by restriction fragment length polymorphism (RFLP) analysis. Results Linkage analysis identified a maximum LOD score of 3.31 (recombination fraction [?]=0.0) with marker D22S1167 on chromosome 22, which flanks the ?-crystallin gene cluster (CRYBB3, CRYBB2, CRYBB1, and CRYBA4). Sequencing the coding regions and the flanking intronic sequences of these four candidate genes identified a novel, heterozygous C?T transition in exon 6 of CRYBB1 in the affected individuals of the family. This single nucleotide change introduced a novel BfaI site and was predicted to result in a nonsense mutation at codon 223 that changed a phylogenetically conserved amino acid to a stop codon (p.Q223X). RFLP analysis confirmed that this mutation co-segregated with the disease phenotype in all available family members and was not found in 100 normal unrelated individuals from the same ethnic background. Conclusions This study has identified a novel nonsense mutation in CRYBB1 (p.Q223X) associated with autosomal dominant congenital nuclear cataract. PMID:18432316

Yang, Juhua; Zhu, Yihua; Gu, Feng; He, Xiang; Cao, Zongfu; Li, Xuexi; Tong, Yi

2008-01-01

137

Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations.  

PubMed

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms. PMID:25260562

Böhm, Johann; Biancalana, Valérie; Malfatti, Edoardo; Dondaine, Nicolas; Koch, Catherine; Vasli, Nasim; Kress, Wolfram; Strittmatter, Matthias; Taratuto, Ana Lia; Gonorazky, Hernan; Laforêt, Pascal; Maisonobe, Thierry; Olivé, Montse; Gonzalez-Mera, Laura; Fardeau, Michel; Carrière, Nathalie; Clavelou, Pierre; Eymard, Bruno; Bitoun, Marc; Rendu, John; Fauré, Julien; Weis, Joachim; Mandel, Jean-Louis; Romero, Norma B; Laporte, Jocelyn

2014-12-01

138

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly is caused by a duplication in RUNX2.  

PubMed

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth. We performed genome-wide SNP genotyping in five affected and four unaffected members of an extended family with MDMHB. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2. Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function. Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease. PMID:23290074

Moffatt, Pierre; Ben Amor, Mouna; Glorieux, Francis H; Roschger, Paul; Klaushofer, Klaus; Schwartzentruber, Jeremy A; Paterson, Andrew D; Hu, Pingzhao; Marshall, Christian; Fahiminiya, Somayyeh; Majewski, Jacek; Beaulieu, Chandree L; Boycott, Kym M; Rauch, Frank

2013-02-01

139

Metaphyseal Dysplasia with Maxillary Hypoplasia and Brachydactyly Is Caused by a Duplication in RUNX2  

PubMed Central

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth. We performed genome-wide SNP genotyping in five affected and four unaffected members of an extended family with MDMHB. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2. Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function. Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease. PMID:23290074

Moffatt, Pierre; Ben Amor, Mouna; Glorieux, Francis H.; Roschger, Paul; Klaushofer, Klaus; Schwartzentruber, Jeremy A.; Paterson, Andrew D.; Hu, Pingzhao; Marshall, Christian; Fahiminiya, Somayyeh; Majewski, Jacek; Beaulieu, Chandree L.; Boycott, Kym M.; Rauch, Frank

2013-01-01

140

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

PubMed Central

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

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

2013-01-01

141

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

PubMed Central

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

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

2012-01-01

142

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

PubMed

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

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

143

Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease.  

PubMed

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-?1-42 (A?1-42) associated with the presence of A? plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials. PMID:24598588

Fagan, Anne M; Xiong, Chengjie; Jasielec, Mateusz S; Bateman, Randall J; Goate, Alison M; Benzinger, Tammie L S; Ghetti, Bernardino; Martins, Ralph N; Masters, Colin L; Mayeux, Richard; Ringman, John M; Rossor, Martin N; Salloway, Stephen; Schofield, Peter R; Sperling, Reisa A; Marcus, Daniel; Cairns, Nigel J; Buckles, Virginia D; Ladenson, Jack H; Morris, John C; Holtzman, David M

2014-03-01

144

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

PubMed Central

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

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

145

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy.  

PubMed

Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology. PMID:23509295

Logan, Sreemathi; Agbaga, Martin-Paul; Chan, Michael D; Kabir, Nabila; Mandal, Nawajes A; Brush, Richard S; Anderson, Robert E

2013-04-01

146

Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics  

PubMed Central

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds. PMID:21619691

2011-01-01

147

Expression and Cellular Localisation of Renal Endothelin1 and Endothelin Receptor Subtypes in Autosomal-Dominant Polycystic Kidney Disease  

Microsoft Academic Search

The major factors influencing the rate of progression of chronic renal disease in autosomal-dominant polycystic kidney disease (ADPKD) are unknown and there are currently no effective treatments for slowing the progression of chronic renal failure in ADPKD patients. As a first step in investigating the potential role of endothelin-1 (ET1) and its receptors (ETA and ETB) in the pathophysiology of

Albert C. M. Ong; Linda J. Newby; Michael R. Dashwood

2003-01-01

148

A novel PRPF31 splice-site mutation in a Chinese family with autosomal dominant retinitis pigmentosa  

Microsoft Academic Search

Purpose: The autosomal dominant form of retinitis pigmentosa (ADRP) can be caused by mutations in 13 genes and a further locus for which the gene remains to be identified. This study was intended to identify mutations in a large Chinese pedigree with ADRP. Methods: A genome scan was conducted in the family. The whole coding sequences and the intron-exon boundaries

Kun Xia; Duo Zheng; Qian Pan; Zheng Liu; Xinghua Xi; Zhengmao Hu; Hao Deng; Xiaoping Liu; Deyong Jiang; Hanxiang Deng; Jiahui Xia

149

ROLE AND LONG-TERM RESULTS OF LAPAROSCOPIC DECORTICATION IN SOLITARY CYSTIC AND AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE  

Microsoft Academic Search

PurposeAccess to retroperitoneal structures via the laparoscope has become established for various conditions. This minimally invasive approach has distinct advantages over conventional open surgery. We document our experience with laparoscopic cyst decortication for diseases of the kidney, including simple and complex cysts, multiple cysts and autosomal dominant polycystic kidney disease.

BARRY J. LIFSON; JOEL M. H. TEICHMAN; JOHN C. HULBERT

1998-01-01

150

Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease is characterized by clinical and genetic heterogeneity. Two loci implicated in the disease have previously been mapped (PKD1 on chromosome 16 and PKD2 on chromosome 4). By two point and multipoint linkage analysis, negative lod scores have been found for both chromosome 16 and chromosome 4 markers in a large Portuguese family, indicating that a

Salomé Almeida; Edgar Almeida; Dorien Peters; José Reimão Pinto; Isabel Távora; João Lavinha; Martjn Breuning; Mateus Martins Prata

1995-01-01

151

Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population  

Microsoft Academic Search

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) often develop hypertension before any abnormalities in renal function are detected clinically. Therefore, standard screening (serum creatinine and urinalysis) of young individuals with unexplained hypertension to exclude renal parenchymal disease would rarely detect ADPKD.Methods: Data from 516 subjects with ADPKD (217 male and 299 female), aged newbornto 55 years with a

Catherine L. Kelleher; Kim K. McFann; Ann M. Johnson; Robert W. Schrier

2004-01-01

152

Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease  

PubMed Central

The classic role of the Na-K-ATPase is that of a primary active transporter that utilizes cell energy to establish and maintain transmembrane Na+ and K+ gradients to preserve cell osmotic stability, support cell excitability, and drive secondary active transport. Recent studies have revealed that Na-K-ATPase located within cholesterol-containing lipid rafts serves as a receptor for cardiotonic steroids, including ouabain. Traditionally, ouabain was viewed as a toxin produced only in plants, and it was used in relatively high concentrations to experimentally block the pumping action of the Na-K-ATPase. However, the new and unexpected role of the Na-K-ATPase as a signal transducer revealed a novel facet for ouabain in the regulation of a myriad of cell functions, including cell proliferation, hypertrophy, apoptosis, mobility, and metabolism. The seminal discovery that ouabain is endogenously produced in mammals and circulates in plasma has fueled the interest in this endogenous molecule as a potentially important hormone in normal physiology and disease. In this article, we review the role of the Na-K-ATPase as an ion transporter in the kidney, the experimental evidence for ouabain as a circulating hormone, the function of the Na-K-ATPase as a signal transducer that mediates ouabain's effects, and novel results for ouabain-induced Na-K-ATPase signaling in cystogenesis of autosomal dominant polycystic kidney disease. PMID:23761677

Wallace, Darren P.

2013-01-01

153

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease  

PubMed Central

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide–dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-?, which is present in cyst fluid during cyst development. Double conditional knockouts of Pkd1 and Sirt1 demonstrated delayed renal cyst formation in postnatal mouse kidneys compared with mice with single conditional knockout of Pkd1. Furthermore, treatment with a pan-sirtuin inhibitor (nicotinamide) or a SIRT1-specific inhibitor (EX-527) delayed cyst growth in Pkd1 knockout mouse embryonic kidneys, Pkd1 conditional knockout postnatal kidneys, and Pkd1 hypomorphic kidneys. Increased SIRT1 expression in Pkd1 mutant renal epithelial cells regulated cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulated cystic epithelial cell death through deacetylation of p53. This newly identified role of SIRT1 signaling in cystic renal epithelial cells provides the opportunity to develop unique therapeutic strategies for ADPKD. PMID:23778143

Zhou, Xia; Fan, Lucy X.; Sweeney, William E.; Denu, John M.; Avner, Ellis D.; Li, Xiaogang

2013-01-01

154

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome.  

PubMed Central

Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3. Images PMID:9192261

Kang, S; Allen, J; Graham, J M; Grebe, T; Clericuzio, C; Patronas, N; Ondrey, F; Green, E; Schäffer, A; Abbott, M; Biesecker, L G

1997-01-01

155

Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer.  

PubMed

Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32-80 years). The estimated CRC relative risks for mutation carriers aged 60-69 and ?70 years were 19 (95% CI: 1.77-204.08) and 45 (95% CI: 11.32-180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5-99.9%), and for women, 84% (95% CI: 50.9-99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance. PMID:24549056

Ibrahim, Abdulla; Barnes, Daniel R; Dunlop, Jacqueline; Barrowdale, Daniel; Antoniou, Antonis C; Berg, Jonathan N

2014-11-01

156

Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy.  

PubMed

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterised by pyramidal, cerebellar, and autonomic disturbances. Duplication of the LMNB1 gene is the genetic cause of ADLD, yet the pathogenetic mechanism is not defined. In this study, we analysed cells and muscle tissue from three patients affected by ADLD, carrying an extra copy of the LMNB1 gene. Lamin B1 levels were dramatically increased in ADLD nuclei, both in skin fibroblasts and skeletal muscle fibres. Since lamin B1 is known to bind Oct-1, a transcription factor involved in the oxidative stress pathway, we investigated Oct-1 fate in ADLD. Oct-1 recruitment to the nuclear periphery was increased in ADLD cells, while nucleoplasmic localisation of the transcription factor under oxidative stress conditions was reduced. Importantly, lamin B1 degradation occurring in some, but not all ADLD cell lines, slowed down lamin B1 and Oct-1 accumulation. In skeletal muscle, focal disorganisation of sarcomeres was observed, while IIB-myosin heavy chain, an Oct-1 target gene, was under-expressed and rod-containing fibres were formed. These data show that a high degree of regulation of lamin B1 expression is implicated in the different clinical phenotypes observed in ADLD and show that altered Oct-1 nuclear localisation contributes to the disease phenotype. PMID:23261988

Columbaro, Marta; Mattioli, Elisabetta; Maraldi, Nadir M; Ortolani, Michela; Gasparini, Laura; D'Apice, Maria Rosaria; Postorivo, Diana; Nardone, Anna Maria; Avnet, Sofia; Cortelli, Pietro; Liguori, Rocco; Lattanzi, Giovanna

2013-03-01

157

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

PubMed Central

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

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

158

Percutaneous Treatment of Pyocystis in Patients with Autosomal Dominant Polycystic Kidney Disease  

SciTech Connect

The course of autosomal dominant polycystic kidney disease (ADPKD) is frequently complicated by infection of a cyst within a polycystic kidney, which is a diagnostic and therapeutic dilemma damaging the clinical course of patients. The aim of this study was to demonstrate the safety and efficacy of percutaneous drainage in management of infected cysts in ADPKD patients. Between May 2003 and December 2006, percutaneous drainage was performed in 16 infected renal cysts of four kidneys in three patients (two females, one male), with a mean age of 57.3 years. Cyst dimensions, total amount of drained cyst fluid, catheterization duration, isolated microorganisms, and follow-up duration were recorded. Technical, clinical success rates were 100%; the complication rate was 0%. Diameters of cysts ranged between 3 and 8 cm. Average volume of drained fluid and average duration of catheterization for one cyst were 226 ml and 9.8 days. No recurrence was encountered but one patient (no. 3), who had pyocystis in the right kidney and was treated with catheterization, referred with left flank pain due to pyocystis in her left kidney 3 months later. Follow-up durations were 35, 47, and 11 months for patients 1, 2, and 3, respectively. For patient 3, follow-up duration for the second procedure was 7 months. We conclude that percutaneous drainage with antibiotic therapy should be the initial method in management of infected cysts in ADPKD patients, with high success and low complication rates.

Akinci, Devrim, E-mail: akincid@yahoo.com; Turkbey, Baris, E-mail: bturkbey@yahoo.co [Hacettepe University School of Medicine, Department of Radiology (Turkey); Yilmaz, Rahmi [Hacettepe University School of Medicine, Department of Nephrology (Turkey); Akpinar, Erhan; Ozmen, Mustafa N.; Akhan, Okan [Hacettepe University School of Medicine, Department of Radiology (Turkey)

2008-09-15

159

A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families.  

PubMed

Proximal symphalangism (SYM1) is an autosomal dominant disorder characterized by ankylosis of the proximal interphalangeal joints and fusion of carpal and tarsal bones. We identified and characterized two five-generation Chinese families with SYM1. The two families share some similarities (e.g., osseous fusion of interphalangeal joints of the 2-4 fingers) with SYM1 families with mutations in the NOG gene or the family with mutation R438L recently reported in the GDF5 gene (encoding a bone morphogenetic protein family member). However, they show some unique features including the absence of cuboid bone, the lack of shortness of the first and fifth metacarpal bones, and manifestation of flat feet. Genome-wide linkage analysis of the two families mapped the disease gene to marker D20S112 with a combined LOD score of 4.32. Mutational analysis revealed a novel E491K mutation in the GDF5 gene in both families. The mutation occurs at a highly conserved residue in the TGF-beta domain of GDF5 and represents the second GDF5 mutation identified for SYM1 to date. The E491K mutation co-segregated with the affected individuals in the two families, and did not exist in unaffected family members or 200 normal controls. These results indicate that defects in GDF5 can cause SYM1 in the Chinese population, and expand the spectrum of clinical phenotypes associated with mutant GDF5. PMID:16892395

Wang, Xu; Xiao, Fuying; Yang, Qinbo; Liang, Bo; Tang, Zhaohui; Jiang, Linbin; Zhu, Qihui; Chang, Wei; Jiang, Jiuxi; Jiang, Chuanming; Ren, Xiang; Liu, Jing-Yu; Wang, Qing K; Liu, Mugen

2006-09-01

160

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

PubMed

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

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

161

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

PubMed

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

Mekahli, Djalila; Bacchetta, Justine

2013-11-01

162

Twenty patients including 7 probands with autosomal dominant cutis laxa confirm clinical and molecular homogeneity  

PubMed Central

Background Elastin gene mutations have been associated with a variety of phenotypes. Autosomal dominant cutis laxa (ADCL) is a rare disorder that presents with lax skin, typical facial characteristics, inguinal hernias, aortic root dilatation and pulmonary emphysema. In most patients, frameshift mutations are found in the 3’ region of the elastin gene (exons 30-34) which result in a C-terminally extended protein, though exceptions have been reported. Methods We clinically and molecularly characterized the thus far largest cohort of ADCL patients, consisting of 19 patients from six families and one sporadic patient. Results Molecular analysis showed C-terminal frameshift mutations in exon 30, 32, and 34 of the elastin gene and identified a mutational hotspot in exon 32 (c.2262delA). This cohort confirms the previously reported clinical constellation of skin laxity (100%), inguinal hernias (51%), aortic root dilatation (55%) and emphysema (37%). Conclusion ADCL is a clinically and molecularly homogeneous disorder, but intra- and interfamilial variability in the severity of organ involvement needs to be taken into account. Regular cardiovascular and pulmonary evaluations are imperative in the clinical follow-up of these patients. PMID:23442826

2013-01-01

163

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

PubMed Central

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

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

2012-01-01

164

Arterial dysfunction in early autosomal dominant polycystic kidney disease independent of fibroblast growth factor 23.  

PubMed

Introduction. Recent studies report reduced vascular compliance and elevated levels of fibroblast growth factor 23 (FGF23) in patients with autosomal dominant polycystic kidney disease (ADPKD) and preserved kidney function. In the present study, we investigated the relationship between vascular compliance and FGF23 in patients in early phases of ADPKD. Materials and Methods. We studied 54 ADPKD patients with preserved kidney function and 24 healthy individuals. All participants underwent noninvasive pulse wave analysis in order to determine large arterial elasticity index (LAEI) and small arterial elasticity index (SAEI) using a modi?ed Windkessel model. Levels of FGF23 in addition to several cardiovascular risk factors were evaluated. Linear regression analyses were performed to determine independent correlates of LAEI, SAEI, and FGF23. Results. In the ADPKD group, 33 patients were hypertensive and the remaining patients were normotensive. Serum FGF23 levels of both ADPKD groups were significantly higher than that in the controls. Both hypertensive and normotensive ADPKD patients had lower LAEI and SAEI levels compared to the controls. There was no significant correlation between vascular compliance parameters and FGF23 levels. Having ADPKD was independently associated with increased FGF23 levels and decreased SAEI. Conclusions. Fibroblast growth factor 23 was found substantially elevated and arterial compliance was found significantly decreased in early ADPKD patients regardless of hypertension. However, there was no significant correlation between FGF23 levels and arterial function parameters. Additional studies are required to determine possible mechanisms of these disturbances and cardiovascular effects of FGF23 in ADPKD patients. PMID:25362218

Yildiz, Abdulmecit; Gul, Cuma; Ersoy, Alparslan; Asiltas, Burak; Ermurat, Selime; Dogan, Selda; Karaagac, Kemal; Sag, Saim; Oruc, Aysegul; Aktas, Nimet; Ocakoglu, Gokhan; Dogan, Ibrahim; Gullulu, Sumeyye; Gullulu, Mustafa

2014-11-01

165

A Novel Missense SNRNP200 Mutation Associated with Autosomal Dominant Retinitis Pigmentosa in a Chinese Family  

PubMed Central

The SNRNP200 gene encodes hBrr2, a helicase essential for pre-mRNA splicing. Six mutations in SNRNP200 have recently been discovered to be associated with autosomal dominant retinitis pigmentosa (adRP). In this work, we analyzed a Chinese family with adRP and identified a novel missense mutation in SNRNP200. To identify the genetic defect in this family, exome of the proband was captured and sequencing analysis was performed to exclude known genetic defects and find possible pathogenic mutations. Subsequently, candidate mutations were validated in affected family members using Sanger sequencing. A novel missense mutation, c.2653C>G transition (p.Q885E), in exon 20 of SNRNP200 was identified. The mutation co-segregated with the disease phenotype over four generations and was absent in 100 normal unaffected individuals. This mutation occurs at highly conserved position in hBrr2 and is predicted to have a functional impact, suggesting that hBrr2-dependent small nuclear riboproteins (snRNPs) unwinding and spliceosome activation is important in the pathogenesis of some variants of RP. PMID:23029027

Yuan, Huijun; Cheng, Jing; Lee, Janet; Zhang, Baoquan; Zhang, Maonian; Wu, Jing; Wang, Lijuan; Tian, Geng; Wang, Weifeng

2012-01-01

166

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

PubMed

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 splicing is affected by mutations in PRPF31. Using an immunoprecipitation-coupled-microarray method, we identified a number of transcripts associated with PRPF31-containing complexes, including peripherin/RDS, FSCN2 and other photoreceptor-expressed genes. We constructed minigenes to study the effects of PRPF31 mutations on the pre-mRNA splicing of these photoreceptor specific genes. Our experiments demonstrated that mutant PRPF31 significantly inhibited pre-mRNA splicing of RDS and FSCN2. These observations suggest a functional link between ubiquitously expressed and retina-specifically expressed adRP genes. Our results indicate that PRPF31 mutations lead to defective pre-mRNA splicing of photoreceptor-specific genes and that the ubiquitously expressed adRP gene, PRPF31, is critical for pre-mRNA splicing of a subset of photoreceptor genes. Our results provide an explanation for the photoreceptor-specific phenotype of PRPF31 mutations. PMID:17350276

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

2007-05-01

167

Genotyping microarray: Mutation screening in Spanish families with autosomal dominant retinitis pigmentosa  

PubMed Central

Purpose Presently, 22 genes have been described in association with autosomal dominant retinitis pigmentosa (adRP); however, they explain only 50% of all cases, making genetic diagnosis of this disease difficult and costly. The aim of this study was to evaluate a specific genotyping microarray for its application to the molecular diagnosis of adRP in Spanish patients. Methods We analyzed 139 unrelated Spanish families with adRP. Samples were studied by using a genotyping microarray (adRP). All mutations found were further confirmed with automatic sequencing. Rhodopsin (RHO) sequencing was performed in all negative samples for the genotyping microarray. Results The adRP genotyping microarray detected the mutation associated with the disease in 20 of the 139 families with adRP. As in other populations, RHO was found to be the most frequently mutated gene in these families (7.9% of the microarray genotyped families). The rate of false positives (microarray results not confirmed with sequencing) and false negatives (mutations in RHO detected with sequencing but not with the genotyping microarray) were established, and high levels of analytical sensitivity (95%) and specificity (100%) were found. Diagnostic accuracy was 15.1%. Conclusions The adRP genotyping microarray is a quick, cost-efficient first step in the molecular diagnosis of Spanish patients with adRP. PMID:22736939

Garcia-Hoyos, Maria; Corton, Marta; Avila-Fernandez, Almudena; Riveiro-Alvarez, Rosa; Gimenez, Ascension; Hernan, Inma; Carballo, Miguel; Ayuso, Carmen

2012-01-01

168

Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease.  

PubMed

The classic role of the Na-K-ATPase is that of a primary active transporter that utilizes cell energy to establish and maintain transmembrane Na(+) and K(+) gradients to preserve cell osmotic stability, support cell excitability, and drive secondary active transport. Recent studies have revealed that Na-K-ATPase located within cholesterol-containing lipid rafts serves as a receptor for cardiotonic steroids, including ouabain. Traditionally, ouabain was viewed as a toxin produced only in plants, and it was used in relatively high concentrations to experimentally block the pumping action of the Na-K-ATPase. However, the new and unexpected role of the Na-K-ATPase as a signal transducer revealed a novel facet for ouabain in the regulation of a myriad of cell functions, including cell proliferation, hypertrophy, apoptosis, mobility, and metabolism. The seminal discovery that ouabain is endogenously produced in mammals and circulates in plasma has fueled the interest in this endogenous molecule as a potentially important hormone in normal physiology and disease. In this article, we review the role of the Na-K-ATPase as an ion transporter in the kidney, the experimental evidence for ouabain as a circulating hormone, the function of the Na-K-ATPase as a signal transducer that mediates ouabain's effects, and novel results for ouabain-induced Na-K-ATPase signaling in cystogenesis of autosomal dominant polycystic kidney disease. PMID:23761677

Blanco, Gustavo; Wallace, Darren P

2013-09-15

169

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

PubMed Central

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

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

2009-01-01

170

A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q  

PubMed Central

Here we report recruitment of a three-generation Romani (Gypsy) family with autosomal dominant cone-rod dystrophy (adCORD). Involvement of known adCORD genes was excluded by microsatellite (STR) genotyping and linkage analysis. Subsequently, two independent total-genome scans using STR markers and single-nucleotide polymorphisms (SNPs) were performed. Haplotype analysis revealed a single 6.7-Mb novel locus between markers D10S1757 and D10S1782 linked to the disease phenotype on chromosome 10q26. Linkage analysis gave a maximum LOD score of 3.31 for five fully informative STR markers within the linked interval corresponding to the expected maximum in the family. Multipoint linkage analysis of SNP genotypes yielded a maximum parametric linkage score of 2.71 with markers located in the same chromosomal interval. There is no previously mapped CORD locus in this interval, and therefore the data reported here is novel and likely to identify a new gene that may eventually contribute to new knowledge on the pathogenesis of this condition. Sequencing of several candidate genes within the mapped interval led to negative findings in terms of the underlying molecular pathogenesis of the disease in the family. Analysis by comparative genomic hybridization excluded large chromosomal aberrations as causative of adCORD in the pedigree. PMID:22929024

Kamenarova, Kunka; Cherninkova, Sylvia; Romero Duran, Margarita; Prescott, DeQuincy; Valdes Sanchez, Maria Lourdes; Mitev, Vanio; Kremensky, Ivo; Kaneva, Radka; Bhattacharya, Shomi S; Tournev, Ivailo; Chakarova, Christina

2013-01-01

171

A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q.  

PubMed

Here we report recruitment of a three-generation Romani (Gypsy) family with autosomal dominant cone-rod dystrophy (adCORD). Involvement of known adCORD genes was excluded by microsatellite (STR) genotyping and linkage analysis. Subsequently, two independent total-genome scans using STR markers and single-nucleotide polymorphisms (SNPs) were performed. Haplotype analysis revealed a single 6.7-Mb novel locus between markers D10S1757 and D10S1782 linked to the disease phenotype on chromosome 10q26. Linkage analysis gave a maximum LOD score of 3.31 for five fully informative STR markers within the linked interval corresponding to the expected maximum in the family. Multipoint linkage analysis of SNP genotypes yielded a maximum parametric linkage score of 2.71 with markers located in the same chromosomal interval. There is no previously mapped CORD locus in this interval, and therefore the data reported here is novel and likely to identify a new gene that may eventually contribute to new knowledge on the pathogenesis of this condition. Sequencing of several candidate genes within the mapped interval led to negative findings in terms of the underlying molecular pathogenesis of the disease in the family. Analysis by comparative genomic hybridization excluded large chromosomal aberrations as causative of adCORD in the pedigree. PMID:22929024

Kamenarova, Kunka; Cherninkova, Sylvia; Romero Durán, Margarita; Prescott, DeQuincy; Valdés Sánchez, Maria Lourdes; Mitev, Vanio; Kremensky, Ivo; Kaneva, Radka; Bhattacharya, Shomi S; Tournev, Ivailo; Chakarova, Christina

2013-03-01

172

Pathogenesis of Autosomal Dominant Hereditary Spastic Paraplegia (SPG6) Revealed by a Rat Model  

PubMed Central

Abstract Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1G106R) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1G106R mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1G106R Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms. PMID:24128679

Watanabe, Fumihiro; Arnold, William D.; Hammer, Robert E.; Ghodsizadeh, Odelia; Moti, Harmeet; Schumer, Mackenzie; Hashmi, Ahmed; Hernandez, Anthony; Sneh, Amita; Sahenk, Zarife

2013-01-01

173

Cellular Activation Triggered by the Autosomal Dominant Polycystic Kidney Disease Gene Product PKD2  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) ?, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N?,N?-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC ? and PKC ?, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts. PMID:10207066

Arnould, Thierry; Sellin, Lorenz; Benzing, Thomas; Tsiokas, Leonidas; Cohen, Herbert T.; Kim, Emily; Walz, Gerd

1999-01-01

174

Liver cysts in autosomal-dominant polycystic kidney disease: clinical and computed tomographic study  

SciTech Connect

Hepatic CT findings were analyzed in 44 patients with autosomal-dominant polycystic kidney disease and were correlated with liver and renal function tests and liver, splenic, and renal CT volume measurements. CT showed many large liver cysts in 31.8% of patients, small liver cysts in 25%, and no liver cysts in 43.2%. Patients with many large cysts often showed increased liver volumes. There was no correlation between severity of liver involvement and extent of renal cystic disease as determined from urea nitrogen and creatinine levels and renal volumes. Liver function tests were normal except in two patients, one with a cholangiocarcinoma, which may have arisen from a cyst, and the other with an infected liver cyst and chronic active hepatitis. Accordingly, if liver function tests are abnormal, an attempt should be made to identify complications of polycystic liver disease such as tumor cyst infection, and biliary obstruction. CT is a useful method for detecting liver cysts and identifying patients at risk for these complications.

Levine, E.; Cook, L.T.; Grantham, J.J.

1985-08-01

175

Identification of the autosomal dominant polycystic kidney disease gene, PKD1  

SciTech Connect

The PKDl gene was localized to an {approximately}480 kb interval of chromosome 16pl3. More than 20 independent transcripts were found in the interval. In view of the high new mutation rate in autosomal dominant polycystic kidney diseases (ADPKD), we anticipated the PKD1 gene would be large. The largest transcript in the region was represented by five cDNA clones located adjacent to the tuberin gene (TSC2). Two of these clones, KG8 and NKG9, contain {approximately}4.5 kb of contiguous sequence corresponding to the 3{prime} end of the 14 kb mRNA which is transcribed from telomeric to centromeric. They spans 11 exons, and to evaluate the reading frame of the cDNA, we have compared the human and monkey sequence using human primers, and found 90-94% identity at the DNA level, and by observing amino acid conservation, determined the reading frame. To date, our open-reading frame of {approximately}800 amino-acids contained only a potential threonine kinase site, but no other recognizable peptide motifs or repeats, and was not homologous to sequences in Swissprot and GenBank. No Southern blot abnormalities have been detected with the cDNA probes used. However, an exon-by-exon scan of 8 exons for mutations by SSCP and genomic sequencing (predicted missense changes) has identified 3 patients with mutations not found in normals, and identify the KG8 gene as the PKD1 gene.

Schneider, M.C.; Zhang, F.; Geng, L. [Harvard Medical School, Boston, MA (United States)] [and others

1994-09-01

176

Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats.  

PubMed

A form of autosomal dominant polycystic kidney disease (ADPKD) similar in clinical features to human ADPKD occurs in the Persian cat. We characterized the morphologic and immunohistochemical features of this disease in a colony of affected cats. Complete postmortem examinations were performed on 11 normal and 22 affected cats ranging in age from 3 months to 10 years. Kidneys were evaluated by gross and histologic examinations, ultrastructure, lectin staining, bromodeoxyuridine immunochemistry for labeling index and immunochemistry for distribution of Na/K ATPase. Feline ADPKD was characterized by variable numbers of cysts in the renal cortex and medullar. Ultrastructural examination and lectin staining suggested that cysts arose from proximal and distal nephron segments. Bromodeoxyuridine labeling demonstrated increased proliferation of epithelium lining some cysts in young cats. Immunohistochemical staining showed variable translocation of Na/K ATPase from the basolateral membranes of cyst-lining cells to the cytoplasm or luminal membranes. Cystic renal disease commonly was associated with chronic tubulointerstitial nephritis and hepatobiliary hyperplasia and fibrosis. Focal hyperplasia of renal tubular epithelium, hepatic cysts, and cardiac lesions were present in some cats. Feline ADPKD shares many morphologic and pathogenetic features with human ADPKD. PMID:9066078

Eaton, K A; Biller, D S; DiBartola, S P; Radin, M J; Wellman, M L

1997-03-01

177

Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore.  

PubMed

We report the prevalence and ethnic differences of autosomal-dominant cerebellar ataxia (ADCA) in Singapore. Amongst 204 patients with ataxia who underwent genetic testing for dentatorubral-pallidoluysian atrophy (DRPLA) and for spinocerebellar ataxias (SCA) 1, 2, 3, 6, 7, 8, 10 and 12, 58 (28.4%) patients from 36 families tested positive. SCA 3 was identified in 31 (53.4%) patients from 15 families, SCA 2 in 17 (29.3%) patients from 12 families and SCA 1 in four (6.9%) patients from four families. Other SCA subtypes were rare. SCA 2 was the only subtype identified amongst ethnic Malay and ethnic Indian families. The estimated prevalence of ADCA in Singaporean families was at least 1 : 27,000. Based on the history and ancestry of Singaporeans, our study supported a founder effect for specific SCA subtypes and the association of ethnicity-specific SCA subtypes. Our findings suggest that SCA 2 is relatively common amongst the Malay race and that priority testing for SCA 3 and SCA 2 for ethnic Chinese, and SCA 2 for ethnic Malay, may be cost effective and relevant for the region. PMID:12485197

Zhao, Y; Tan, E K; Law, H Y; Yoon, C S; Wong, M C; Ng, I

2002-12-01

178

Spanish guidelines for the management of autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on renal replacement therapy (RRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a consensus statement presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence found were C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and RRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are not provided since no drug has regulatory approval for this indication. PMID:25165191

Ars, Elisabet; Bernis, Carmen; Fraga, Gloria; Martínez, Víctor; Martins, Judith; Ortiz, Alberto; Rodríguez-Pérez, José Carlos; Sans, Laia; Torra, Roser

2014-09-01

179

Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease  

PubMed Central

Importance Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile. Design, Setting, and Participants We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites. Main Outcomes and Measures For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs. Results Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers. Conclusions and Relevance rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process. PMID:25069482

Thomas, Jewell B; Brier, Matthew R; Bateman, Randall J; Snyder, Abraham Z; Benzinger, Tammie L; Xiong, Chengjie; Raichle, Marcus; Holtzman, David M; Sperling, Reisa A; Mayeux, Richard; Ghetti, Bernardino; Ringman, John M; Salloway, Stephen; McDade, Eric; Rossor, Martin N; Ourselin, Sebastien; Schofield, Peter R; Masters, Colin L; Martins, Ralph N; Weiner, Michael W; Thompson, Paul M; Fox, Nick C; Koeppe, Robert A; Jack, Clifford R; Mathis, Chester A; Oliver, Angela; Blazey, Tyler M; Moulder, Krista; Buckles, Virginia; Hornbeck, Russ; Chhatwal, Jasmeer; Schultz, Aaron P; Goate, Alison M; Fagan, Anne M; Cairns, Nigel J; Marcus, Daniel S; Morris, John C; Ances, Beau M

2014-01-01

180

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

PubMed

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

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

2014-03-01

181

A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer We report the characterization of a four-generation large Chinese family with ADOA. Black-Right-Pointing-Pointer We find a new heterozygous mutation c.C1198G in OPA1 gene which may be a novel pathogenic mutation in this pedigree. Black-Right-Pointing-Pointer We do not find any mitochondrial DNA mutations associated with optic atrophy. Black-Right-Pointing-Pointer Other factors may also contribute to the phenotypic variability of ADOA in this pedigree. -- Abstract: A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressive visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9 years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree.

Zhang, Juanjuan; Yuan, Yimin; Lin, Bing; Feng, Hao; Li, Yan [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China)] [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Dai, Xianning; Zhou, Huihui [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China)] [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Dong, Xujie [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China)] [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Liu, Xiao-Ling, E-mail: lxl@mail.eye.ac.cn [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China)] [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Guan, Min-Xin, E-mail: min-xin.guan@cchmc.org [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China) [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang 310012 (China); Division of Human Genetics, Cincinnati Children's Hospital Medical Center, OH 45229 (United States)

2012-03-23

182

Prevalence and novelty of PRPF31 mutations in French autosomal dominant rod-cone dystrophy patients and a review of published reports  

Microsoft Academic Search

BACKGROUND: Rod-cone dystrophies are heterogeneous group of inherited retinal disorders both clinically and genetically characterized by photoreceptor degeneration. The mode of inheritance can be autosomal dominant, autosomal recessive or X-linked. The purpose of this study was to identify mutations in one of the genes, PRPF31, in French patients with autosomal dominant RP, to perform genotype-phenotype correlations of those patients, to

Isabelle Audo; Kinga Bujakowska; Saddek Mohand-Saïd; Marie-Elise Lancelot; Veselina Moskova-Doumanova; Naushin H Waseem; Aline Antonio; José-Alain Sahel; Shomi S Bhattacharya; Christina Zeitz

2010-01-01

183

The influence of renal manifestations to the progression of autosomal dominant polycystic kidney disease  

PubMed Central

Background: Renal stones, urinary tract infections (UTI) and gross hematuria (GH) are the most important renal manifestations of autosomal dominant polycystic kidney disease (ADPKD). They are not only common, but are also frequent cause of morbidity, influencing renal dysfunction. The aim of this study was to evaluate the frequency of these manifestations in our patients with ADPKD and their impact on renal function. Methods: One hundred eighty ADPKD patients were included in the study. Subjects were studied for the presence of UTI, gross hematuria frequency and responsible factors of nephrolithiasis. Survival times were calculated as the time to renal replacement therapy or time of serum creatinine value up to 10 mg/dl. Kaplan-Meier product-limit survival curves were constructed, and log rank test was used to compare the survival curves. Results: Kidney stones were present in 76/180 (42% of pts). The stones were composed of urate (47%) calcium oxalate (39%), and other compounds 14%. UTI was observed in 60% (108 patients). Patients treated with urinary disinfectants had a significant lower frequency of urinary infection (p<0.001) and hematuria (p<0.001) after one year than untreated patients. Gross hematuria was present in 113 patients (63%). In 43 patients hematuria was diagnosed before age 30 (38%), while in 70 patients it was diagnosed after age 30 (62%). Conclusions: UTI is frequent in our ADPKD patients. The correct treatment of UTI decreases its frequency and has beneficial role in the rate of progression to renal failure in ADPKD patients. Patients with recurrent episodes of gross hematuria may be at risk for more severe renal disease. PMID:19918304

Idrizi, A; Barbullushi, M; Petrela, E; Kodra, S; Koroshi, A; Thereska, N

2009-01-01

184

Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene  

PubMed Central

Background Autosomal dominant (AD) central core disease (CCD) is a congenital myopathy characterised by the presence of cores in the muscle fibres which correspond to broad areas of myofibrils disorganisation, Z-line streaming and lack of mitochondria. Heterozygous mutations in the RYR1 gene were observed in the large majority of AD-CCD families; however, this gene was excluded in some of AD-CCD families. Objective To enlarge the genetic spectrum of AD-CCD demonstrating mutations in an additional gene. Patients and methods Four affected AD family members over three generations, three of whom were alive and participate in the study: the mother and two of three siblings. The symptoms began during the early childhood with mild delayed motor development. Later they developed mainly tibialis anterior weakness, hypertrophy of calves and significant weakness (amyotrophic) of quadriceps. No cardiac or ocular involvement was noted. Results The muscle biopsies sections showed a particular pattern: eccentric cores in type 1 fibres, associated with type 1 predominance. Most cores have abrupt borders. Electron microscopy confirmed the presence of both unstructured and structured cores. Exome sequencing analysis identified a novel heterozygous missense mutation p.Leu1723Pro in MYH7 segregating with the disease and affecting a conserved residue in the myosin tail domain. Conclusions We describe MYH7 as an additional causative gene for AD-CCD. These findings have important implications for diagnosis and future investigations of AD-congenital myopathies with cores, without cardiomyopathy, but presenting a particular involvement of distal and quadriceps muscles. PMID:24828896

Romero, Norma B; Xie, Ting; Malfatti, Edoardo; Schaeffer, Ursula; Bohm, Johann; Wu, Bin; Xu, Fengping; Boucebci, Samy; Mathis, Stephane; Neau, Jean-Philippe; Monnier, Nicole; Fardeau, Michel; Laporte, Jocelyn

2014-01-01

185

Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred.  

PubMed

Several reports exist of the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and Marfan syndrome, including a report of ADPKD and "overlap" connective tissue disorder in a family with linkage to the PKD1 locus. We report the results of clinical and linkage investigations of an ADPKD family in whom several affected subjects also had aortic vascular complications as well as features of Marfan syndrome. Detailed clinical assessment and linkage analysis were performed with polymorphic microsatellite markers closely linked to the PKD1 and FBN1 loci. Survival data were compared with 10 geographically matched PKD1 families. Although several subjects had features of both ADPKD and Marfan syndrome, detailed clinical examination of the extended family indicated that the two conditions had converged within the kindred. For those with ADPKD, linkage was established to the PKD1 locus (lod score, 6.04). Among those with features of Marfan syndrome, linkage was confirmed to the FBN1 locus (lod score, 1.87). Five of six subjects with both ADPKD and the high-risk FBN1 haplotype had associated vascular complications. In contrast, among the remaining nine individuals with PKD1 alone, seven had aortic assessments, and none were found to have aortic complications. Our experience suggests that when prominent features of connective tissue disease or vascular complications are found in ADPKD patients, alternative additional diagnoses should be considered, including the possibility of a coinherited FBN1 mutation responsible for Marfan syndrome or, alternatively, an associated milder FBN1 phenotype in the absence of sufficient other clinical features to allow Marfan syndrome to be diagnosed. PMID:10739800

Hateboer, N; Buchalter, M; Davies, S J; Lazarou, L P; Ravine, D

2000-04-01

186

Novel PRPF31 mutations associated with Chinese autosomal dominant retinitis pigmentosa patients  

PubMed Central

Purpose To identify the mutations in the pre-mRNA processing factor 31 homolog (PRPF31) gene in Chinese families with autosomal dominant retinitis pigmentosa (adRP) and to characterize the clinical features of those patients who were found to have mutations in the PRPF31 gene. Methods Detailed ocular examinations were performed, and genomic DNA was isolated by standard methods for genetic diagnosis. Probands from each family were screened for mutations in the PRPF31 gene that was known to cause adRP. Cosegregation analysis was performed in the available family members. Linkage analysis was performed for one missense mutation to calculate the likelihood of its pathogenicity. Two hundred unrelated, healthy Chinese subjects were screened to exclude nonpathogenic polymorphisms. Results Forty Chinese families with adRP were selected by an analysis of pedigrees. We identified four mutations (c.196_197delAA, c.544_618del75bp, c.615delC, and c.895T>C) in total, and three deletions were novel. Cosegregation analysis of the available family members (20 patients and 17 unaffected family members) revealed that each index patient and all affected family members showed a heterozygous mutation in the PRPF31 gene. In two families, incomplete penetrance was observed. Linkage analysis achieved the maximum LOD score of c.895T>C is 2.09, achieved at ?=0. The four probands with PRPF31 mutations showed classical signs of RP, with relatively preserved central vision and severe visual field constriction. Conclusions Our studies extended the mutation spectrum of PRPF31, and mutations in PRPF31 were found at a relatively high frequency (10%, 4 of 40 adRP families) in our cohort. PMID:23288994

Xu, Fei; Sui, Ruifang; Liang, Xiaofang; Li, Hui; Jiang, Ruxin

2012-01-01

187

The Genetics of Vascular Complications in Autosomal Dominant Polycystic Kidney Disease (ADPKD)  

PubMed Central

The most important extra-renal manifestation of autosomal dominant polycystic kidney disease (ADPKD) in terms of debilitating injury and premature death is the development of intracranial aneurysms (IAs) and other vascular complications, resulting in subarachnoid hemorrhage (SAH). IAs are found at a rate approximately five times higher in ADPKD patients than in the general population and in patients with a family history of SAH/IAs the frequency is elevated further three to five times, indicating the importance of genetic factors in its etiology. Expression of the ADPKD gene products, polycystin-1 (PKD1) and polycystin-2 (PKD2), in vascular smooth muscle and the endothelium, and evidence that reduced levels of these proteins leads to IA development in mouse models, suggests a direct role of these proteins in the vascular disease. PKD1 and PKD2 patients seem equally likely to develop IAs, while patients with mutations to the 5’ half of PKD1 may more likely have vascular complications. Genome wide association and candidate studies of multiplex families with IAs without ADPKD have identified a number of genes/proteins that may be risk factors for the development of IAs. These candidate proteins largely have roles in the maintenance and remodeling of the arterial wall of small brain arteries. The development of the genetic methodologies of massively parallel sequencing mean it is now possible to test these and other candidates in ADPKD families with multiplex and singleton IA cases. Identifying strong modifiers of this phenotype will be important for prioritizing patients for presymptomatic screening and interventions. PMID:23971643

Rossetti, Sandro; Harris, Peter C.

2014-01-01

188

Berberine slows cell growth in autosomal dominant polycystic kidney disease cells  

SciTech Connect

Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 ?g/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 ?g/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G{sub 0}/G{sub 1} phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new opportunities for the therapy of ADPKD patients.

Bonon, Anna; Mangolini, Alessandra [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)] [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Pinton, Paolo [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy)] [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy); Senno, Laura del [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)] [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Aguiari, Gianluca, E-mail: dsn@unife.it [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)] [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)

2013-11-22

189

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

Microsoft Academic Search

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

B. Mueller; U. Orth; C. Duvigneau; E. Schwinger; A. Gal; C. Fuhrmann; H. Laqua; C. E. van Nouhuys

1994-01-01

190

Investigating the pathogenicity of mutations in two ubiquitously expressed housekeeping genes that cause autosomal dominant retinitis pigmentosa  

Microsoft Academic Search

The purpose of this dissertation research was to investigate potential mechanisms through which mutations in two ubiquitously expressed genes, inosine monophosphate dehydrogenase 1 (IMPDH1) and pre-mRNA processing factor 31 (PRPF31), cause autosomal dominant retinitis pigmentosa (adRP) but have no other apparent clinical consequences. Basic properties of the gene and gene product, such as expression and protein levels, were examined. The

Catherine Jean Spellicy

2009-01-01

191

The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) strikes 1 in 1000 individuals and often results in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95% of all cases [1–3]. It has recently been demonstrated that polycystin-1 and polycystin-2 (encoded by PKD1 and PKD2, respectively) assemble to form a cation channel in vitro [4]. Here we determine that the

Maureen M. Barr; John DeModena; Douglas Braun; Can Q. Nguyen; David H. Hall; Paul W. Sternberg

2001-01-01

192

Congenital conductive or mixed deafness, preauricular sinus, external ear anomaly, and commissural lip pits: an autosomal dominant inherited syndrome.  

PubMed

Branchiogenic syndromes such as branchio-oto-renal syndrome, Treacher Collins syndrome, and hemifacial microsomia are well delineated. From a clinical study in a large family spanning three generations, it can be concluded that the association of conductive deafness, commissural lip pits, preauricular sinuses, and external ear anomalies can be differentiated from the above-mentioned syndromes and is a separate autosomal dominant syndrome. PMID:1746829

Marres, H A; Cremers, C W

1991-11-01

193

Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation.  

PubMed

The molecular basis of autosomal dominant microcephaly, a disorder associated with small head circumferences that results in variable mental retardation, is largely unknown. In the present study, we conducted a variation analysis of the DPP6 gene in patients with autosomal dominant microcephaly and variable mental retardation. The copy number variation analysis of DPP6 was performed on DNA samples from 22 patients with microcephaly using high-resolution, array-based genomic hybridization, and sequence analysis was performed to screen mutations in another 50 microcephalic patients. Two de novo deletions and one missense mutation in familial microcephalic patients were identified. The transfection of plasmids encoding green fluorescent protein-pLLU2G-shDPP6 fusion proteins in mouse brains revealed that the decreased expression of the DPP6 gene slightly reduced the weight of the mouse brains and resulted in mouse learning disabilities compared with their wild-type littermates. Our data indicate that the loss-of-function variations in DPP6 are associated with autosomal dominant microcephaly and mental retardation. DPP6 appears to play a major role in the regulation of proliferation and migration of neurons in neurogenesis, most likely by participating in neuronal electrical excitability, synaptic integration, and plasticity. PMID:23832105

Liao, Can; Fu, Fang; Li, Ru; Yang, Wen-Qing; Liao, Hua-Yi; Yan, Jia-Rong; Li, Jian; Li, Shi-Yuan; Yang, Xin; Li, Dong-Zhi

2013-09-01

194

Autosomal Dominant Hemorrhagic Macular Dystrophy Not Associated With the TIMP3 Gene  

Microsoft Academic Search

Objective: To describe the ophthalmic and genetic find- ings of a large kindred (UM:H389) with autosomal domi- nant hemorrhagic macular dystrophy. Methods: The disease state of family members was docu- mented by dilated fundus examination, electroretinog- raphy, color vision tests, fluorescein angiography, mea- surement of visual fields, biomicroscopy, gonioscopy, and intraocular pressure measurement. Linkage and haplo- type analyses were carried

Radha Ayyagari; Irina B. Griesinger; Eve Bingham; Kurt K. Lark; Sayoko E. Moroi; Paul A. Sieving

2000-01-01

195

A Nonsense Mutation in CRYBB1 Associated with Autosomal Dominant Cataract Linked to Human Chromosome 22q  

PubMed Central

Autosomal dominant cataract is a clinically and genetically heterogeneous lens disorder that usually presents as a sight-threatening trait in childhood. Here we have mapped dominant pulverulent cataract to the ?-crystallin gene cluster on chromosome 22q11.2. Suggestive evidence of linkage was detected at markers D22S1167 (LOD score [Z] 2.09 at recombination fraction [?] 0) and D22S1154 (Z=1.39 at ?=0), which closely flank the genes for ?B1-crystallin (CRYBB1) and ?A4-crystallin (CRYBA4). Sequencing failed to detect any nucleotide changes in CRYBA4; however, a G?T transversion in exon 6 of CRYBB1 was found to cosegregate with cataract in the family. This single-nucleotide change was predicted to introduce a translation stop codon at glycine 220 (G220X). Expression of recombinant human ?B1-crystallin in bacteria showed that the truncated G220X mutant was significantly less soluble than wild type. This study has identified the first CRYBB1 mutation associated with autosomal dominant cataract in humans. PMID:12360425

Mackay, Donna S.; Boskovska, Olivera B.; Knopf, Harry L. S.; Lampi, Kirsten J.; Shiels, Alan

2002-01-01

196

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort1  

Microsoft Academic Search

Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohortBackgroundAutosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to

Arlene B. Chapman; Lisa M. Guay-Woodford; Jared J. Grantham; Vicente E. Torres; Kyongtae T. Bae; Deborah A. Baumgarten; Philip J. Kenney; Bernard F. King; James F. Glockner; Louis H. Wetzel; Marijn E. Brummer; W. Charles O'Neill; Michelle L. Robbin; William M. Bennett; Saulo Klahr; Gladys H. Hirschman; Paul L. Kimmel; Paul A. Thompson; J. Philip Miller

2003-01-01

197

Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity  

Microsoft Academic Search

We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging\\u000a studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A\\u000a similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide\\u000a linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage

Ali Jalali; Kimberly A. Aldinger; Ajit Chary; David G. Mclone; Robin M. Bowman; Luan Cong Le; Phillip Jardine; Ruth Newbury-Ecob; Andrew Mallick; Nadereh Jafari; Eric J. Russell; John Curran; Pam Nguyen; Karim Ouahchi; Charles Lee; William B. Dobyns; Kathleen J. Millen; Joao M. Pina-Neto; John A. Kessler; Alexander G. Bassuk

2008-01-01

198

Evaluation of candidate genes for familial brachydactyly  

Microsoft Academic Search

Type A1 brachydactyly in humans is a recognisable syndrome characterised by shortening of the middle phalanx of all digits with occasional fusion of the middle and terminal phalanges. The purpose of this study was to evaluate candidate genes for type A1 brachydactyly in two families with multiple affected members. Several classes of genes have been implicated in the control of

J M Mastrobattista; P Dollé; S H Blanton; H Northrup

1995-01-01

199

Signal sequence mutation in autosomal dominant form of hypoparathyroidism induces apoptosis that is corrected by a chemical chaperone  

PubMed Central

Autosomal dominant familial isolated hypoparathyroidism (AD-FIH) is caused by a Cys ? Arg mutation (C18R) in the hydrophobic core of the signal peptide of human preproparathyroid hormone (PPTH). Although this mutation impairs secretion of the hormone, the mechanism by which one mutant allele produces the autosomal-dominant disease is unexplained. Using transfected HEK293 cells, we demonstrate that the expressed mutant hormone is trapped intracellularly, predominantly in the endoplasmic reticulum (ER). This ER retention was found to be toxic for the cells, which underwent apoptosis, as evident from the marked increase in the number of cells staining positive for Annexin V binding and for the TUNEL reaction. The cells producing mutant hormone also had marked up-regulation of the ER stress-responsive proteins, BiP and PERK, as well as the proapoptotic transcription factor, CHOP. Up-regulation of these markers of the unfolded protein response supported a causal link between the ER stress and the cell death cascade. When the C18R PPTH was expressed in the presence of 4-phenylbutyric acid, which is a pharmacological chaperone, intracellular accumulation was reduced and normal secretion was restored. This treatment also produced remarkable reduction of ER stress signals and protection against cell death. These data implicate ER stress-induced cell death as the underlying mechanism for AD-FIH and suggest that the pharmacological manipulation of this pathway by using chemical chaperones offers a therapeutic option for treating this disease. PMID:18056632

Datta, Rupak; Waheed, Abdul; Shah, Gul N.; Sly, William S.

2007-01-01

200

BRAIN ABNORMALITIES IN YOUNG ADULTS AT GENETIC RISK FOR AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE: A CROSS-SECTIONAL STUDY  

PubMed Central

Summary Background We previously detected functional brain imaging abnormalities in young adults at genetic risk for late-onset Alzheimer’s disease (AD). Here, we sought to characterize structural and functional magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma biomarker abnormalities in young adults at risk for autosomal dominant early-onset AD. Biomarker measurements were characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the world’s largest known autosomal dominant early-onset AD kindred, more than two decades before the carriers’ estimated median age of 44 at the onset of mild cognitive impairment (MCI) and before their estimated age of 28 at the onset of amyloid-? (A?) plaque deposition. Methods Biomarker data for this cross-sectional study were acquired in Antioquia, Colombia between July and August, 2010. Forty-four participants from the Colombian Alzheimer’s Prevention Initiative (API) Registry had structural MRIs, functional MRIs during associative memory encoding/novel viewing and control tasks, and cognitive assessments. They included 20 mutation carriers and 24 non-carriers, who were cognitively normal, 18-26 years old and matched for their gender, age, and educational level. Twenty of the participants, including 10 mutation carriers and 10 non-carriers, had lumbar punctures and venipunctures. Primary outcome measures included task-dependent hippocampal/parahippocampal activations and precuneus/posterior cingulate deactivations, regional gray matter reductions, CSF A?1-42, total tau and phospho-tau181 levels, and plasma A?1-42 levels and A?1-42/A?1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and AD-related search regions. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings The mutation carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ?4 carriers. Compared to the non-carriers, carriers had higher CSF A?1-42 levels (p=0·008), plasma A?1-42 levels (p=0·01), and plasma A?1-42/A?1-40 ratios (p=0·001), consistent with A?1-42 overproduction. They also had greater hippocampal/parahippocampal activations (as low as p=0·008, after correction for multiple comparisons), less precuneus/posterior cingulate deactivations (as low as p=0·001, after correction), less gray matter in several regions (p-values <0·005, uncorrected, and corrected p=0·008 in the parietal search region), similar to findings in the later preclinical and clinical stages of autosomal dominant and late-onset AD. Interpretation Young adults at genetic risk for autosomal dominant AD have functional and structural MRI abnormalities, along with CSF and plasma biomarker findings consistent with A?1-42 over-production. While the extent to which the underlying brain changes are progressive or developmental remain to be determined, this study demonstrates the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant AD. Funding Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias (1115-408-20512, 1115-545-31651), National Institute on Aging (R01 AG031581, P30 AG19610, UO1 AG024904, RO1 AG025526, RF1AG041705), National Institute of Neurological Disorders and Stroke (F31-NS078786) and state of Arizona. PMID:23137948

Reiman, Eric M.; Quiroz, Yakeel T.; Fleisher, Adam S.; Chen, Kewei; Velez-Pardo, Carlos; Jimenez-Del-Rio, Marlene; Fagan, Anne M.; Shah, Aarti R.; Alvarez, Sergio; Arbelaez, Andres; Giraldo, Margarita; Acosta-Baena, Natalia; Sperling, Reisa A.; Dickerson, Brad; Stern, Chantal E.; Tirado, Victoria; Munoz, Claudia; Reiman, Rebecca A.; Huentelman, Matthew J.; Alexander, Gene E.; Langbaum, Jessica B.S.; Kosik, Kenneth S.; Tariot, Pierre N.; Lopera, Francisco

2013-01-01

201

Short trunk stature, brachydactyly, and platyspondyly in three sibs: a new form of brachyolmia or a new skeletal dysplasia?  

PubMed

We present a 27-year-old girl with short trunk stature, generalized rectangular platyspondyly and strike precocious calcification of costal cartilage. She had also brachydactyly, small nails, strabismus and delay of menarche. Her 16-year-old sister had also short trunk stature with severe kyphoscoliosis, hearing loss, brachydactyly, platyspondyly and mild precocious calcification of costal cartilages. Their 12-year-old brother had short trunk stature, kyphoscoliosis, brachydactyly, and platyspondyly but did not show precocious calcification of costal cartilage. The patients shared the following features: short trunk stature, brachydactyly, severe rectangular platyspondyly, broad and short femoral necks and hypoplasia of the ileum. In addition, the older sister had strike precocious calcification of costal cartilage while her sister and brother had severe kyphoscoliosis. Although short trunk stature and severe rectangular platyspondyly without significant epiphyseal or metaphyseal changes were in favor of Hobaek type brachyolmia, this diagnosis was not considered, both because, there were no specific radiological findings of this syndrome, such as elongated vertebral bodies extending beyond the pedicles laterally and all of the patients had brachydactyly which was not present in Hobaek type brachyolmia. The parents were healthy and first cousins signifying autosomal recessive inheritance. We considered that the patients could be affected by a new distinct autosomal recessive type brachyolmia or a new skeletal dysplasia. PMID:12784309

Tüysüz, Beyhan; Ungür, Sava?

2003-06-15

202

Autosomal-dominant Alport syndrome: Natural history of a disease due to COL4A3 or COL4A4 gene  

Microsoft Academic Search

Autosomal-dominant Alport syndrome: Natural history of a disease due to COL4A3 or COL4A4 gene.BackgroundAlport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either

Chiara Pescucci; Francesca Mari; Ilaria Longo; Paraskevi Vogiatzi; Rossella Caselli; Elisa Scala; Cataldo Abaterusso; Rosanna Gusmano; Marco Seri; Nunzia Miglietti; Elena Bresin; Alessandra Renieri

2004-01-01

203

A novel COL4A1 gene mutation results in autosomal dominant non-syndromic congenital cataract in a Chinese family  

PubMed Central

Background Almost one-third of congenital cataracts are primarily autosomal dominant disorders, which are also called autosomal dominant congenital cataract, resulting in blindness and clouding of the lens. The purpose of this study was to identify the disease-causing mutation in a Chinese family affected by bilateral, autosomal dominant congenital cataract. Methods The detection of candidate gene mutation and the linkage analysis of microsatellite markers were performed for the known candidate genes. Molecular mapping and cloning of candidate genes were used in all affected family members to screen for potential genetic mutations and the mutation was confirmed by single enzyme digestion. Results The proband was diagnosed with isolated, congenital cataract without the typical clinical manifestations of cataract, which include diabetes, porencephaly, sporadic intracerebral hemorrhage, and glomerulopathy. A novel mutation, c.2345 G?>?C (Gly782Ala), in exon 31 of the collagen type IV ?lpha1 (COL4A1) gene, which encodes the collagen alpha-1(IV) chain, was found to be associated with autosomal dominant congenital cataract in a Chinese family. This mutation was not found in unaffected family members or in 200 unrelated controls. Sequence analysis confirmed that the Gly782 amino acid residue is highly conserved. Conclusions The novel mutation (c.2345 G?>?C) of the COL4A1 gene is the first report of a non-syndromic, autosomal dominant congenital cataract, thereby highlighting the important role of type IV collagen in the physiological and optical properties of the lens. PMID:25124159

2014-01-01

204

Mutations in AQP5, Encoding a Water-Channel Protein, Cause Autosomal-Dominant Diffuse Nonepidermolytic Palmoplantar Keratoderma  

PubMed Central

Autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma is characterized by the adoption of a white, spongy appearance of affected areas upon exposure to water. After exome sequencing, missense mutations were identified in AQP5, encoding water-channel protein aquaporin-5 (AQP5). Protein-structure analysis indicates that these AQP5 variants have the potential to elicit an effect on normal channel regulation. Immunofluorescence data reveal the presence of AQP5 at the plasma membrane in the stratum granulosum of both normal and affected palmar epidermis, indicating that the altered AQP5 proteins are trafficked in the normal manner. We demonstrate here a role for AQP5 in the palmoplantar epidermis and propose that the altered AQP5 proteins retain the ability to form open channels in the cell membrane and conduct water. PMID:23830519

Blaydon, Diana C.; Lind, Lisbet K.; Plagnol, Vincent; Linton, Kenneth J.; Smith, Francis J.D.; Wilson, Neil J.; McLean, W.H. Irwin; Munro, Colin S.; South, Andrew P.; Leigh, Irene M.; O'Toole, Edel A.; Lundstrom, Anita; Kelsell, David P.

2013-01-01

205

A Locus for an Autosomal Dominant Form of Progressive Renal Failure and Hypertension at Chromosome 1q21  

PubMed Central

Linkage studies were performed in a large family with an autosomal dominant phenotype characterized by nephropathy and hypertension. In this family of Iraqi Jewish origin, the nephropathy develops into progressive renal failure. By performing a genomewide linkage search, we localized the disease gene to chromosome 1q21; the highest LOD score was obtained for the marker at locus D1S305, which yielded a maximum LOD score of 4.71 at a recombination fraction of 0. Recombination mapping defined an interval of ?11.6 cM, between the markers at loci D1S2696 and D1S2635, that contains the disease gene. Localization of the disease-causing gene in this family represents a necessary step toward isolation of the defective gene and toward a deeper understanding of the mechanisms of hypertension and progressive renal failure. PMID:10930359

Cohn, Daniel H.; Shohat, Tamy; Yahav, Michal; Ilan, Tsafra; Rechavi, Gidi; King, Lily; Shohat, Mordechai

2000-01-01

206

A Novel CRYGD Mutation (p.Trp43Arg) Causing Autosomal Dominant Congenital Cataract in a Chinese Family  

PubMed Central

To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family, molecular genetic investigation via haplotype analysis and direct sequencing were performed Sequencing of the CRYGD gene revealed a c.127T>C transition, which resulted in a substitution of a highly conserved tryptophan with arginine at codon 43 (p.Trp43Arg). This mutation co-segregated with all affected individuals and was not observed in either unaffected family members or in 200 normal unrelated individuals. Biophysical studies indicated that the p.Trp43Arg mutation resulted in significant tertiary structural changes. The mutant protein was much less stable than the wild-type protein, and was more prone to aggregate when subjected to environmental stresses such as heat and UV irradiation. © 2010 Wiley-Liss, Inc. PMID:21031598

Wang, Binbin; Yu, Changhong; Xi, Yi-Bo; Cai, Hong-Chen; Wang, Jing; Zhou, Sirui; Zhou, Shiyi; Wu, Yi; Yan, Yong-Bin; Ma, Xu; Xie, Lixin

2011-01-01

207

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

SciTech Connect

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.

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

1994-09-01

208

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

PubMed Central

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

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

2012-01-01

209

A novel GJA8 mutation (p.I31T) causing autosomal dominant congenital cataract in a Chinese family  

PubMed Central

Purpose To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family. Methods Family history and clinical data were recorded. The genomic DNA was extracted from peripheral blood leukocytes. All the members were genotyped with microsatellite markers at loci considered to be associated with cataracts. Two-point logarithm of odds (LOD) scores were calculated by using the Linkage software after genotyping. Mutations were detected by DNA sequence analysis of the candidate genes. Effects of amino acid changes on the structure and function of proteins were predicted by bioinformatics analysis. Results Evidence of a linkage was obtained at markers D1S514 (LOD score [Z]=3.48, recombination fraction [?]=0.0) and D1S1595 (Z=2.49, ?=0.0). Haplotype analysis indicated that the cataract gene was close to these two markers. Sequencing of the connexin 50 (GJA8) gene revealed a T>C transition at nucleotide position c.92. This nucleotide change resulted in the substitution of highly conserved isoleucine by threonine at codon 31(I31T). This mutation co-segregated with all affected individuals and was not observed in unaffected or 110 normal unrelated individuals. Bioinformatics analysis showed that a highly conserved region was located at Ile31, and the mutation was predicted to affect the function and secondary structure of the GJA8 protein. Conclusion A novel mutation in GJA8 was detected in a Chinese family with autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype. PMID:20019893

Wang, Kaijie; Wang, Binbin; Wang, Jing; Zhou, Shiyi; Yun, Bo; Suo, Peisu; Cheng, Jie; Ma, Xu

2009-01-01

210

Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter A? production.  

PubMed

Autosomal-dominant Alzheimer's disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studying the mechanisms underlying these mutations can provide insight into the pathways that lead to AD pathology. The majority of biochemical studies on APP mutations to-date have focused on comparing mechanisms between mutations at different codons. It has been assumed that amino acid position is a major determinant of protein dysfunction and clinical phenotype. However, the differential effect of mutations at the same codon has not been sufficiently addressed. In the present study we compared the effects of the aggressive ADAD-associated APP I716F mutation with I716V and I716T on APP processing in human neuroglioma and CHO-K1 cells. All APP I716 mutations increased the ratio of A?42/40 and changed the product line preference of ?-secretase towards A?38 production. In addition, the APP I716F mutation impaired the ?-cleavage and the fourth cleavage of ?-secretase and led to abnormal APP ?-CTF accumulation at the plasma membrane. Taken together, these data indicate that APP mutations at the same codon can induce diverse abnormalities in APP processing, some resembling PSEN1 mutations. These differential effects could explain the clinical differences observed among ADAD patients bearing different APP mutations at the same position. The amyloid precursor protein (APP) I716F mutation is associated with autosomal dominant Alzheimer's disease with the youngest age-at-onset for the APP locus. Here, we describe that this mutation, when compared to two other familial Alzheimer's disease mutations at the same codon (I716V and I716T), interfered distinctly with ?-secretase cleavage. While all three mutations direct ?-secretase cleavage towards the 48?38 production line, the APP I716F mutation also impaired the ?-cleavage and the fourth cleavage of ?-secretase, resembling a PSEN1 mutation. These features may contribute to the aggressiveness of this mutation. PMID:24117942

Suárez-Calvet, Marc; Belbin, Olivia; Pera, Marta; Badiola, Nahuai; Magrané, Jordi; Guardia-Laguarta, Cristina; Muñoz, Laia; Colom-Cadena, Martí; Clarimón, Jordi; Lleó, Alberto

2014-01-01

211

Clinical variability of autosomal dominant cataract, microcornea and corneal opacity and novel mutation in the alpha A crystallin gene (CRYAA).  

PubMed

We studied 28 individuals from a four-generation Chilean family (ADC54) including 13 affected individuals with cataracts, microcornea and/or corneal opacity. All individuals underwent a complete ophthalmologic exam. We screened with a panel of polymorphic DNA markers for known loci that cause autosomal dominant cataracts, if mutated, and refined the locus using the ABI Prism Linkage Mapping Set Version 2.5, and calculated two-point lod scores. Novel PCR primers were designed for the three coding exons, including intron-exon borders, of the candidate gene alpha A crystallin (CRYAA). Clinically, affected individuals had diverse and novel cataracts with variable morphology (anterior polar, cortical, embryonal, fan-shaped, anterior subcapsular). Microcornea and corneal opacity was evident in some. Marker D21S171 gave a lod score of 4.89 (theta(m) = theta(f) = 0). CRYAA had a G414A transition that segregated with the disease and resulted in an amino acid alteration (R116H). The phenotypic variability within this family was significant with novel features of the cataracts and a corneal opacity. With the exception of iris coloboma, the clinical features in all six previously reported families with mutations in the CRYAA gene were found in this family. We identified a novel G414A transition in exon 3 of CRYAA that co-segregated with an autosomal dominant phenotype. The resulting amino acid change R116H is in a highly conserved region and represents a change in charge. The genotype-phenotype correlation of this previously unreported mutation provides evidence that other factors, genetic and/or environmental, may influence the development of cataract as a result of this alteration. PMID:18302245

Richter, Leslie; Flodman, Pamela; Barria von-Bischhoffshausen, Fernando; Burch, Douglas; Brown, Sandra; Nguyen, Linda; Turner, Julia; Spence, M Anne; Bateman, J Bronwyn

2008-04-01

212

A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia.  

PubMed

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 identified in three siblings with PEO, one of them additionally suffered from schizoaffective disorder. Microsatellite analysis showed that the mutation was dominant and inherited from the mother who did not carry the mutation in blood, indicating germ-line mosaicism. PMID:15792871

Deschauer, Marcus; Hudson, Gavin; Müller, Tobias; Taylor, Robert W; Chinnery, Patrick F; Zierz, Stephan

2005-04-01

213

Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign  

PubMed Central

Background Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced. Methods Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy. Results Rates of rare (minor allele frequency ?0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not. Conclusions We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation. PMID:23687434

Strom, Samuel P.

2013-01-01

214

Confirmation of linkage to 1q21-31 in a Danish autosomal dominant juvenile-onset glaucoma family and evidence of genetic heterogeneity  

Microsoft Academic Search

Autosomal dominant juvenile-onset open-angle glaucoma has been mapped to 1q21-31 in a number of American families. Our study confirms linkage in a Danish five-generation dominant juvenile-onset glaucoma family with a maximum two-point lod score of 6.67 at the D1S210 locus. Multipoint linkage analysis in a nine-generation Swedish family with dominant juvenile-onset glaucoma and iris hypoplasia excludes linkage to the region

Caroline Graff; Steen F. Urbak; Tord Jerndal; Claes Wadelius

1995-01-01

215

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

PubMed Central

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

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

2012-01-01

216

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

SciTech Connect

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.

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

1995-07-03

217

Linkage of protection against amyloid fibril formation in the mouse to a single, autosomal dominant gene  

PubMed Central

Inbred strains of mice provide a model for studies of the pathogenesis of amyloid A (AA) amyloidosis. All susceptible strains of mice described to date codominantly express two serum amyloid A (apoSAA) isoforms, apoSAA1 and apoSAA2, of which only apoSAA2 serves as a precursor for amyloid fibrils. In previous studies, we have shown that the CE/J strain, which produces a single, novel apoSAA isoform, apoSAACE/J, is amyloid resistant. In the present study amyloid- resistant CE/J females were mated with amyloid-susceptible CBA/J males to produce F1 hybrid offspring which were then backcrossed to the parental CBA/J mouse strain. Amyloid susceptibility was determined in 30 backcrossed mice 72 h after injection of murine amyloid enhancing factor and silver nitrate. ApoSAA isoforms in plasma were separated by isoelectric focusing gel electrophoresis and visualized after immunoblotting with anti-AA antiserum. Amyloid A fibrils in spleen homogenates were denatured by formic acid and AA protein was quantified by ELISA using anti-mouse apoSAA antibodies. Values < 5 apoSAA equivalent units were considered negative. 13 mice expressed an apoSAA1 and apoSAA2 doublet characteristic of CBA/J mice, whereas 17 mice, expressed the apoSAACE/J isoform codominantly with apoSAA1 and apoSAA2. The correlation of amyloid resistance to expression of the apoSAACE/J isoform was absolute (17/17 were negative; mean score 2.6 +/- 0.17 [standard error of the mean] apoSAA equivalent units) and the correlation between amyloid susceptibility and the expression of apoSAA2/apoSAA1 was also striking (12/13 were amyloid positive; mean score 47.9 +/- 9.0 [standard error of the mean] apoSAA equivalent units (P < 0.001). This is not significantly different from the 50% segregation of apoSAA phenotypes expected for linkage to a single gene. These results indicate that a single gene governs apoSAACE/J expression and thus confers protection against amyloid deposition even in the presence of apoSAA1 and apoSAA2 isoforms and show for the first time that resistance to AA amyloidosis is a dominant trait governed by a single gene. PMID:7760010

1995-01-01

218

Mutant ELOVL4 That Causes Autosomal Dominant Stargardt-3 Macular Dystrophy Is Misrouted to Rod Outer Segment Disks  

PubMed Central

Purpose. Autosomal dominant Stargardt macular dystrophy caused by mutations in the Elongation of Very Long Chain fatty acids (ELOVL4) gene results in macular degeneration, leading to early childhood blindness. Transgenic mice and pigs expressing mutant ELOVL4 develop progressive photoreceptor degeneration. The mechanism by which these mutations cause macular degeneration remains unclear, but have been hypothesized to involve the loss of an ER-retention dilysine motif located in the extreme C-terminus. Dominant negative mechanisms and reduction in retinal polyunsaturated fatty acids also have been suggested. To understand the molecular mechanisms involved in disease progression in vivo, we addressed the hypothesis that the disease-linked C-terminal truncation mutant of ELOVL4 exerts a dominant negative effect on wild-type (WT) ELOVL4, altering its subcellular localization and function, which subsequently induces retinal degeneration and loss of vision. Methods. We generated transgenic Xenopus laevis that overexpress HA-tagged murine ELOVL4 variants in rod photoreceptors. Results. Tagged or untagged WT ELOVL4 localized primarily to inner segments. However, the mutant protein lacking the dilysine motif was mislocalized to post-Golgi compartments and outer segment disks. Coexpression of mutant and WT ELOVL4 in rods did not result in mislocalization of the WT protein to outer segments or in the formation of aggregates. Full-length HA-tagged ELOVL4 lacking the dilysine motif (K308R/K310R) necessary for targeting the WT ELOVL4 protein to the endoplasmic reticulum was similarly mislocalized to outer segments. Conclusions. We propose that expression and outer segment mislocalization of the disease-linked 5–base-pair deletion mutant ELOVL4 protein alters photoreceptor structure and function, which subsequently results in retinal degeneration, and suggest three possible mechanisms by which mutant ELOVL4 may induce retinal degeneration in STGD3. PMID:24833735

Agbaga, Martin-Paul; Tam, Beatrice M.; Wong, Jenny S.; Yang, Lee Ling; Anderson, Robert E.; Moritz, Orson L.

2014-01-01

219

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

PubMed Central

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

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, Rene J. M.; Cox, Roger D.; Thakker, Rajesh V.

2013-01-01

220

Autosomal dominant epidermolysis bullosa dystrophica: are the Cockayne-Touraine, the Pasini and the Bart-types different expressions of the same mutant gene?  

PubMed

We report on a family with autosomal dominant dystrophic epidermolysis bullosa and congenital localized absence of skin, resembling the features of Bart's Syndrome. This type of epidermolysis bullosa and the Cockayne-Touraine and Pasini types may represent different expressions of the same gene defect. PMID:3621647

Bouwes Bavinck, J N; van Haeringen, A; Ruiter, D; van der Schroeff, J G

1987-06-01

221

Mutations in the Gene Coding for the Pre-mRNA Splicing Factor, PRPF31, in Patients with Autosomal Dominant Retinitis Pigmentosa  

Microsoft Academic Search

PURPOSE. Retinitis pigmentosa is a clinically and genetically heterogeneous disorder. It is characterized by progressive de- generation of the peripheral retina, leading to night blindness and loss of the peripheral visual field. PRPF31 is one of four pre-mRNA splicing factors identified as causing autosomal dominant retinitis pigmentosa, with incomplete penetrance being the unique feature associated with mutations in this gene.

Naushin H. Waseem; Veronika Vaclavik; Andrew Webster; Sharon A. Jenkins; Alan C. Bird; Shomi S. Bhattacharya

2007-01-01

222

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

Microsoft Academic Search

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

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

2006-01-01

223

A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss  

Microsoft Academic Search

Hearing loss is the most common sensory disorder, affecting 1 in 650 newborns. Linkage analysis revealed linkage to locus DFNA22 in two Belgian families 1 and 2 with autosomal dominant sensorineural hearing loss. As MYO6 has previously been reported as responsible for the hearing loss at loci DFNA22 and DFNB37, respectively, DNA sequencing of the coding region and the promoter

Nele Hilgert; Vedat Topsakal; Joost van Dinther; Erwin Offeciers; Paul Van de Heyning; Guy Van Camp

2008-01-01

224

Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23  

SciTech Connect

At least two loci are known to exist for autosomal dominant polycystic kidney disease (ADPKD). One was localized to 16p, but the second less common locus has remained unlinked. Over 100 microsatellite markers, distributed across all chromosomes, have been typed on informative family members from the large Sicilian kindred in which the genetic heterogeneity was first discovered. Both the affected and the unaffected status of every family member used in the study were consulted in the successful localization of a second ADPKD gene to chromosome 4q. It was found to be flanked by the markers D4S231 and D4S414, defining a segment that spans about 9 cM. The new locus has been designated PKD4. This second localization will allow researchers to target another ADPKD gene for isolation in an effort to understand the pathogenesis of this common disorder. Furthermore, when flanking markers for the second ADPKD gene are used in conjunction with flanking markers for PKD1, the accuracy of the diagnosis of the subtype of ADPKD present in any particular family will be enhanced. This will improve the accuracy of linkage-based presymptomatic diagnoses by reducing the error due to genetic heterogeneity. 42 refs., 3 figs., 1 tab.

Kimberling, W.J.; Kumar, S.; Kenyon, J.B.; Connolly, C.J. (Creighton Univ. Medical School, Omaha, NE (United States)); Gabow, P.A. (Colorado Univ. Health Sciences Center, Denver, CO (United States)); Somlo, S. (Albert Einstein School of Medicine, Bronx, NY (United States))

1993-12-01

225

Type III Bartter-like syndrome in an infant boy with Gitelman syndrome and autosomal dominant familial neurohypophyseal diabetes insipidus.  

PubMed

We report the case of an infant boy with polyuria and a familial history of central diabetes insipidus. Laboratory blood tests disclosed hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism. Plasma magnesium concentration was slightly low. Urine analysis showed hypercalciuria, hyposthenuria, and high excretion of potassium. Such findings oriented toward type III Bartter syndrome (BSIII). Direct sequencing of the CLCNKB gene revealed no disease-causing mutations. The water deprivation test was positive. Magnetic resonance imaging showed a lack of posterior pituitary hyperintensity. Finally, direct sequencing of the AVP-NPII gene showed a point mutation (c.1884G>A) in a heterozygous state, confirming an autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). This condition did not explain the patient's phenotype; thus, we investigated for Gitelman syndrome (GS). A direct sequencing of the SLC12A3 gene showed c.269A>C and c.1205C>A new mutations. In conclusion, the patient had a genetic combination of GS and adFNDI with a BSIII-like phenotype. PMID:24825090

Brugnara, Milena; Gaudino, Rossella; Tedeschi, Silvana; Syrèn, Marie-Louise; Perrotta, Silverio; Maines, Evelina; Zaffanello, Marco

2014-09-01

226

Identification of the first deletion in the LRP5 gene in a patient with autosomal dominant osteopetrosis type I.  

PubMed

In the last decade, the low-density lipoprotein receptor-related protein 5 (LRP5) gene, coding for a coreceptor in the canonical Wnt signalling pathway, has been shown to play an important role in regulating bone mass and to be involved in the pathogenesis of several bone disorders. Here we describe a patient who presented with a clinical picture of Autosomal Dominant Osteopetrosis type I (ADO I), in whom we could identify the first deletion in the LRP5 gene causing increased bone mass. This mutation caused the in-frame deletion of two amino acids in the fourth blade of the first propeller of the protein, namely the highly conserved glycine at position 171 and the following glutamate residue. In vitro studies suggested that the pathogenic effect of this novel mutation could be due to a decreased inhibition of Wnt signalling by the antagonistic proteins sclerostin and Dickkopf-1, encoded respectively by the SOST and DKK1 genes, in the presence of mutated LRP5. Our results highlight an increasing molecular heterogeneity in LRP5-related bone diseases. PMID:21600326

Pangrazio, Alessandra; Boudin, Eveline; Piters, Elke; Damante, Giuseppe; Lo Iacono, Nadia; D'Elia, Angela Valentina; Vezzoni, Paolo; Van Hul, Wim; Villa, Anna; Sobacchi, Cristina

2011-09-01

227

Identification of the first deletion in the LRP5 gene in a patient with Autosomal Dominant Osteopetrosis type I  

PubMed Central

In the last decade, the low-density lipoprotein receptor-related protein 5 (LRP5) gene, coding for a coreceptor in the canonical Wnt signalling pathway, has been shown to play an important role in regulating bone mass and to be involved in the pathogenesis of several bone disorders. Here we describe a patient who presented with a clinical picture of Autosomal Dominant Osteopetrosis type I (ADO I), in whom we could identify the first deletion in the LRP5 gene causing increased bone mass. This mutation caused the in-frame deletion of two amino acids in the fourth blade of the first propeller of the protein, namely the highly conserved glycine at position 171 and the following glutamate residue. In vitro studies suggested that the pathogenic effect of this novel mutation could be due to a decreased inhibition of Wnt signalling by the antagonistic proteins sclerostin and Dickkopf-1, encoded respectively by the SOST and DKK1 genes, in the presence of mutated LRP5. Our results highlight an increasing molecular heterogeneity in LRP5-related bone diseases. PMID:21600326

Pangrazio, Alessandra; Boudin, Eveline; Piters, Elke; Damante, Giuseppe; Iacono, Nadia Lo; D'Elia, Angela Valentina; Vezzoni, Paolo; Van Hul, Wim; Villa, Anna; Sobacchi, Cristina

2011-01-01

228

An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract  

PubMed Central

Autosomal dominant congenital cataracts have been associated with mutations of genes encoding several soluble and membrane proteins. By candidate gene screening, we identified a novel mutation in MIP (c.494 G>A) that segregates with a congenital lamellar cataract within a South Indian family and causes the replacement of a highly conserved glycine by aspartate (G165D) within aquaporin0 (AQP0). Unlike wild type AQP0, expression of AQP0-G165D in Xenopus oocytes did not facilitate swelling in hypotonic medium. In transfected HeLa cells, wild type AQP0 localized at the plasma membrane while AQP0-G165D was retained within the secretory pathway, and localized mainly within the endoplasmic reticulum. These results suggest that mutation of this conserved glycine residue leads to improper trafficking of AQP0-G165D and loss of water channel function. They emphasize the importance of AQP0 for maintenance of lens transparency and identify a critical residue that is conserved among aquaporins, but has not previously been associated with disease-associated replacement. PMID:23116563

Kumar, G. Senthil; Kyle, John W.; Minogue, Peter J.; Kumar, K. Dinesh; Vasantha, K.; Berthoud, Viviana M.; Beyer, Eric C.; Sathiyavedu, Santhiya T.

2012-01-01

229

Identification of I411K, a novel missense EYA4 mutation causing autosomal dominant non?syndromic hearing loss.  

PubMed

Hearing loss is the most common sensory deficit in humans and gaining a better understanding of the underlying causes is necessary to improve counseling and rehabilitation. In the present study, a genetic analysis of a Chinese family with autosomal dominant non?syndromic progressive hearing impairment was conducted and assessed. Whole?exome sequencing in combination with a co?segregation analysis identified a novel missense mutation in EYA4 exon 15 (c.T1301A; p.I411K). The mutation segregated with the hearing loss of the family. This mutation was not identified in the databases of 1000 genome Project, dbSNP 130, HapMap and YH project or in matched controls. Bioinformatic analysis confirmed the pathogenic effects of this mutation. To the best of our knowledge, this is the first report to provide a description of a missense mutation in the EYA4 gene resulting in non?syndromic hearing loss. Our results provide additional molecular and clinical information in order to gain improved understanding of the pathogenesis of EYA4 mutations and the genotype?phenotype correlations of DFNA10 hearing loss. PMID:25242383

Tan, Minxing; Shen, Xiaofei; Yao, Jun; Wei, Qinjun; Lu, Yajie; Cao, Xin; Xing, Guangqian

2014-12-01

230

Targeted exome capture and sequencing identifies novel PRPF31 mutations in autosomal dominant retinitis pigmentosa in Chinese families  

PubMed Central

Objectives To identify disease-causing mutations in two Chinese families with autosomal dominant retinitis pigmentosa (adRP). Design Prospective analysis. Patients Two Chinese adRP families underwent genetic diagnosis. A specific hereditary eye disease enrichment panel (HEDEP) based on targeted exome capture technology was used to collect the protein coding regions of targeted 371 hereditary eye disease genes; high throughput sequencing was done with the Illumina HiSeq 2000 platform. The identified variants were confirmed with Sanger sequencing. Setting All experiments were performed in a large laboratory specialising in genetic studies in the Department of Ophthalmology, Peking University Third Hospital. Results Two novel mutations, including one splice site mutation (Int10 c.1074-2 A>T; p.Y359SfsX29) and one insertion (c.824_825insA; p.Y275X) of PRPF31 were identified in the two families. The two mutations segregated with the disease phenotype in their respective families. Conclusions Our findings broaden the spectrum of PRPF31 mutations causing adRP and the phenotypic spectrum of the disease in Chinese patients. The HEDEP based on targeted exome capture technology is an efficient method for molecular diagnosis in adRP patients. PMID:24202059

Yang, Liping; Yin, Xiaobei; Wu, Lemeng; Chen, Ningning; Zhang, Huirong; Li, Genlin; Ma, Zhizhong

2013-01-01

231

Identification of I411K, a novel missense EYA4 mutation causing autosomal dominant non-syndromic hearing loss  

PubMed Central

Hearing loss is the most common sensory deficit in humans and gaining a better understanding of the underlying causes is necessary to improve counseling and rehabilitation. In the present study, a genetic analysis of a Chinese family with autosomal dominant non-syndromic progressive hearing impairment was conducted and assessed. Whole-exome sequencing in combination with a co-segregation analysis identified a novel missense mutation in EYA4 exon 15 (c.T1301A; p.I411K). The mutation segregated with the hearing loss of the family. This mutation was not identified in the databases of 1000 Genome Project, dbSNP 130, HapMap and YH project or in matched controls. Bioinformatic analysis confirmed the pathogenic effects of this mutation. To the best of our knowledge, this is the first report to provide a description of a missense mutation in the EYA4 gene resulting in non-syndromic hearing loss. Our results provide additional molecular and clinical information in order to gain improved understanding of the pathogenesis of EYA4 mutations and the genotype-phenotype correlations of DFNA10 hearing loss. PMID:25242383

TAN, MINXING; SHEN, XIAOFEI; YAO, JUN; WEI, QINJUN; LU, YAJIE; CAO, XIN; XING, GUANGQIAN

2014-01-01

232

Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation  

PubMed Central

Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL), eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess) with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL). Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases. PMID:25379309

Cooper, Chad J.; Said, Sarmad; Hernandez, German T.

2014-01-01

233

A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons  

PubMed Central

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein–induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(–1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss. PMID:14660745

Russell, Theron A.; Ito, Masafumi; Ito, Mika; Yu, Richard N.; Martinson, Fred A.; Weiss, Jeffrey; Jameson, J. Larry

2003-01-01

234

Application of Next-Generation Sequencing to Identify Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa (adRP)  

PubMed Central

The goal of our research is to identify genes and mutations causing auto-somal dominant retinitis pigmentosa (adRP). For this purpose we established a cohort of more than 250 independently ascertained families with adRP in the Houston Laboratory for Molecular Diagnosis of Inherited Eye Diseases. Affected members of each family were screened for disease-causing mutations in genes and gene regions that are commonly associated with adRP. By this approach, we detected mutations in 65 % of the families, leaving 85 families that are likely to harbor mutations outside of the “common” regions or in novel genes. Of these, 32 families were tested by several types of next-generation sequencing (NGS), including (a) targeted polymerase chain reaction (PCR) NGS, (b) whole exome NGS, and (c) targeted retinal-capture NGS. We detected mutations in 11 of these families (31 %) bringing the total detected in the adRP cohort to 70 %. Several large families have also been tested for linkage using Afymetrix single nucleotide polymorphism (SNP) arrays. PMID:24664689

Bowne, Sara J.; Sullivan, Lori S.; Blanton, Susan H.; Weinstock, George M.; Koboldt, Daniel C.; Fulton, Robert S.; Larsen, David; Humphries, Peter; Humphries, Marian M.; Pierce, Eric A.; Chen, Rui; Li, Yumei

2014-01-01

235

Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.  

PubMed

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310

Böhm, Johann; Biancalana, Valérie; Dechene, Elizabeth T; Bitoun, Marc; Pierson, Christopher R; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S; Barger, Melissa A; Mahoney, Lane J; Kang, Peter B; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Bomme Ousager, Lilian; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S B; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Poza Aldea, Juan José; Michel, Fabrice; Furby, Alain; Llona, Jose E Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A H; Smith, Stephen A; Roggenbuck, Jennifer; Crowe, Carol A; Brennan Spitale, Allison; Johal, Sheila C; Amato, Anthony A; Demmer, Laurie A; Jonas, Jessica; Darras, Basil T; Bird, Thomas D; Laurino, Mercy; Welt, Selman I; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H; Laporte, Jocelyn

2012-06-01

236

Molecular detection of autosomal-dominant feline polycystic kidney disease by multiplex amplification refractory mutation system polymerase chain reaction.  

PubMed

Feline autosomal-dominant polycystic kidney disease (ADPKD), with its characteristic growth of fluid-filled cysts of different sizes, is the most prevalent inherited genetic disease of cats. The point mutation (C-->A transversion) in exon 29 of the PKD1 gene is known to contribute to ADPKD development and can thus serve as a target for the molecular genetic diagnosis of ADPKD. To this end, a simple amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) was designed with 3 primers: 2 forward primers specifically targeting either the mutant or normal allele, and 1 universal reverse primer for amplification of both alleles. The new method was tested on the DNA from 35 feline blood samples, which included 15 mutant cats and 20 wild type cats. As verified by direct DNA sequencing, both sensitivity and specificity of this tri-primer ARMS PCR were 100%. As the multiplex ARMS PCR test can be performed in a single PCR reaction without other post-PCR procedures, it is a simple and accurate method for molecular studies of feline ADPKD. PMID:20453219

Lee, Ya-Jane; Chen, Hsin-Yu; Wong, Min-Liang; Hsu, Wei-Li

2010-05-01

237

Renal ultrasonographic and computed tomographic appearance, volume, and function of cats with autosomal dominant polycystic kidney disease.  

PubMed

The purpose of this study was to describe the ultrasonographic (US) and computed tomographic (CT) appearance of autosomal dominant polycystic kidney disease (ADPKD) in cats; to compare renal volume in cats with ADPKD (n = 5; mean age 59 +/- 10 months)) and normal cats (n = 5; mean age 66 +/- 10 months) using 2 imaging modalities, US and CT; and to calculate cyst volume using CT. Glomerular filtration rate (GFR) was determined by 2 methods: 99mTc-diethylene-triaminepentaacetic acid (99mTc-DPTA) scintigraphic uptake and 99-Tc-DTPA plasma clearance. Sonographically, ADPKD affected kidneys were characterized by multiple anechoic to hypoechoic, round to irregularly shaped structures with variation in size. Affected kidneys had indistinct corticomedullary junctions and foci of mineralization. Intravenous (IV) contrast medium administration allowed more definitive identification of cysts with CT, and identification of distortion of renal pelves by cysts. A significant difference (Welch ANOVA, P = 0.05) was detected between the US-estimated renal volumes of normal and affected cats. No statistically significant differences were detected in CT volume (between the normal and affected cats, or between US and CT volume measurements) or the 2 GFR methods. In this group of clinically normal, middle-aged ADPKD cats, renal function was within normal limits and not significantly different than normal. PMID:12175002

Reichle, Jean K; DiBartola, Stephen P; Léveillé, Renée

2002-01-01

238

Application of next-generation sequencing to identify genes and mutations causing autosomal dominant retinitis pigmentosa (adRP).  

PubMed

The goal of our research is to identify genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). For this purpose we established a cohort of more than 250 independently ascertained families with adRP in the Houston Laboratory for Molecular Diagnosis of Inherited Eye Diseases. Affected members of each family were screened for disease-causing mutations in genes and gene regions that are commonly associated with adRP. By this approach, we detected mutations in 65?% of the families, leaving 85 families that are likely to harbor mutations outside of the "common" regions or in novel genes. Of these, 32 families were tested by several types of next-generation sequencing (NGS), including (a) targeted polymerase chain reaction (PCR) NGS, (b) whole exome NGS, and (c) targeted retinal-capture NGS. We detected mutations in 11 of these families (31?%) bringing the total detected in the adRP cohort to 70?%. Several large families have also been tested for linkage using Afymetrix single nucleotide polymorphism (SNP) arrays. PMID:24664689

Daiger, Stephen P; Bowne, Sara J; Sullivan, Lori S; Blanton, Susan H; Weinstock, George M; Koboldt, Daniel C; Fulton, Robert S; Larsen, David; Humphries, Peter; Humphries, Marian M; Pierce, Eric A; Chen, Rui; Li, Yumei

2014-01-01

239

Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing  

PubMed Central

Molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) relies on mutation screening of PKD1 and PKD2, which is complicated by extensive allelic heterogeneity and the presence of six highly homologous sequences of PKD1. To date, specific sequencing of PKD1 requires laborious long-range amplifications. The high cost and long turnaround time of PKD1 and PKD2 mutation analysis using conventional techniques limits its widespread application in clinical settings. We performed targeted next-generation sequencing (NGS) of PKD1 and PKD2. Pooled barcoded DNA patient libraries were enriched by in-solution hybridization with PKD1 and PKD2 capture probes. Bioinformatics analysis was performed using an in-house developed pipeline. We validated the assay in a cohort of 36 patients with previously known PKD1 and PKD2 mutations and five control individuals. Then, we used the same assay and bioinformatics analysis in a discovery cohort of 12 uncharacterized patients. We detected 35 out of 36 known definitely, highly likely, and likely pathogenic mutations in the validation cohort, including two large deletions. In the discovery cohort, we detected 11 different pathogenic mutations in 10 out of 12 patients. This study demonstrates that laborious long-range PCRs of the repeated PKD1 region can be avoided by in-solution enrichment of PKD1 and PKD2 and NGS. This strategy significantly reduces the cost and time for simultaneous PKD1 and PKD2 sequence analysis, facilitating routine genetic diagnostics of ADPKD. PMID:25333066

Trujillano, Daniel; Bullich, Gemma; Ossowski, Stephan; Ballarin, Jose; Torra, Roser; Estivill, Xavier; Ars, Elisabet

2014-01-01

240

Defining a Link with Autosomal-Dominant Polycystic Kidney Disease in Mice with Congenitally Low Expression of Pkd1  

PubMed Central

Mouse models for autosomal-dominant polycystic kidney disease (ADPKD), derived from homozygous targeted disruption of Pkd1 gene, generally die in utero or perinatally because of systemic defects. We introduced a loxP site and a loxP-flanked mc1-neo cassette into introns 30 and 34, respectively, of the Pkd1 locus to generate a conditional, targeted mutation. Significantly, before excision of the floxed exons and mc1-neo from the targeted locus by Cre recombinase, mice homozygous for the targeted allele appeared normal at birth but developed polycystic kidney disease with a slower progression than that of Pkd-null mice. Further, the homozygotes continued to produce low levels of full-length Pkd1-encoded protein, suggesting that slight Pkd1 expression is sufficient for renal cyst formation in ADPKD. In this viable model, up-regulation of heparin-binding epidermal growth factor-like growth factor accompanied increased epidermal growth factor receptor signaling, which may be involved in abnormal proliferation of the cyst-lining epithelia. Increased apoptosis in cyst epithelia was only observed in the later period that correlated with the cyst regression. Abnormalities in Na+/K+-ATPase, aquaporin-2, and vasopressin V2 receptor expression were also identified. This mouse model may be suitable for further studies of progression and therapeutic interventions of ADPKD. PMID:16400024

Jiang, Si-Tse; Chiou, Yuan-Yow; Wang, Ellian; Lin, Hsiu-Kuan; Lin, Yuan-Ta; Chi, Ying-Chih; Wang, Chi-Kuang Leo; Tang, Ming-Jer; Li, Hung

2006-01-01

241

Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis  

PubMed Central

Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSP?). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSP? in neuronal cells. The resulting depletion of functional CSP? might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSP? in humans and demonstrates the need for detailed investigation of CSP? in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. PMID:21820099

Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; P?istoupilová, Anna; Barešová, Veronika; Ivánek, Robert; H?lková, Helena; Jahnová, Helena; van der Zee, Julie; Staropoli, John F.; Sims, Katherine B.; Tyynelä, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C.G.; Mole, Sara E.; Elleder, Milan; Kmoch, Stanislav

2011-01-01

242

Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.  

PubMed

Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSP?). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSP? in neuronal cells. The resulting depletion of functional CSP? might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSP? in humans and demonstrates the need for detailed investigation of CSP? in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. PMID:21820099

Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; P?istoupilová, Anna; Barešová, Veronika; Ivánek, Robert; H?lková, Helena; Jahnová, Helena; van der Zee, Julie; Staropoli, John F; Sims, Katherine B; Tyynelä, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C G; Mole, Sara E; Elleder, Milan; Kmoch, Stanislav

2011-08-12

243

Embryology of familial (non-syndromic) brachydactyly of the hand.  

PubMed

Isolated familial non-syndromic brachydactyly is interesting from the embryological point of view because the phenotypes of isolated brachydactyly are frequently overlapping, yet they are caused by different gene mutations and the ring finger is frequently relatively preserved. We review the embryology of isolated familial brachydactyly with special attention to these two features. PMID:24300509

Al-Qattan, M M

2014-11-01

244

Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease  

PubMed Central

Background Urinary tract infection (UTI) occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD). However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown. Methods We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined. Results With a mean follow-up duration of 65.3 months, 176 (68.8%) out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01) and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension). The annual change in estimated glomerular filtration rate (?eGFR) was significantly larger in magnitude in group B than in group A (-2.7±4.56 vs. -1.17±5.8, respectively; P=0.01). Age and Group B found to be the independent variables for ?eGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001). Conclusions Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD. PMID:23295127

2013-01-01

245

Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease  

PubMed Central

Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4?), c.652C>T (p.Arg218?), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218?) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology. PMID:24387993

Basmanav, F. Buket; Oprisoreanu, Ana-Maria; Pasternack, Sandra M.; Thiele, Holger; Fritz, Gunter; Wenzel, Jorg; Grosser, Leopold; Wehner, Maria; Wolf, Sabrina; Fagerberg, Christina; Bygum, Anette; Altmuller, Janine; Rutten, Arno; Parmentier, Laurent; El Shabrawi-Caelen, Laila; Hafner, Christian; Nurnberg, Peter; Kruse, Roland; Schoch, Susanne; Hanneken, Sandra; Betz, Regina C.

2014-01-01

246

Extended Follow-Up of Unruptured Intracranial Aneurysms Detected by Presymptomatic Screening in Patients with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Summary Background and objectives Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). The importance of screening for unruptured IAs (UIAs) depends on their risks for growth and rupture. Design, setting, participants, & measurements ADPKD patients with UIAs found by presymptomatic screening with magnetic resonance angiography (MRA) during 1989 to 2009 were followed initially at 6 months and annually, and less frequently after demonstration of stability. Results Forty-five saccular aneurysms were detected in 38 patients from 36 families. Most were small (median diameter 3.5 mm) and in the anterior circulation (84%). Median age at diagnosis was 49 years. During cumulative imaging follow-up of 243 years, one de novo UIA was detected and increased in size from 2 to 4.4 mm over 144 months and two UIAs grew from 4.5 to 5.9 mm and 4.7 to 6.2 mm after 69 and 184 months, respectively. Seven patients did not have imaging follow-up. No change was detected in the remaining 28 patients. During cumulative clinical follow-up of 316 years, no aneurysm ruptured. Five patients died from unrelated causes and two were lost to follow-up after 8 and 120 months. Three patients underwent surgical clipping. Conclusions Most UIAs detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. Growth and rupture risks are not higher than those of UIAs in the general population. These data support very selective screening for UIAs in ADPKD patients, and widespread screening is not indicated. PMID:21551026

Irazabal, Maria V.; Huston, John; Kubly, Vickie; Rossetti, Sandro; Sundsbak, Jamie L.; Hogan, Marie C.; Harris, Peter C.; Brown, Robert D.

2011-01-01

247

Non-Image-Forming Light Driven Functions Are Preserved in a Mouse Model of Autosomal Dominant Optic Atrophy  

PubMed Central

Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies. PMID:23409176

Perganta, Georgia; Barnard, Alun R.; Katti, Christiana; Vachtsevanos, Athanasios; Douglas, Ron H.; MacLaren, Robert E.; Votruba, Marcela; Sekaran, Sumathi

2013-01-01

248

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

PubMed Central

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

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

1999-01-01

249

Transcriptional expression of cis-acting and trans-acting splicing mutations cause autosomal dominant retinitis pigmentosa.  

PubMed

Two types of mutations may lead to deficient pre-mRNA splicing: cis-acting mutations that inactivate a constitutive or alternative splice site within the pre-mRNA, and trans-acting mutations that affect the function of a basal factor of the splicing machinery. Autosomal dominant retinitis pigmentosa (adRP) is caused by mutations in at least 12 genes, with mutations in rhodopsin being the most prevalent. Two cis-acting mutations, g.3811A>G and g.5167G>T at the splice site in the rhodopsin gene (RHO; GenBank U49742.1) are linked to adRP in a Spanish population; while a cis-acting mutation, g.4335G>T, has been linked to recessive RP (arRP). Transcriptional expression analysis showed that the cis-acting splicing mutations linked to adRP promoted alternative splice sites, while the arRP linked mutation results in exclusion of exon 4. Trans-acting splicing mutations associated with adRP have also been found, and mutations in the pre-mRNA splicing factors PRPF3, PRPF8, PRPF31, and RP9 are associated with adRP in several populations. This report describes a new mutation in PRPF3 in a Spanish adRP family. We also investigated the transcriptional patterns in Epstein-Barr virus (EBV)-transformed lymphoblastoid cells from patients carrying a mutation in PRPF8. Despite the role of PRPF8 in the minor U12 splicing processes, microarray analysis revealed that mutations in PRPF8 not only did not result in significant differences in splicing efficiency of rhodopsin, but no apparent changes in expression of U12-type intron genes and splicing processes was observed. Microarray analysis revealed a panel of differentially expressed genes mapped to the RP loci, and future work will determine their role in RP. PMID:18412284

Gamundi, María José; Hernan, Imma; Muntanyola, Marta; Maseras, Miquel; López-Romero, Pedro; Alvarez, Rebeca; Dopazo, Ana; Borrego, Salud; Carballo, Miguel

2008-06-01

250

Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex  

PubMed Central

Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery. PMID:23246290

Pasternack, Sandra M.; Refke, Melanie; Paknia, Elham; Hennies, Hans Christian; Franz, Thomas; Schafer, Niklas; Fryer, Alan; van Steensel, Maurice; Sweeney, Elizabeth; Just, Miquel; Grimm, Clemens; Kruse, Roland; Ferrandiz, Carlos; Nothen, Markus M.; Fischer, Utz; Betz, Regina C.

2013-01-01

251

Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance.  

PubMed

The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome-wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans. PMID:23664119

Peeters, Kristien; Litvinenko, Ivan; Asselbergh, Bob; Almeida-Souza, Leonardo; Chamova, Teodora; Geuens, Thomas; Ydens, Elke; Zimo?, Magdalena; Irobi, Joy; De Vriendt, Els; De Winter, Vicky; Ooms, Tinne; Timmerman, Vincent; Tournev, Ivailo; Jordanova, Albena

2013-06-01

252

Autosomal recessive  

MedlinePLUS

Genetics - autosomal recessive; Inheritance - autosomal recessive ... an autosomal disorder. Genes come in pairs. Recessive inheritance means ... OF INHERITING A TRAIT If you are born to parents who both ...

253

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1  

Microsoft Academic Search

Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic\\u000a heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism\\u000a of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically\\u000a characterized. Two known DSAP loci, DSAP1 and

Ping Liu; Shouyan Zhang; Qi Yao; Xiangyang Liu; Xu Wang; Changzheng Huang; Xinyuan Huang; Pengyun Wang; Mingxiong Yuan; Jing Yu Liu; Qing K. Wang; Mugen Liu

2008-01-01

254

Breakpoint characterization of a novel ?59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance  

Microsoft Academic Search

The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene

Linda Köhn; Sara J Bowne; Lori S Sullivan; Stephen P Daiger; Marie SI Burstedt; Konstantin Kadzhaev; Ola Sandgren; Irina Golovleva

2009-01-01

255

Clinical features of a Japanese family with autosomal dominant retinitis pigmentosa associated with a Thr494Met mutation in the HPRP3 gene  

Microsoft Academic Search

Purpose To determine the clinical features of a Japanese family with autosomal dominant retinitis pigmentosa (ADRP) associated with a Thr494Met mutation in the HPRP3 gene. Methods Mutational screening by direct sequencing was performed on 96 unrelated patients with ADRP. The clinical features were determined by visual acuity, slit-lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing. Results A Thr494Met

Yuko Wada; Toshitaka Itabashi; Hajime Sato; Makoto Tamai

2004-01-01

256

A Human Homolog of Yeast Pre-mRNA Splicing Gene, PRP31, Underlies Autosomal Dominant Retinitis Pigmentosa on Chromosome 19q13.4 ( RP11)  

Microsoft Academic Search

We report mutations in a gene (PRPF31) homologous to Saccharomyces cerevisiae pre-mRNA splicing gene PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (RP11; MIM 600138). A positional cloning approach supported by bioinformatics identified PRPF31 comprising 14 exons and encoding a protein of 499 amino acids. The level of sequence identity to the yeast PRP31 gene indicates

Eranga N. Vithana; Leen Abu-Safieh; Maxine J. Allen; Alisoun Carey; Myrto Papaioannou; Christina Chakarova; Mai Al-Maghtheh; Neil D. Ebenezer; Catherine Willis; Anthony T. Moore; Alan C. Bird; David M. Hunt; Shomi S. Bhattacharya

2001-01-01

257

Prevalence of Disease-Causing Mutations in Families with Autosomal Dominant Retinitis Pigmentosa: A Screen of Known Genes in 200 Families  

Microsoft Academic Search

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 af-

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

2006-01-01

258

Strong homophilic interactions of the Ig-like domains of polycystin-1, the protein product of an autosomal dominant polycystic kidney disease gene, PKD1  

Microsoft Academic Search

The 14 kb mRNA of the polycystic kidney disease gene PKD1 encodes a novel large (~460 kDa) protein, polycystin-1, of unknown function that is responsible for autosomal dominant polycystic kidney disease (ADPKD). The unique organization of multiple adhe- sive domains of polycystin-1, including 16 Ig-like domains (or PKD domains) suggests that it may play an important role in cell-cell\\/cell-matrix interactions.

Oxana Ibraghimov-Beskrovnaya; Nikolay O. Bukanov; Lincoln C. Donohue; William R. Dackowski; Katherine W. Klinger; Gregory M. Landes

2000-01-01

259

Autosomal dominant Stargardt-like macular dystrophy: I. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14  

Microsoft Academic Search

Purpose: Characterize the phenotype of autosomal dominant Stargardt-like macular dystrophy in two families linked to chromosome 6q14 and determine whether they share a common ancestry.Methods: Two families spanning 10 generations were identified and studied independently. Participating members were examined and genetic linkage and genotyping performed.Results: Presenting symptoms included decreased vision, hemeralopia, and mild photophobia. The subjective onset of visual loss

Albert O Edwards; Anita Miedziak; Tamara Vrabec; Janneke Verhoeven; Ted S Acott; Richard G Weleber; Larry A Donoso

1999-01-01

260

Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation  

Microsoft Academic Search

Expansion of CTG\\/CAG trinucleotide repeats has been shown to cause a number of autosomal dominant cerebellar ataxias (ADCA) such as SCA1, SCA2, SCA3\\/MJD, SCA6, SCA7, SCA8 and DRPLA. There is a wide variation in the clinical phenotype and prevalence of these ataxias in different populations. An analysis of ataxias in 42 Indian families indicates that SCA2 is the most frequent

Quasar Saleem; Shweta Choudhry; Mitali Mukerji; Leena Bashyam; M. V. Padma; A. Chakravarthy; M. C. Maheshwari; S. Jain; S. K. Brahmachari

2000-01-01

261

Classification and identification of inherited brachydactylies  

Microsoft Academic Search

A search for patterns of malformation in the brachydactylies has resulted in new ways to identify the different types. Type A-1 can be characterised by a proportionate reduction of the middle phalanges. Type B is thought to be an amputation-like defect. In type C the fourth middle phalanx is usually the longest, and type E (Riccardi and Holmes, 1974) is

Naomi Fitch

1979-01-01

262

Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia  

SciTech Connect

We report three unrelated families in which hyperthyroidism associated with thyroid hyperplasia was transmitted in an autosomal dominant fashion, in the absence of signs of autoimmunity. Exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from DNA of peripheral leukocytes. In one family, a C to A transversion resulted in an S505R substitution in the third transmembrane segment; in the second, an A to T transversion caused an N650Y substitution in the sixth transmembrane segment; and in the third family, an A to G transition resulted in an N670S substitution in the seventh transmembrane segment. When expressed by transfection in COS-7 cells, each mutated receptor displayed an increase in constitutive stimulation of cAMP production; no effect on basal accumulation of inositol phosphates (IP) could be detected. In binding studies, cells transfected with wild-type of mutated receptors showed similar levels of expression, with the mutated receptors displaying similar or slightly increased affinity for bovine TSH (bTSH) binding. Cells transfected with S505R and N650Y mutants showed a similar cAMP maximal TSH-stimulated accumulation over the cells transfected with the wild type, whereas N670S transfectants showed a blunted response with an increase in EC{sub 50}. A higher IP response to 100 mU/mL bTSH over that obtained with the wild-type receptor was obtained in cells transfected with N650Y; in contrast, cells transfected with S505R showed a blunted IP production (50% less), and the N670S mutant completely lost the ability to stimulate IP accumulation in response to bTSH. The differential effects of individual mutations on stimulation by bTSH of cAMP or IP accumulation suggest that individual mutant receptors may achieve different active conformations with selective abilities to couple to G{sub s}{alpha} and to G{sub q}{alpha}. 17 refs., 8 figs.

Tonacchera, M.; Van Sande, J.; Cetani, F. [Universite Libre de Bruxelles, Brussels (Belgium)] [and others] [Universite Libre de Bruxelles, Brussels (Belgium); and others

1996-02-01

263

Sirolimus ameliorates the enhanced expression of metalloproteinases in a rat model of autosomal dominant polycystic kidney disease  

Microsoft Academic Search

Background. Remodelling of matrix and tubular basement membranes (TBM) is a characteristic of polycystic kid- ney disease. We hypothesized that matrix and TBM degra- dation by metalloproteinases (MMPs) could promote cyst formation. We therefore investigated the renal expression of MMPs in the Han:SPRD rat model of autosomal domi- nant polycystic kidney disease (ADPKD) and examined the effect of sirolimus treatment

C. Berthier; Patricia R. Wahl; M ichel Le Hir; Hans-Peter Marti; Ulrich Wagner; Hubert Rehrauer; Andreas L. Serra

2008-01-01

264

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in the RDS Gene  

Microsoft Academic Search

PURPOSE. To examine the molecular genetic basis and pheno- typic characteristics of an unusual late-onset autosomal domi- nant macular dystrophy with features of age-related macular degeneration (AMD) in a large family (SUNY901), by using linkage and mutation analyses. METHODS. Blood samples were collected from 17 affected mem- bers, 17 clinically unaffected members, and 5 unrelated spouses. Clinical analyses included a

Shahrokh C. Khani; Athanasios J. Karoukis; Joyce E. Young; Rajesh Ambasudhan; Tracy Burch; Richard Stockton; Richard Alan Lewis; Lori S. Sullivan; Stephen P. Daiger; Elias Reichel; Radha Ayyagari

265

Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2  

PubMed Central

Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of ?1.3 Mb was performed. A microduplication of ?5.5 kb in a noncoding sequence ?110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb. PMID:19327734

Dathe, Katarina; Kjaer, Klaus W.; Brehm, Anja; Meinecke, Peter; Nurnberg, Peter; Neto, Jordao C.; Brunoni, Decio; Tommerup, Nils; Ott, Claus E.; Klopocki, Eva; Seemann, Petra; Mundlos, Stefan

2009-01-01

266

Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus.  

PubMed Central

We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome. Images Figure 1 PMID:9399901

Howard, T D; Guttmacher, A E; McKinnon, W; Sharma, M; McKusick, V A; Jabs, E W

1997-01-01

267

Mutation c. 1142 del G in the PRPF31 Gene in a Family with Autosomal Dominant Retinitis Pigmentosa (RP11) and Its Implications  

Microsoft Academic Search

Purpose  To identify a mutation in the PRPF31 gene in a family (Family K) with autosomal dominant retinitis pigmentosa (adRP) linked to 19q13.4 (RP11) and to find the\\u000a frequency of mutations in the PRPF31 gene among Japanese families with adRP.\\u000a \\u000a \\u000a \\u000a Methods  Genomic DNA specimens were prepared from five symptomatic and two asymptomatic members of Family K and an additional 39 patients\\u000a of

Kurenai Taira; Mitsuru Nakazawa; Motoya Sato

2007-01-01

268

A novel locus ( CORD12 ) for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1  

Microsoft Academic Search

Background  Rod-cone dystrophy, also known as retinitis pigmentosa (RP), and cone-rod dystrophy (CRD) are degenerative retinal dystrophies\\u000a leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French\\u000a family with autosomal dominant (ad) CRD.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome\\u000a SNP analysis with the use

Gaël Manes; Maxime Hebrard; Béatrice Bocquet; Isabelle Meunier; Delphine Coustes-Chazalette; Audrey Sénéchal; Anne Bolland-Augé; Diana Zelenika; Christian P Hamel

2011-01-01

269

Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis.  

PubMed

We report a missense mutation in the gap junction protein beta-3 (encoding Connexin 31), which was detected in only the affected members of a family in which the autosomal dominant skin disease erythrokeratoderma variabilis was segregating. The nucleotide change results in an arginine to proline substitution in codon 42. This residue is positioned on the first transmembrane/first extracellular domain of the gap junction protein with the mutation replacing a negatively charged residue with a nonpolar residue. This change may disrupt the conformation of the protein and voltage gating polarity leading to impaired channel function. PMID:10594760

Wilgoss, A; Leigh, I M; Barnes, M R; Dopping-Hepenstal, P; Eady, R A; Walter, J M; Kennedy, C T; Kelsell, D P

1999-12-01

270

The Deleted in Brachydactyly B Domain of ROR2 Is Required for Receptor Activation by Recruitment of Src  

Microsoft Academic Search

The transmembrane receptor 'ROR2' resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its' signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach,

Shiva Akbarzadeh; Lee M. Wheldon; Steve M. M. Sweet; Sonia Talma; Faraz Khosravi Mardakheh; John K. Heath

2008-01-01

271

Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.  

PubMed

Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process. PMID:11773002

Chakarova, Christina F; Hims, Matthew M; Bolz, Hanno; Abu-Safieh, Leen; Patel, Reshma J; Papaioannou, Myrto G; Inglehearn, Chris F; Keen, T Jeffrey; Willis, Catherine; Moore, Anthony T; Rosenberg, Thomas; Webster, Andrew R; Bird, Alan C; Gal, Andreas; Hunt, David; Vithana, Eranga N; Bhattacharya, Shomi S

2002-01-01

272

A Complex Phenotype of Peripheral Neuropathy, Myopathy, Hoarseness and Hearing Loss is Linked to an Autosomal Dominant Mutation in MYH14  

PubMed Central

Both peripheral neuropathy and distal myopathy are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. A complex phenotype of peripheral neuropathy, myopathy, hoarseness and hearing loss was diagnosed in a large autosomal dominant Korean family. A high density SNP-based linkage study mapped the underlying gene to a region on chromosome 19q13.3. The maximum multipoint LOD score was 3.794. Sequencing of 34 positional candidate genes in the segregating haplotype revealed a novel c.2822G>T (p.Arg941Leu) mutation in the gene MYH14, which encodes the nonmuscle myosin heavy chain 14. Clinically we observed a sequential pattern of the onset of muscle weakness starting from the anterior to the posterior leg muscle compartments followed by involvement of intrinsic hand and proximal muscles. The hearing loss and hoarseness followed the onset of distal muscle weakness. Histopathologic and electrodiagnostic studies revealed both chronic neuropathic and myopathic features in the affected patients. While mutations in MYH14 have been shown to cause nonsyndromic autosomal dominant hearing loss (DFNA4), the peripheral neuropathy, myopathy, and hoarseness have not been associated with MYH14. Therefore, we suggest that the identified mutation in MYH14 significantly expands the phenotypic spectrum of this gene. PMID:21480433

Choi, Byung-Ok; Kang, Sung Hee; Hyun, Young Se; Kanwal, Sumaria; Park, Sun Wha; Koo, Heasoo; Kim, Sang-Beom; Choi, Young-Chul; Yoo, Jeong Hyun; Kim, Jong-Won; Park, Kee Duk; Choi, Kyoung-Gyu; Kim, Song Ja; Züchner, Stephan; Chung, Ki Wha

2011-01-01

273

Two double non allelic heterozygotes for autosomal dominant polycystic kidney disease at loci PKD1 and PKD4 are not more affected than heterozygous relatives  

SciTech Connect

We describe a family in which both members of a non-consanguineous couple are affected by autosomal dominant polycystic kidney disease (ADPKD). They have three affected children without obvious clinical differences, and three affected grand-children. Two different morbid loci for this disease have been localized, PKD1 on chromosome 16p and PKD4 on chromosome 4q. There were four a priori mating possibilities for this couple: PKD1xPKD1, PKD1xPKD4 or PKD4xPKD1 and PKD4xPKD4. We demonstrate by linkage analysis that: (i) the father is heterozygous at the PKD1 locus (most probably a de novo mutation); (ii) the mother is heterozygous at the PKD4 locus. The abnormal alleles segregates as follows: one child has the abnormal PKD1, another child has the abnormal PKD4 while the third child is a compound heterozygote for both abnormal PKD1 and PKD4 alleles, which were both transmitted to one offspring. The clinical status of these subjects is similar to the status of their relatives in the same age range, suggesting that both PKD1 and PKD4 are truly dominant disease. As there is no other example of such a situation for heterogeneous dominant diseases, we discuss this issue and some possible pathogenic processes by comparison with the similar problem of expressivity in homozygotes for dominant diseases.

Bachner, L.; Vinet, M.C.; Kaplan, J.C. [ICGM-INSERM U129-CHU Cochin 24, Paris (France)] [and others

1994-09-01

274

[18F-FDG PET/CT diagnosis of liver cyst infection in a patient with autosomal dominant polycystic kidney disease and fever of unknown origin].  

PubMed

The diagnosis, localization and treatment of infected cysts in the kidney or liver of patients with autosomal dominant polycystic kidney disease (ADPKD) remain a clinical challenge. We report the findings of (18)F-FDG PET-CT in an ADPKD diagnosed patient who required renal transplantation five years before and in his follow up presented repeated episodes of bacteriemia without known focus on radiological tests performed. The (18)F-FDG PET-CT scan showed numerous hypermetabolic images with focal or ring-shaped morphology related to the content and the wall of some hepatic cysts. The increased metabolic activity was localized on segments VI and VII. We proceeded to drainage of one cyst in segment VI, removing 110 cc of purulent fluid which grew E. Coli BLEE. The (18)F-FDG PET/CT scan should be included in the diagnostic algorithm for detecting infected liver cysts in patients with ADPKD and fever of unknown origin. PMID:23153986

Banzo, J; Ubieto, M A; Gil, D; Prats, E; Razola, P; Tardín, L; Andrés, A; Rambalde, E F; Ayala, S M; Cáncer, L; Velilla, J

2013-01-01

275

A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11).  

PubMed

We report mutations in a gene (PRPF31) homologous to Saccharomyces cerevisiae pre-mRNA splicing gene PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (RP11; MIM 600138). A positional cloning approach supported by bioinformatics identified PRPF31 comprising 14 exons and encoding a protein of 499 amino acids. The level of sequence identity to the yeast PRP31 gene indicates that PRPF31 is also likely to be involved in pre-mRNA splicing. Mutations that include missense substitutions, deletions, and insertions have been identified in four RP11-linked families and three sporadic RP cases. The identification of mutations in a pre-mRNA splicing gene implicates defects in the splicing process as a novel mechanism of photoreceptor degeneration. PMID:11545739

Vithana, E N; Abu-Safieh, L; Allen, M J; Carey, A; Papaioannou, M; Chakarova, C; Al-Maghtheh, M; Ebenezer, N D; Willis, C; Moore, A T; Bird, A C; Hunt, D M; Bhattacharya, S S

2001-08-01

276

A novel INF2 mutation in a Korean family with autosomal dominant intermediate Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis.  

PubMed

Mutations in the inverted formin-2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot-Marie-Tooth (DI-CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI-CMT and FSGS by whole-exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS. PMID:24750328

Park, Hyung J; Kim, Hye J; Hong, Young B; Nam, Soo H; Chung, Ki W; Choi, Byung-Ok

2014-06-01

277

Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy phenotype in two siblings of a large family showing the same mutation  

PubMed Central

A 44-year-old Albanian male was consulted and diagnosed with dementia. His magnetic resonance imaging suggested diffuse white matter changes. The suspicion of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was raised, and a genetic analysis confirmed such a suspicion through uncovering a pathogenic mutation at the level of exon 4 (c.475C>T) of chromosome 19. The patient came from a large family of 13 children, all of whom underwent clinical, genetic, and imaging examination. The pathogenic mutation was found present only in his eldest sister (50 years old), and she presented also very suggestive signs of CADASIL in her respective imaging study, but without any clinically significant counterpart. All other siblings were free from clinical and radiological signs of the disorder. Our opinion was that we were dealing with a mutation showing a very low level of penetrance, with only two siblings affected in a large Albanian family with 13 children. PMID:24124395

Vyshka, Gentian; Kruja, Jera

2013-01-01

278

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval  

SciTech Connect

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal dominant cerebral arteriopathy characterized by the recurrence of subcortical infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. In the present study, these first 2 families and 13 additional ones, including a total of 199 potentially informative meiosis, have been genotyped with eight polymorphic markers located between D19S221 and D19S215. All families were linked to chromosome 19. The highest combined lod score (Z{sub max} = 37.24 at {theta} = .01) was obtained with marker D19S841, a new CA{sub n} microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families were used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S199 on 19p13.1. These data strongly suggest the genetic homogeneity of this recently identified condition and establish the value of its clinical and neuroimaging diagnostic criteria. Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region. 35 refs., 5 figs., 2 tabs.

Ducros, A.; Alamowitch, S.; Nagy, T. [INSERM U25, Paris (France)] [and others

1996-01-01

279

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

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.

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

1994-09-01

280

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

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

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

281

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

Microsoft Academic Search

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

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

282

Autosomal recessive polycystic kidney disease  

Microsoft Academic Search

Autosomal recessive polycystic kidney disease is a rare inherited disorder which usually becomes clinically manifest in early childhood, whereas autosomal dominant polycystic kidney disease usually is a disorder of adult onset. With increasing knowledge and improving diagnostic techniques, it becomes evident that the spectrum of both entities is much more variable than generally known. The presentation of autosomal recessive polycystic

K. Zerres

1992-01-01

283

SLC3A1 and SLC7A9 Mutations in Autosomal Recessive or Dominant Canine Cystinuria: A New Classification System  

PubMed Central

Background Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. Hypothesis/Objectives To determine urinary cystine concentrations, inheritance and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Animals Mixed and purebred Labrador Retrievers (n=6), Australian Cattle Dogs (6), Miniature Pinschers (4) and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Methods Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. Results In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed specific DNA tests were developed, but the prevalence of each mutation remains unknown. Conclusions and clinical importance These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. PMID:24001348

Brons, A.-K.; Henthorn, P. S.; Raj, K.; Fitzgerald, C. A.; Liu, J.; Sewell, A. C.; Giger, U.

2013-01-01

284

A missense mutation in the human connexin50 gene (GJA8) underlies autosomal dominant "zonular pulverulent" cataract, on chromosome 1q.  

PubMed Central

CZP1, a locus for autosomal dominant "zonular pulverulent" cataract, previously had been linked with the Duffy blood-group-antigen locus on chromosome 1q. Here we report genetic refinement of the CZP1 locus and show that the underlying mutation is present in GJA8, the gene for connexin50. To map the CZP1 locus we performed linkage analysis using microsatellite markers on two distantly related branches of the original Ev. pedigree, which now spans eight generations. Significantly positive two-point LOD score (Z) values were obtained for markers D1S2669 (maximum Z [Zmax] = 4.52; maximum recombination frequency [thetamax] = 0) and D1S514 (Zmax = 4.48; thetamax = 0). Multipoint analysis gave Zmax = 5.22 (thetamax = 0) at marker D1S2669. Haplotyping indicated that CZP1 probably lies in the genetic interval D1S2746-(20.6 cM)-D1S2771. Sequence analysis of the entire protein-coding region of the GJA8 gene from the pedigree detected a C-->T transition in codon 88, which introduced a novel MnlI restriction-enzyme site that also cosegregated with the cataract. This missense mutation is predicted to result in the nonconservative substitution of serine for a phylogenetically conserved proline (P88S). These studies provide the first direct evidence that GJA8 plays a vital role in the maintenance of human lens transparency and identify the genetic defect believed to underlie the first inherited disease to be linked to a human autosome. PMID:9497259

Shiels, A; Mackay, D; Ionides, A; Berry, V; Moore, A; Bhattacharya, S

1998-01-01

285

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

PubMed Central

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

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

2014-01-01

286

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

PubMed

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

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

287

A Novel DFNA36 Mutation in TMC1 Orthologous to the Beethoven (Bth) Mouse Associated with Autosomal Dominant Hearing Loss in a Chinese Family  

PubMed Central

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

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

288

A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family.  

PubMed

Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive rare disorder characterized by hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation. Loss of function mutations have been recently reported in the CHSY1 gene to cause the TPBS. Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene in two TPBS patients from a consanguineous Pakistani family. The mutation predicted substitution of a highly conserved aspartate amino acid residue to asparagine at position 633 in the protein (D633N). Polyphen analysis supported the pathogenicity of D36N mutation. Our finding extends the body of recent evidence that supports the role of CHSY1 as a potential mediator of BMP signaling. PMID:24269551

Sher, Gulab; Naeem, Muhammad

2014-01-01

289

Characteristic MR Lesion Pattern and Correlation of T1 and T2 Lesion Volume with Neurologic and Neuropsychological Findings in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)  

Microsoft Academic Search

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcor- tical infarcts and leukoencephalopathy (CADASIL) is an arteriopathy related to a genetic defect of the notch 3 gene on chromosome 19. The purpose of this study was to evaluate lesion distribution and volume using MR imaging and to correlate the lesion volume with the neu- rologic and neuropsychological findings. METHODS: Twenty

Tarek A. Yousry; Klaus Seelos; Michael Mayer; Roland Bruning; Ingo Uttner; Martin Dichgans; Sylvia Mammi; Andreas Straube; Norbert Mai; Massimo Filippi

290

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

PubMed Central

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

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

2011-01-01

291

Fine mapping of the Autosomal Dominant Split Hand/Split Foot Locus on Chromosome 7, Band q21.3-q22.1  

PubMed Central

Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locus (gene SHFD1) maps to 7q21-q22. To characterize the SHFD1 locus, somatic cell hybrid lines were constructed from cytogenetically abnormal individuals with SHFD. Molecular analysis resulted in the localization of 93 DNA markers to one of 10 intervals surrounding the SHFD1 locus. The translocation breakpoints in four SHFD patients were encompassed by the smallest region of overlap among the SHFD-associated deletions. The order of DNA markers in the SHFD1 critical region has been defined as PON–D7S812–SHFD1–D7S811–ASNS. One DNA marker, D7S811, detected altered restriction enzyme fragments in three patients with translocations when examined by pulsed-field gel electro-phoresis (PFGE). These data map SHFD1, a gene that is crucial for human limb differentiation, to a small interval in the q21.3-q22.1 region of human chromosome 7. ImagesFigure 1Figure 2Figure 4 PMID:8023840

Scherer, Stephen W.; Poorkaj, Parvoneh; Allen, Todd; Kim, Julia; Geshuri, Dorrit; Nunes, Mark; Soder, Sylvia; Stephens, Karen; Pagon, Roberta A.; Patton, Michael A.; Berg, Mary Anne; Donlon, Tim; Rivera, Horacio; Pfeiffer, R. A.; Naritomi, Kenji; Hughes, Helen; Genuardi, Maurizio; Gurrieri, Fiorella; Neri, Giovanni; Lovrein, Everett; Magenis, Ellen; Tsui, Lap-Chee; Evans, James P.

1994-01-01

292

Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.  

PubMed

A clinical impact of cognitive reserve (CR) has been demonstrated in Alzheimer's disease, whereas its role in vascular cognitive impairment (VCI) is largely unknown. In this study, we investigated the impact of CR in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic variant of pure VCI. A total of 247 NOTCH3 mutation carriers from a two-center study were investigated using detailed neuropsychological and neuroimaging protocols. CR was operationalized as years of formal education. Brain pathology was assessed by MRI using normalized brain volume and lacunar lesion volume as proxies. Multivariate analyses were done for each structural measure with scores of processing speed, executive function, and memory as dependent variables. Additional linear regression models were conducted with interaction terms for education × brain volume and education × lacunar lesion volume. Education had an independent impact on cognitive performance in subjects with mild and moderate degrees of brain pathology, whereas there was no significant influence of education on cognition in patients with severe MRI changes. This interaction was found for processing speed, the cognitive domain most impaired in our patients. Our findings demonstrate an interaction of education and brain pathology in regard to cognitive impairment: the effect of education seems most pronounced in early disease stages but may ultimately be overwhelmed by the pathological changes. The results extend the concept of CR to VCI. PMID:22626524

Zieren, Nikola; Duering, Marco; Peters, Nils; Reyes, Sonia; Jouvent, Eric; Hervé, Dominique; Gschwendtner, Andreas; Mewald, Yvonne; Opherk, Christian; Chabriat, Hugues; Dichgans, Martin

2013-02-01

293

Mutation in the PCSK9 Gene in Omani Arab Subjects with Autosomal Dominant Hypercholesterolemia and its Effect on PCSK9 Protein Structure  

PubMed Central

Proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. Mutations in the PCSK9 gene have previously been found to segregate with autosomal dominant familial hypercholesterolemia (ADFH). In this study, DNA sequencing of the 12 exons of the PCSK9 gene has been performed for two patients with a clinical diagnosis of familial hypercholesterolemia where mutation in the LDL-receptor gene hasn't been excluded. One missense mutation was detected in the exon 9 PCSK9 gene in the two ADFH patients. The patients were found to be heterozygote for Ile474Val (SNP rs562556). Using an array of in silico tools, we have investigated the effect of the above mutation on different structural levels of the PCSK9 protein. Although, the mutation has already been reported in the literature for other populations, to the best of our knowledge this is the first report of a mutation in the PCSK9 gene from the Arab population, including the Omani population. PMID:23386946

Al-Waili, Khalid; Al-Zidi, Ward Al-Muna; Al-Abri, Abdul Rahim; Al-Rasadi, Khalid; Al-Sabti, Hilal Ali; Shah, Karna; Al-Futaisi, Abdullah; Al-Zakwani, Ibrahim; Banerjee, Yajnavalka

2013-01-01

294

The gene for autosomal dominant craniometaphyseal dysplasia maps to chromosome 5p and is distinct from the growth hormone-receptor gene.  

PubMed Central

Craniometaphyseal dysplasia (CMD) is an osteochondrodysplasia of unknown etiology characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that finally may result in hearing loss and facial palsy. We have analyzed a large German kindred with autosomal dominant (AD) CMD and found tight linkage between the disorder and microsatellite markers on chromosome 5p (maximum two-point LOD score 4.82; theta = 0). Our results clearly establish the existence of a locus for AD CMD on central chromosome 5p (5p15.2-p14.1). This region overlaps with the mapping interval of the growth hormone-receptor (GHR) gene (5p14-p12), which is known to be involved in the mitogenic activation of osteoblasts. Therefore, we tested the GHR gene as a candidate gene. However, recombination events between the CMD locus and the GHR gene identified in two members of this family clearly exclude this candidate. PMID:9382103

Nürnberg, P; Tinschert, S; Mrug, M; Hampe, J; Müller, C R; Fuhrmann, E; Braun, H S; Reis, A

1997-01-01

295

Breakpoint characterization of a novel approximately 59 kb genomic deletion on 19q13.42 in autosomal-dominant retinitis pigmentosa with incomplete penetrance.  

PubMed

The aim of this study was to identify and characterize the underlying molecular mechanisms in autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance in two Swedish families. An extended genealogical study and haplotype analysis indicated a common origin. Mutation identification was carried out by multiplex ligation-dependent probe amplification (MLPA) and sequencing. Clinical examinations of adRP families including electroretinography revealed obligate gene carriers without abnormalities, which indicated incomplete penetrance. Linkage analysis resulted in mapping of the disease locus to 19q13.42 (RP11). Sequence analyses did not reveal any mutations segregating with the disease in eight genes including PRPF31. Subsequent MLPA detected a large genomic deletion of 11 exons in the PRPF31 gene and, additionally, three genes upstream of the PRPF31. Breakpoints occurred in intron 11 of PRPF31 and in LOC441864, 'similar to osteoclast-associated receptor isoform 5.' An almost 59 kb deletion segregated with the disease in all affected individuals and was present in several asymptomatic family members but not in 20 simplex RP cases or 94 healthy controls tested by allele-specific PCR. A large genomic deletion resulting in almost entire loss of PRPF31 and three additional genes identified as the cause of adRP in two Swedish families provide an additional evidence that mechanism of the disease evolvement is haploinsufficiency. Identification of the deletion breakpoints allowed development of a simple tool for molecular testing of this genetic subtype of adRP. PMID:19050727

Köhn, Linda; Bowne, Sara J; S Sullivan, Lori; Daiger, Stephen P; Burstedt, Marie S I; Kadzhaev, Konstantin; Sandgren, Ola; Golovleva, Irina

2009-05-01

296

Novel deletion in the pre-mRNA splicing gene PRPF31 causes autosomal dominant retinitis pigmentosa in a large Chinese family.  

PubMed

We report the identification of a novel 12 bp deletion of the pre-mRNA splicing gene PRPF31 in a large Chinese family with autosomal dominant retinitis pigmentosa (adRP). This mutation results in the deletion of four amino acids (DeltaH(111)K(112)F(113)I(114)) including H(111), an amino acid residue that is highly conserved throughout evolution. The 12 bp deletion co-segregates with the disease phenotype in 19 RP patients in the family, but is not present in unaffected relatives or 100 normal individuals. Our data indicate that the novel 12 bp deletion in PRPF31 causes retinitis pigementosa in this Chinese adRP family. In contrast to the incomplete penetrance observed in most adRP families linked to chromosome band 19q13.4 (RP11), the 12 bp PRPF31 deletion identified in this study appears to show high penetrance. These data expand the spectrum of PRPF31 mutations causing adRP, and confirm the role of PRPF31 in the pathogenesis of RP. PMID:12923864

Wang, Lejin; Ribaudo, Michael; Zhao, Kanxing; Yu, Ning; Chen, Qiuyun; Sun, Qiuxiang; Wang, Liming; Wang, Qing

2003-09-01

297

Intermediate Volume on Computed Tomography Imaging Defines a Fibrotic Compartment that Predicts Glomerular Filtration Rate Decline in Autosomal Dominant Polycystic Kidney Disease Patients  

PubMed Central

Total kidney and cyst volumes have been used to quantify disease progression in autosomal dominant polycystic kidney disease (ADPKD), but a causal relationship with progression to renal failure has not been demonstrated. Advanced image processing recently allowed to quantify extracystic tissue, and to identify an additional tissue component named “intermediate,” appearing hypoenhanced on contrast-enhanced computed tomography (CT). The aim of this study is to provide a histological characterization of intermediate volume, investigate its relation with renal function, and provide preliminary evidence of its role in long-term prediction of functional loss. Three ADPKD patients underwent contrast-enhanced CT scans before nephrectomy. Histological samples of intermediate volume were drawn from the excised kidneys, and stained with hematoxylin and eosin and with saturated picrosirius solution for histological analysis. Intermediate volume showed major structural changes, characterized by tubular dilation and atrophy, microcysts, inflammatory cell infiltrate, vascular sclerosis, and extended peritubular interstitial fibrosis. A significant correlation (r = ?0.69, P < 0.001) between relative intermediate volume and baseline renal function was found in 21 ADPKD patients. Long-term prediction of renal functional loss was investigated in an independent cohort of 13 ADPKD patients, followed for 3 to 8 years. Intermediate volume, but not total kidney or cyst volume, significantly correlated with glomerular filtration rate decline (r = ?0.79, P < 0.005). These findings suggest that intermediate volume may represent a suitable surrogate marker of ADPKD progression and a novel therapeutic target. PMID:21683674

Caroli, Anna; Antiga, Luca; Conti, Sara; Sonzogni, Aurelio; Fasolini, Giorgio; Ondei, Patrizia; Perico, Norberto; Remuzzi, Giuseppe; Remuzzi, Andrea

2011-01-01

298

Intermediate volume on computed tomography imaging defines a fibrotic compartment that predicts glomerular filtration rate decline in autosomal dominant polycystic kidney disease patients.  

PubMed

Total kidney and cyst volumes have been used to quantify disease progression in autosomal dominant polycystic kidney disease (ADPKD), but a causal relationship with progression to renal failure has not been demonstrated. Advanced image processing recently allowed to quantify extracystic tissue, and to identify an additional tissue component named "intermediate," appearing hypoenhanced on contrast-enhanced computed tomography (CT). The aim of this study is to provide a histological characterization of intermediate volume, investigate its relation with renal function, and provide preliminary evidence of its role in long-term prediction of functional loss. Three ADPKD patients underwent contrast-enhanced CT scans before nephrectomy. Histological samples of intermediate volume were drawn from the excised kidneys, and stained with hematoxylin and eosin and with saturated picrosirius solution for histological analysis. Intermediate volume showed major structural changes, characterized by tubular dilation and atrophy, microcysts, inflammatory cell infiltrate, vascular sclerosis, and extended peritubular interstitial fibrosis. A significant correlation (r = -0.69, P < 0.001) between relative intermediate volume and baseline renal function was found in 21 ADPKD patients. Long-term prediction of renal functional loss was investigated in an independent cohort of 13 ADPKD patients, followed for 3 to 8 years. Intermediate volume, but not total kidney or cyst volume, significantly correlated with glomerular filtration rate decline (r = -0.79, P < 0.005). These findings suggest that intermediate volume may represent a suitable surrogate marker of ADPKD progression and a novel therapeutic target. PMID:21683674

Caroli, Anna; Antiga, Luca; Conti, Sara; Sonzogni, Aurelio; Fasolini, Giorgio; Ondei, Patrizia; Perico, Norberto; Remuzzi, Giuseppe; Remuzzi, Andrea

2011-08-01

299

Refining the localization of the PKD2 locus on chromosome 4q by linkage analysis in Spanish families with autosomal dominant polycystic kidney disease type 2  

SciTech Connect

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder. At least two distinct forms of ADPKD are now well defined. In {approximately}86% of affected European families, a gene defect localized to 16p13.3 was responsible for ADPKD, while a second locus has been recently localized to 4q13-q23 as candidate for the disease in the remaining families. We present confirmation of linkage to microsatellite markers on chromosome 4q in eight Spanish families with ADPKD, in which the disease was not linked to 16p13.3. By linkage analysis with marker D4S423, a maximum lod score of 9.03 at a recombination fraction of .00 was obtained. Multipoint linkage analysis, as well as a study of recombinant haplotypes, placed the PKD2 locus between D4S1542 and D4S1563, thereby defining a genetic interval of {approximately}1 cM. The refined map will serve as a genetic framework for additional genetic and physical mapping of the region and will improve the accuracy of presymptomatic diagnosis of PKD2. 25 refs., 4 figs., 1 tab.

San Millan, J.L.; Viribay, M.; Peral, B.; Moreno, F. [Unidad de Genetica Molecular, Madrid (Spain); Martinez, I. [Hospital de Galdacano (Spain); Weissenbach, J. [Genethon, Evry (France)

1995-01-01

300

A Non-Synonymous Mutation in the Canine Pkd1 Gene Is Associated with Autosomal Dominant Polycystic Kidney Disease in Bull Terriers  

PubMed Central

Polycystic Kidney Disease is an autosomal dominant disease common in some lines of Bull Terriers (BTPKD). The disease is linked to the canine orthologue of human PKD1 gene, Pkd1, located on CFA06, but no disease-associated mutation has been reported. This study sequenced genomic DNA from two Bull Terriers with BTPKD and two without the disease. A non-synonymous G>A transition mutation in exon 29 of Pkd1 was identified. A TaqMan® SNP Genotyping Assay was designed and demonstrated the heterozygous detection of the mutation in 47 Bull Terriers with BTPKD, but not in 102 Bull Terriers over one year of age and without BTPKD. This missense mutation replaces a glutamic acid residue with a lysine residue in the predicted protein, Polycystin 1. This region of Polycystin 1 is highly conserved between species, and is located in the first cytoplasmic loop of the predicted protein structure, close to the PLAT domain and the second transmembrane region. Thus, this change could alter Polycystin 1 binding or localization. Analytic programs PolyPhen 2, Align GVGD and SIFT predict this mutation to be pathogenic. Thus, BTPKD is associated with a missense mutation in Pkd1, and the application of this mutation specific assay could reduce disease transmission by allowing diagnosis of disease in young animals prior to breeding. PMID:21818326

Gharahkhani, Puya; O'Leary, Caroline A.; Kyaw-Tanner, Myat; Sturm, Richard A.; Duffy, David L.

2011-01-01

301

Detection of the single nucleotide polymorphism causing feline autosomal-dominant polycystic kidney disease in Persians from the UK using a novel real-time PCR assay.  

PubMed

Autosomal-dominant polycystic kidney disease (AD-PKD) is the most prevalent inherited genetic disease of cats, particularly affecting Persians. Until recently the condition has been diagnosed by renal ultrasound screening. With the identification of the genetic mutation responsible for AD-PKD it is now possible to use advanced molecular techniques to screen for the disease. We have developed a rapid, sensitive and specific real-time PCR genotyping assay that can detect the single nucleotide polymorphism responsible for AD-PKD. Of 72 UK Persian and Exotic Shorthair cats submitted for AD-PKD ultrasound screening, 29 were found to have the disease, 41 were negative and 2 were equivocal. The recently published PCR-RFLP method showed the AD-PKD mutation to be present in all 29 diseased cats and absent in the 41 negative and 2 equivocal cats. Our real-time PCR genotyping assay was in complete agreement with the PCR-RFLP results. Of 600 blood or buccal swabs analysed from April 2005 to January 2006, 165 were found to be AD-PKD positive and 435 were negative, giving a prevalence of 27.5%. All 194 cats with AD-PKD were found to be heterozygous for the mutation. PMID:16950597

Helps, Chris R; Tasker, Séverine; Barr, Frances J; Wills, Sheila J; Gruffydd-Jones, Timothy J

2007-02-01

302

Molecular heterogeneity of autosomal dominant cerebellar ataxia: analysis of flanking microsatellites of the spinocerebellar ataxia 1 locus in a northern European family unequivocally demonstrates non-linkage.  

PubMed

This study addresses the question whether the different forms of autosomal dominant cerebellar ataxia (ADCA) are related to different ethnic/geographical regions in Europe. One mutation in families originating from Holland, Prussia and Italy has previously been localized to chromosome 6p (SCA1 locus), whereas the mutation in families of Iberic origin has been excluded from chromosome 6p. In a Danish five-generation pedigree with ADCA and in which previous HLA-serotyping had shown inconclusive linkage results, the present study shows unequivocal exclusion from the SCA1 locus, firstly through the use of the new, highly informative microsatellites D6S89 and D6S109, which closely flank the SCA1 locus, and secondly through the manifestation of disease in four pedigree members previously scored as unaffected. Additional molecular genetic analysis of the HLA DRbeta and F13A polymorphisms also argue against a cluster of ADCA genes on chromosome 6p. Since this study demonstrates the existence of non-SCA1 families and therefore heterogeneity in the North-European population, molecular family counselling remains restricted to the few known SCA1 families. PMID:8099059

Lunkes, A; Gispert, S; Enczmann, J; Auburger, G

1993-05-01

303

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families.  

PubMed

Autosomal dominant cerebellar ataxia (ADCA) is a genetically heterogeneous group of neurodegenerative disorders. To shed further light on the clinical and genetic spectrum of ADCA in Japan, we conducted a study to determine the frequency of a new variety of different subtypes of SCAs among ADCA patients. This current study was carried out from April 1999 to December 2006 on the basis of patients with symptoms and signs of ADCA disorders. PCR and/or direct sequencing were evaluated in a total of 113 families. Among them, 35 families were found to have the mutation associated with SCA6, 30 with SCA3, 11 with SCA1, five with SCA2, five with DRPLA, and one with SCA14. We also detected the heterozygous -16C --> T single nucleotide substitution within the puratrophin-1 gene responsible for 16q22.1-linked ADCA in ten families. In this study, unusual varieties of SCA, including 27, 13, 5, 7, 8, 12, 17, and 16 were not found. Of the 113 patients, 14% had as yet unidentified ADCA mutations. The present study validates the prevalence of genetically distinct ADCA subtypes based on ethnic origin and geographical variation, and shows that 16q-linked ADCA has strong hereditary effects in patients with ADCAs in Japan. PMID:17805477

Basri, Rehana; Yabe, Ichiro; Soma, Hiroyuki; Sasaki, Hidenao

2007-01-01

304

Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis  

SciTech Connect

Postaxial polydactyly type-A (PAP-A) in humans is an autosomal dominant trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is well formed and articulates with the fifth, or extra, metacarpal/metatarsal, and thus it is usually functional. In order to map the gene responsible for PAP-A, we studied a five-generation Indian family of 37 individuals (15 of whom were affected). A genomewide search with highly informative polymorphic markers on part of the pedigree showed linkage between the PAP-A phenotype and markers on chromosome 7p15-q11.23 (no crossovers were found with D7S526, D7S795, D7S528, D7S521, D7S691, D7S667, D7S478, D7S1830, D7S803, D7S801, or ELN). The highest LOD score was obtained with marker D7S801 (Z{sub max} = 4.21; {theta} = 0). Haplotype analysis enabled the mapping of the PAP-A phenotype in this family between markers D7S2848 and D7S669. Analysis of additional families with PAP-A will narrow down the critical genomic region, facilitate positional cloning of the PAP-A gene, and/or uncover potential genetic heterogeneity. 42 refs., 4 figs., 1 tab.

Radhakrishna, U.; Mehenni, H.; Antonarakis, S.E. [Geneva Medical School (Switzerland)] [and others

1997-03-01

305

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

PubMed

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

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

306

Autosomal-dominant branchio-otic (BO) syndrome is not allelic to the branchio-oto-renal (BOR) gene at 8q13.  

PubMed

The manifestations of branchio-oto-renal syndrome (BOR), Treacher Collins syndrome, tricho-rhino-phalangeal syndrome, van der Woude syndrome, and Langer-Giedion syndrome are well-defined; these conditions represent clinically and genetically separate syndromes. Autosomal-dominant branchio-oto-renal syndrome comprises preauricular pits, branchial fistulas, hearing loss, and renal anomalies. However, several families have been described without one or more of these clinical findings. In some families, the phenotypic expression is limited to branchial anomalies, preauricular pits, and hearing loss, with no renal dysplasia (branchio-otic or BO syndrome). In other families, branchial and renal anomalies occur without hearing impairment. It is not known whether the variable clinical manifestations are due to the effect of a single gene or whether these represent different syndromes. We investigated BO syndrome in a large family to determine whether BOR and BO syndromes are allelic to each other. The genetic linkage analysis provides evidence that BO syndrome is not allelic to the BOR gene at 8q13. PMID:9556298

Kumar, S; Marres, H A; Cremers, C W; Kimberling, W J

1998-04-13

307

Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa  

PubMed Central

Purpose The purpose of this project was to determine the spectrum and frequency of mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) that cause autosomal dominant retinitis pigmentosa (adRP). Methods A well-characterized adRP cohort of 251 families was tested for mutations in the exons and intron/exon junctions of SNRNP200 using fluorescent dideoxy sequencing. An additional 21 adRP families from the eyeGENE® Network were tested for possible mutations. Bioinformatic and segregation analysis was performed on novel variants. Results SNRNP200 mutations were identified in seven of the families tested. Two previously reported mutations, p.Arg681Cys and p.Ser1087Leu, were found in two families each. One family had the previously reported p.Arg681His mutation. Two novel SNRNP200 variants, p.Pro682Ser and p.Ala542Val, were also identified in one family each. Bioinformatic and segregation analyses suggested that these novel variants are likely to be pathogenic. Clinical examination of patients with SNRNP200 mutations showed a wide range of clinical symptoms and severity, including one instance of non-penetrance. Conclusions Mutations in SNRNP200 caused 1.6% of disease in our adRP cohort. Pathogenic mutations were found primarily in exons 16 and 25, but the novel p.Ala542Val mutation in exon 13 suggests that variation in other genetic regions is also responsible for causing dominant disease. SNRNP200 mutations were associated with a wide range of clinical symptoms similar to those of individuals with other splice-factor gene mutations. PMID:24319334

Sullivan, Lori S.; Avery, Cheryl E.; Sasser, Elizabeth M.; Roorda, Austin; Duncan, Jacque L.; Wheaton, Dianna H.; Birch, David G.; Branham, Kari E.; Heckenlively, John R.; Sieving, Paul A.; Daiger, Stephen P.

2013-01-01

308

Role of endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism on the progression of renal disease in autosomal dominant polycystic kidney disease  

PubMed Central

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder, and it is mainly associated with renal cyst formation. Several studies have also shown that these mutations regulate the physiology of epithelial tissues and determine renal cyst formation and growth in polycystic kidney disease (PKD). Nitric oxide (NO) is also considered to be an important factor involved in the deterioration of renal function. Objectives: The aim of the current study is to determine the frequency of NOS3 27-bp VNTR in ADPKD patients and to investigate the role of NOS3 27-bp VNTR genotypes in the modification of progression of renal disease in ADPKD.Patients and Methods: The hypothesis was investigated by studying the South Indian population of 53 ADPKD patients and 94 unrelated healthy controls. The genotyping was performed by polymerase chain reaction and electrophoresis. Genotypes were compared between ADPKD and controls using the ?2-test. Univariate and multivariate logistic regression analyses were performed to assess the effect of genotypes and hypertension on the progress of chronic kidney disease (CKD). A stratified analysis was also performed to assess the evidence of the modification of hypertension-CKD relationship among VNTR genotypes. Results: The NOS3 4a allele frequencies were 21.3% and 13.2% respectively for controls and ADPKD groups. The NOS3 VNTR genotypes and alleles were not associated with ADPKD. The univariate analysis showed that age, hypertension and NOS3 VNTR influenced the advancement of CKD. Conclusion: The present study confirms the significant association between the 27-bp VNTR and CKD advancement among the ADPKD patients in the South Indian population. PMID:25340172

Elumalai, Ramprasad; Periasamy, Soundararajan; Ramanathan, Gnanasambandan; Lakkakula, Bhaskar VKS

2014-01-01

309

Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin.  

PubMed

Although fixation of the stapes is usually progressive and secondary to otosclerosis, it may present congenitally, with other skeletal manifestations, as an autosomal dominant syndrome-such as proximal symphalangism (SYM1) or multiple-synostoses syndrome (SYNS1), both of which are caused by mutations in NOG, the gene encoding noggin. We describe a family that was ascertained to have nonsyndromic otosclerosis but was subsequently found to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism. A heterozygous nonsense NOG mutation-c.328C-->T (Q110X), predicted to truncate the latter half of the protein-was identified, and a heterozygous insertion in NOG-c.252-253insC, in which the frameshift is predicted to result in 96 novel amino acids before premature truncation-was identified in a previously described second family with a similar phenotype. In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain. These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism. PMID:12089654

Brown, David J; Kim, Theresa B; Petty, Elizabeth M; Downs, Catherine A; Martin, Donna M; Strouse, Peter J; Moroi, Sayoko E; Milunsky, Jeff M; Lesperance, Marci M

2002-09-01

310

Erythropoietin production in renal cell carcinoma and renal cysts in autosomal dominant polycystic kidney disease in a chronic dialysis patient with polycythemia: A case report  

PubMed Central

In patients undergoing chronic hemodialysis (HD), erythropoietin (EPO) production from the kidney generally decreases and renal anemia develops. Patients without anemia, but with high serum EPO (sEPO) levels are rare among HD patients. The current study presents the case of a 67-year-old female HD patient with autosomal dominant polycystic kidney disease (ADPKD) and renal cell carcinoma (RCC), manifesting polycythemia with elevated sEPO levels. A radical nephrectomy was performed, which diminished the polycythemia, but the sEPO levels remained high. To determine the origin of the EPO production, immunohistochemistry was performed to detect EPO in the RCC and the renal cysts of the surgically resected kidney. In addition, the sEPO and EPO levels in a renal cyst were determined by enzyme immunoassay. EPO expression was demonstrated in RCC and cyst epithelial cells using immunohistochemistry, revealing extremely high EPO levels in the cyst fluid. Due to the remission of polycythemia following the nephrectomy, EPO production from the resected kidney appeared to have been the cause of the polycythemia. Positive EPO staining of the renal cysts in the resected polycystic kidney and sustained sEPO elevation following nephrectomy led to the hypothesis of EPO production in the renal cysts of the contralateral polycystic kidney. Although the postoperative EPO level was higher than the normal range, the hematocrit (Hct) level gradually decreased and recombinant human EPO was required again three months following the nephrectomy. Eight months after the nephrectomy, the Hct level was 30.2% with the use of rHuEPO. In conclusion, EPO production from RCC and renal cysts in ADPKD appeared to cause polycythemia in the HD patient.

ITO, KEIICHI; ASANO, TAKAKO; TOMINAGA, SUSUMU; YOSHII, HIDEHIKO; SAWAZAKI, HARUTAKE; ASANO, TOMOHIKO

2014-01-01

311

A Mutation in the 5?-UTR of IFITM5 Creates an In-Frame Start Codon and Causes Autosomal-Dominant Osteogenesis Imperfecta Type V with Hyperplastic Callus  

PubMed Central

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ?65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5?-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.?14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.?14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation. PMID:22863195

Semler, Oliver; Garbes, Lutz; Keupp, Katharina; Swan, Daniel; Zimmermann, Katharina; Becker, Jutta; Iden, Sandra; Wirth, Brunhilde; Eysel, Peer; Koerber, Friederike; Schoenau, Eckhard; Bohlander, Stefan K.; Wollnik, Bernd; Netzer, Christian

2012-01-01

312

Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity  

SciTech Connect

Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. The authors have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analyses and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the [open quotes]linked[close quotes] families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

Othmane, K.B.; Loprest, L.J.; Wilkinson, K.M. (Duke Univ. Medical Center, Durham, NC (United States)); Middleton, L.T. (Cyprus Institute of Neurology and Genetics, Nicosia (Cyprus)) (and others)

1993-08-01

313

Detection of novel mutations that cause autosomal dominant retinitis pigmentosa in candidate genes by long-range PCR amplification and next-generation sequencing  

PubMed Central

Purpose To devise an effective method for detecting mutations in 12 genes (CA4, CRX, IMPDH1, NR2E3, RP9, PRPF3, PRPF8, PRPF31, PRPH2, RHO, RP1, and TOPORS) commonly associated with autosomal dominant retinitis pigmentosa (adRP) that account for more than 95% of known mutations. Methods We used long-range PCR (LR-PCR) amplification and next-generation sequencing (NGS) performed in a GS Junior 454 benchtop sequencing platform. Twenty LR-PCR fragments, between 3,000 and 10,000 bp, containing all coding exons and flanking regions of the 12 genes, were obtained from DNA samples of patients with adRP. Sequencing libraries were prepared with an enzymatic (Fragmentase technology) method. Results Complete coverage of the coding and flanking sequences of the 12 genes assayed was obtained with NGS, with an average sequence depth of 380× (ranging from 128× to 1,077×). Five previous known mutations in the adRP genes were detected with a sequence variation percentage between 35% and 65%. We also performed a parallel sequence analysis of four samples, three of them new patients with index adRP, in which two novel mutations were detected in RHO (p.Asn73del) and PRPF31 (p.Ile109del). Conclusions The results demonstrate that genomic LR-PCR amplification together with NGS is an effective method for analyzing individual patient samples for mutations in a monogenic heterogeneous disease such as adRP. This approach proved effective for the parallel analysis of adRP and has been introduced as routine. Additionally, this approach could be extended to other heterogeneous genetic diseases. PMID:23559859

Dias, Miguel de Sousa; Hernan, Imma; Pascual, Beatriz; Borras, Emma; Mane, Begona; Gamundi, Maria Jose

2013-01-01

314

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

PubMed

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

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

1993-12-01

315

Network Analysis of a Pkd1-Mouse Model of Autosomal Dominant Polycystic Kidney Disease Identifies HNF4? as a Disease Modifier  

PubMed Central

Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095) leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation and cyst formation by applying transcriptomics and metabolomics to follow disease progression in a large number of animals induced before P10. Weighted gene co-expression network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. Knowledge-based Ingenuity Pathway Analysis (IPA) software identifies HNF4? as a likely network node. These results are further supported by a meta-analysis of 1,114 published gene expression arrays in Pkd1 wild-type tissues. These analyses also predict that metabolic pathways are key elements in postnatal kidney maturation and early steps of cyst formation. Consistent with these findings, urinary metabolomic studies show that Pkd1 cystic mutants have a distinct profile of excreted metabolites, with pathway analysis suggesting altered activity in several metabolic pathways. To evaluate their role in disease, metabolic networks were perturbed by inactivating Hnf4? and Pkd1. The Pkd1/Hnf4? double mutants have significantly more cystic kidneys, thus indicating that metabolic pathways could play a role in Pkd1-cystogenesis. PMID:23209428

Menezes, Luis F.; Zhou, Fang; Patterson, Andrew D.; Piontek, Klaus B.; Krausz, Kristopher W.; Gonzalez, Frank J.; Germino, Gregory G.

2012-01-01

316

Genetic mapping of autosomal dominant Charcot-Marie-Tooth disease in a large French-Acadian kindred: identification of new linked markers on chromosome 17.  

PubMed Central

We have performed linkage analysis in a large French-Acadian kindred segregating one form of autosomal dominant Charcot-Marie-Tooth disease (CMTD) (type IA) using 17 polymorphic DNA markers spanning human chromosome 17 and demonstrate linkage to several markers in the pericentromeric region, including DNA probes pA10-41, EW301, S12-30, pTH17.19, c11-2B, and p11-2c11.5. Linkage of markers pA10-41 and EW301 to CMTD type IA has been reported elsewhere. Four new markers, 1516, 1517, 1541, and LL101, which map to chromosome 17 have been identified. The marker 1516 appears to be closely linked to the CMTD locus on chromosome 17 as demonstrated by a maximum lod score of 3.42 at theta (recombination fraction) = 0. This marker has been mapped to 17p11.2 using a somatic cell hybrid constructed from a patient with Smith-Magenis syndrome [46,XY, del(17)(p11.2p11.2)]. A lod score of 6.16 has been obtained by multipoint linkage analysis with 1516 and two markers from 17q11.2, pTH17.19, and c11-2B. The markers 1517 and 1541 have been mapped to 17p12-17q11.2 and demonstrate maximum lod scores of 2.35 and 0.63 at recombination values of .1 and .2, respectively. The marker LL101 has been mapped to 17p13.105-17p13.100 and demonstrates a maximum lod score of 1.56 at a recombination value of .1. Our study confirms the localization of CMTD type IA to the pericentromeric region of chromosome 17. Images Figure 3 Figure 4 PMID:2316525

Patel, P I; Franco, B; Garcia, C; Slaugenhaupt, S A; Nakamura, Y; Ledbetter, D H; Chakravarti, A; Lupski, J R

1990-01-01

317

A Truncated Form of Rod Photoreceptor PDE6 ?-Subunit Causes Autosomal Dominant Congenital Stationary Night Blindness by Interfering with the Inhibitory Activity of the ?-Subunit  

PubMed Central

Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin ?-subunit (GNAT1), and cGMP phosphodiesterase type 6 ?-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928-9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6?1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6?1-313. We found that PDE6?1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory ?-subunit (P?), and interferes with the inhibition of normal PDE6?? catalytic subunits by P?. Moreover, both truncated forms of the PDE6? protein, PDE6?1-313 and PDE6?1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds P? and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation. PMID:24760071

Majumder, Anurima; Bocquet, Beatrice; Senechal, Audrey; Artemyev, Nikolai O.; Hamel, Christian P.; Brabet, Philippe

2014-01-01

318

A missense mutation in the exon 8 of lamin A\\/C gene in a Japanese case of autosomal dominant limb-girdle muscular dystrophy and cardiac conduction block  

Microsoft Academic Search

A case of autosomal dominant limb-girdle muscular dystrophy with atrioventricular conduction block (LGMD1B) has been documented. In this family, 13 members, nine males and four females, had cardiac arrhythmia requiring pacemakers. The proband, a 67-year-old male, had longstanding proximal muscle weakness later associated with cardiac arrhythmia but showed neither rigid spine nor joint contracture. His muscle enzymes were within normal

Tetsuo Kitaguchi; Shiro Matsubara; Masaru Sato; Kazuhito Miyamoto; Shunsaku Hirai; Ketty Schwartz; Gisèle Bonne

2001-01-01

319

Spastic paraplegia associated with brachydactyly and cone shaped epiphyses  

Microsoft Academic Search

Male uniovular twins presented at the age of 20 years with spastic paraplegia which had been slowly progressing over the years. Both have skeletal anomalies of their hands and feet with brachydactyly, cone shaped epiphyses, and an abnormal metaphyseal phalangeal pattern profile. In addition, they have a non-specific dysarthria and low-normal intellectual ability.

J S Fitzsimmons; P R Guilbert

1987-01-01

320

Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume  

PubMed Central

Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication. PMID:24919173

Balbo, B.E.P.; Sapienza, M.T.; Ono, C.R.; Jayanthi, S.K.; Dettoni, J.B.; Castro, I.; Onuchic, L.F.

2014-01-01

321

Urine MicroRNA as Potential Biomarkers of Autosomal Dominant Polycystic Kidney Disease Progression: Description of miRNA Profiles at Baseline  

PubMed Central

Background Autosomal dominant polycystic kidney disease (ADPKD) is clinically heterogenic. Biomarkers are needed to predict prognosis and guide management. We aimed to profile microRNA (miRNA) in ADPKD to gain molecular insight and evaluate biomarker potential. Methods Small-RNA libraries were generated from urine specimens of ADPKD patients (N?=?20) and patients with chronic kidney disease of other etiologies (CKD, N?=?20). In this report, we describe the miRNA profiles and baseline characteristics. For reference, we also examined the miRNA transcriptome in primary cultures of ADPKD cyst epithelia (N?=?10), normal adult tubule (N?=?8) and fetal tubule (N?=?7) epithelia. Results In primary cultures of ADPKD kidney cells, miRNA cistrons mir-143(2) (9.2-fold), let-7i(1) (2.3-fold) and mir-3619(1) (12.1-fold) were significantly elevated compared to normal tubule epithelia, whereas mir-1(4) members (19.7-fold), mir-133b(2) (21.1-fold) and mir-205(1) (3.0-fold) were downregulated (P<0.01). Expression of the dysregulated miRNA in fetal tubule epithelia resembled ADPKD better than normal adult cells, except let-7i, which was lower in fetal cells. In patient biofluid specimens, mir-143(2) members were 2.9-fold higher in urine cells from ADPKD compared to other CKD patients, while expression levels of mir-133b(2) (4.9-fold) and mir-1(4) (4.4-fold) were lower in ADPKD. We also noted increased abundance mir-223(1) (5.6-fold), mir-199a(3) (1.4-fold) and mir-199b(1) (1.8-fold) (P<0.01) in ADPKD urine cells. In ADPKD urine microvesicles, miR-1(2) (7.2-fold) and miR-133a(2) (11.8-fold) were less abundant compared to other CKD patients (P<0.01). Conclusions We found that in ADPKD urine specimens, miRNA previously implicated as kidney tumor suppressors (miR-1 and miR-133), as well as miRNA of presumed inflammatory and fibroblast cell origin (miR-223/miR-199), are dysregulated when compared to other CKD patients. Concordant with findings in the primary tubule epithelial cell model, this suggests roles for dysregulated miRNA in ADPKD pathogenesis and potential use as biomarkers. We intend to assess prognostic potential of miRNA in a followup analysis. PMID:24489795

Ben-Dov, Iddo Z.; Tan, Ying-Cai; Morozov, Pavel; Wilson, Patricia D.; Rennert, Hanna; Blumenfeld, Jon D.; Tuschl, Thomas

2014-01-01

322

Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics  

PubMed Central

Background Congenital cataracts are clinically and genetically heterogeneous with more than 45 known loci and 38 identified genes. They can occur as isolated defects or in association with anterior segment developmental anomalies. One of the disease genes for congenital cataract with or without anterior segment dysgenesis (ASD) is PITX3, encoding a transcription factor with a crucial role in lens and anterior segment development. Only five unique PITX3 mutations have been described, of which the 17-bp duplication c.640_656dup, p.(Gly220Profs*95), is the most common one and the only one known to cause cataract with ASD. The aim of this study was to perform a genetic study of the PITX3 gene in five probands with autosomal dominant congenital cataract (ADCC) and ASD, to compare their clinical presentations to previously reported PITX3-associated phenotypes and to functionally evaluate the PITX3 mutations found. Methods Sanger sequencing of the coding region and targeted exons of PITX3 was performed in probands and family members respectively. Transactivation, DNA-binding and subcellular localization assays were performed for the PITX3 mutations found. Ophthalmological examinations included visual acuity measurement, slit-lamp biomicroscopy, tonometry and fundoscopy. Results In four Belgian families with ADCC and ASD the recurrent 17-bp duplication c.640_656dup, p.(Gly220Profs*95), was found in a heterozygous state. A novel PITX3 mutation c.573del, p.(Ser192Alafs*117), was identified in heterozygous state in a Belgo-Romanian family with a similar phenotype. Functional assays showed that this novel mutation retains its nuclear localization but results in decreased DNA-binding and transactivation activity, similar to the recurrent duplication. Conclusions Our study identified a second PITX3 mutation leading to congenital cataract with ASD. The similarity in phenotypic expression was substantiated by our in vitro functional studies which demonstrated comparable molecular consequences for the novel p.(Ser192Alafs*117) and the recurrent p.(Gly220Profs*95) mutations. PMID:24555714

2014-01-01

323

A novel 7 bp deletion in PRPF31 associated with autosomal dominant retinitis pigmentosa with incomplete penetrance in an Indian family.  

PubMed

To localize and identify the gene linked with non-syndromic autosomal dominant retinitis pigmentosa (adRP) with high but not complete penetrance in an Indian family. A detailed family history and clinical data were recorded. A genome-wide scan by 2-point linkage analysis using nearly 400 fluorescently labeled microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bidirectional sequence analysis of the amplified products. A maximum 2-point lod score of 3.553 at theta = 0.0 was obtained with marker D19S572. Haplotype analysis placed the RP locus distal to marker D19S572, in close proximity to the gene for pre-mRNA processing factor 31 (PRPF31) at 19q13.42. Mutation screening in all 14 exonic regions and adjacent flanking intronic sequences of PRPF31 revealed a novel 7 bp deletion, c.59_65del7 (p.Gly20AlafsX43), in the first coding exon of PRPF31. This leads to a premature termination codon (PTC) in the next exon, 43 amino acids downstream. The observed 7 bp deletion in PRPF31 was identified in all the tested 10 affected members and in an unaffected individual, consistent with a high, but not the complete penetrance of c.59_65del7 (p.Gly20AlafsX43). This deletion was not observed in other tested six unaffected family members or in 100 ethnically matched control subjects. The present study describes mapping of a locus for non-syndromic adRP at 19q13.42 (RP11 locus) in a family of Indian origin and identifies a novel deletion, c.59_65del7, in PRPF31 within the mapped interval. Since the mutant PRPF31 is truncated relatively close to the N-terminus of the protein, haploinsufficiency rather than aberrant protein formation is likely to be the underlying mechanism of the disease. The present findings further substantiate the role of PRPF31 that encodes a component of the spliceosome complex in relation to ADRP. PMID:23041261

Saini, Seema; Robinson, Peter N; Singh, Jai Rup; Vanita, Vanita

2012-11-01

324

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

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

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

325

Fitzsimmons syndrome: spastic paraplegia, brachydactyly and cognitive impairment.  

PubMed

Fitzsimmons syndrome is an infrequently described entity comprising slowly progressive spastic paraplegia, brachydactyly, and cone-shaped epiphyses, dysarthria, and low-normal intelligence. Five patients with this syndrome have been reported. The cause remains unknown. Here we describe a 16-year-old boy with Fitzsimmons syndrome. He was noted to toe-walk at age 18 months and spasticity progressed slowly into a spastic gait with contractures. He has mild dysarthria and hypernasal speech. Brachydactyly is notable but cannot be classified into one of the recognized types. A cone-shaped epiphysis was apparent on the only available childhood radiograph. He has moderate cognitive handicap and pervasive developmental delay. A detailed comparison of this patient with the earlier described cases is presented to further delineate the condition and increase awareness of this syndrome. PMID:19760657

Armour, Christine M; Humphreys, Peter; Hennekam, Raoul C M; Boycott, Kym M

2009-10-01

326

Brachydactyly E: isolated or as a feature of a syndrome.  

PubMed

Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypopthyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals. PMID:24028571

Pereda, Arrate; Garin, Intza; Garcia-Barcina, Maria; Gener, Blanca; Beristain, Elena; Ibañez, Ane Miren; Perez de Nanclares, Guiomar

2013-01-01

327

Clinical and radiological assessment of a family with mild brachydactyly type A1: the usefulness of metacarpophalangeal profiles  

Microsoft Academic Search

The brachydactylies are a group of conditions in which various subtypes have been defined based upon the specific pattern of digital bones involved. Type A1 brachydactyly is principally characterised by maximal involvement of the middle phalanges. We report an extended family with a mild brachydactyly A1 which was, except for some short stature, not associated with any of the additional

C M Armour; D E Bulman; A G W Hunter

2000-01-01

328

A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C\\/symphalangism-like phenotype or brachydactyly type A2  

Microsoft Academic Search

Heterozygous missense mutations in the serine-threonine kinase receptor BMPR1B result typically in brachydactyly type A2 (BDA2), whereas mutations in the corresponding ligand GDF5 cause brachydactyly type C (BDC). Mutations in the GDF inhibitor Noggin (NOG) or activating mutations in GDF5 cause proximal symphalangism (SYM1). Here, we describe a novel mutation in BMPR1B (R486Q) that is associated with either BDA2 or

Katarina Lehmann; Petra Seemann; Jan Boergermann; Gilles Morin; Silke Reif; Petra Knaus; Stefan Mundlos

2006-01-01

329

Autosomal dominant retinitis pigmentosa secondary to pre-mRNA splicing-factor gene PRPF31 (RP11): review of disease mechanism and report of a family with a novel 3-base pair insertion.  

PubMed

Several forms of autosomal dominant retinitis pigmentosa (adRP) are caused by mutations in genes encoding proteins that are ubiquitously expressed and involved in the pre-mRNA spliceosome such as PRPF31. This paper provides an overview of the molecular genetics, pathophysiology, and mechanism for incomplete penetrance and retina-specific disease in pedigrees of families who harbor mutations in PRPF31 (RP11). The molecular and clinical features of a family with a novel 3-base insertion, c.914_915insTGT (p.Val305_Asp306insVal) in exon 9 of PRPF31 are described to illustrate the salient clinical features of mutations in this gene. PMID:23343310

Utz, Virginia M; Beight, Craig D; Marino, Meghan J; Hagstrom, Stephanie A; Traboulsi, Elias I

2013-12-01

330

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.  

PubMed

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia. PMID:9106530

Geschwind, D H; Perlman, S; Figueroa, C P; Treiman, L J; Pulst, S M

1997-04-01

331

Mutations in the X-Linked Retinitis Pigmentosa Genes RPGR and RP2 Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa  

PubMed Central

Purpose. We determined the fraction of families in a well-characterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. Methods. Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in “adRP” families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families. Results. Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these “adRP” families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously. Conclusions. These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa. PMID:23372056

Churchill, Jennifer D.; Bowne, Sara J.; Sullivan, Lori S.; Lewis, Richard Alan; Wheaton, Dianna K.; Birch, David G.; Branham, Kari E.; Heckenlively, John R.; Daiger, Stephen P.

2013-01-01

332

Identification of a novel missense mutation in the WFS1 gene as a cause of autosomal dominant nonsyndromic sensorineural hearing loss in all-frequencies.  

PubMed

Hearing loss is the most common sensory disorder affecting 278 million people in the world, and more than 60% of hearing loss patients can be attributed to genetic causes. Although many loci have been linked to hereditary hearing impairment, most of the causative genes have not been identified as yet. The goal of this study was to investigate the cause of dominantly inherited sensorineural all-frequency hearing loss in a six-generation Chinese family. We performed exome sequencing to screen responsible candidate genes in three family members with all-frequency hearing loss and one member with normal hearing. Sanger sequencing was employed to examine the variant mutations in the members of this family and 200 healthy persons. PCR-RFLP was performed to further confirm the nucleotide mutation. A novel missense mutation c.2389G?>?A (GAC???AAC) in WFS1 gene was identified, which was co-segregated with the hearing loss phenotype. No mutation was found in 200 controls and the family members with normal hearing in this site. The present study identifies, for the first time, a novel mutation in WFS1 gene that causes non-syndromic hearing loss in all, rather than in low or high, frequencies. © 2014 Wiley Periodicals, Inc. PMID:25250959

Bai, Xiaohui; Lv, Huaiqing; Zhang, Fengguo; Liu, Jinzhi; Fan, Zhaomin; Xu, Lei; Han, Yuhang; Chai, Renjie; Li, Jianfeng; Wang, Haibo

2014-12-01

333

Osteoclasts from Patients with Autosomal Dominant Osteopetrosis Type I Caused by a T253I Mutation in Low-Density Lipoprotein Receptor-Related Protein 5 Are Normal in Vitro, but Have Decreased Resorption Capacity in Vivo  

PubMed Central

Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts. To investigate the effect of the T253I mutation in LRP5 on osteoclasts, we isolated CD14+ monocytes from ADOI patients and assessed their ability to generate osteoclasts when treated with RANKL and M-CSF compared to that of age- and sex-matched control osteoclasts. We found normal osteoclastogenesis, expression of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found attenuated resorptive response to T3 stimulation, despite a normal bone formation response, in alignment with the reduced number of osteoclasts in vivo. These data demonstrate that ADOI osteoclasts are normal with respect to all aspects investigated in vitro. We speculate that the mutations causing ADOI alter the osteoblastic phenotype toward a smaller potential for supporting osteoclastogenesis. PMID:16251418

Henriksen, Kim; Gram, Jeppe; H?egh-Andersen, Pernille; Jemtland, Rune; Ueland, Thor; Dziegiel, Morten H.; Schaller, Sophie; Bollerslev, Jens; Karsdal, Morten A.

2005-01-01

334

Autosomal Dominant Polycystic Kidney Disease (ADPKD) in an Italian family carrying a novel nonsense mutation and two missense changes in exons 44 and 45 of the PKD1 gene  

SciTech Connect

Sixty-seven Italian patients with autosomal dominant polycystic kidney disease (ADPKD) were screened for mutations in the 3{prime} unique region of the PKD1 gene, using heteroduplex DNA analysis. Novel aberrant bands were detected in 3 patients from the same family. DNA sequencing showed a C to T transition in exon 44 (C12269T), resulting in a premature stop codon (R4020X), predicted to impair the synthesis of the putative intracytoplasmic C-terminus tail of the PKD1 protein, polycystin. The mutation also generates a novel DdeI restriction site, and the abnormal restriction pattern was observed both on genomic DNA and on cDNA from the affected relatives, indicating that this is indeed the pathogenetic molecular lesion. Reverse transcriptase-polymerase chain reaction (RT-PCR) performed on lymphocyte mRNA showed that the mutant transcript is normally present and stable. No aberrantly spliced mRNAs were detected. Interestingly, the mutant PKD1 chromosome in this family also bears two missense mutations downstream (A12341G and C12384T), not found in the other ADPKD families studied. 19 refs., 4 figs.

Rossetti, S.; Bresin, E.; Corra, S. [Univ. of Verona School of Medicine (Italy)] [and others] [Univ. of Verona School of Medicine (Italy); and others

1996-10-16

335

RESEARCH ARTICLE Open Access A novel locus (CORD12) for autosomal  

E-print Network

- somal dominant (ad) CRD, six (ABCA4, RPGRIP1, RAX2, CORD8, ADAM9 and CERKL) in autosomal recessive (arRESEARCH ARTICLE Open Access A novel locus (CORD12) for autosomal dominant cone-rod dystrophy for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad) CRD

Paris-Sud XI, Université de

336

Protein 61K, encoded by a gene (PRPF31) linked to autosomal dominant retinitis pigmentosa, is required for U4/U6*U5 tri-snRNP formation and pre-mRNA splicing.  

PubMed

In each round of nuclear pre-mRNA splicing, the U4/U6*U5 tri-snRNP must be assembled from U4/U6 and U5 snRNPs, a reaction that is at present poorly understood. We have characterized a 61 kDa protein (61K) found in human U4/U6*U5 tri-snRNPs, which is homologous to yeast Prp31p, and show that it is required for this step. Immunodepletion of protein 61K from HeLa nuclear extracts inhibits tri-snRNP formation and subsequent spliceosome assembly and pre-mRNA splicing. Significantly, complementation with recombinant 61K protein restores each of these steps. Protein 61K is operationally defined as U4/U6 snRNP-specific as it remains bound to this particle at salt concentrations where the tri-snRNP dissociates. However, as shown by two-hybrid analysis and biochemical assays, protein 61K also interacts specifically with the U5 snRNP-associated 102K protein, indicating that it physically tethers U4/U6 to the U5 snRNP to yield the tri-snRNP. Interestingly, protein 61K is encoded by a gene (PRPF31) that has been shown to be linked to autosomal dominant retinitis pigmentosa. Thus, our studies suggest that disruptions in tri-snRNP formation and function resulting from mutations in the 61K protein may contribute to the manifestation of this disease. PMID:11867543

Makarova, Olga V; Makarov, Evgeny M; Liu, Sunbin; Vornlocher, Hans-Peter; Lührmann, Reinhard

2002-03-01

337

Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADPKD patients, but with inconclusive results. To help resolve this we determined changes in RRT incidence rates as an indicator for increasing effective renoprotection over time in ADPKD. We analyzed data from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients starting RRT in 12 European countries between 1991 and 2010, grouped into four 5-year periods. Of them, 20,596 were due to ADPKD. Between the first and last period the mean age at onset of RRT increased from 56.6 to 58.0 years. The age- and gender-adjusted incidence rate of RRT for ADPKD increased slightly over the four periods from 7.6 to 8.3 per million population. No change over time was found in the incidence of RRT for ADPKD up to age 50, whereas in recent time periods the incidence in patients above the age of 70 clearly increased. Among countries there was a significant positive association between RRT take-on rates for non-ADPKD kidney disease and ADPKD. Thus, the increased age at onset of RRT is most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than the consequence of effective emerging renoprotective treatments for ADPKD. PMID:24827775

Spithoven, Edwin M; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Caskey, Fergus; Collart, Frederic; Finne, Patrik; Fogarty, Damian G; Groothoff, Jaap W; Hoitsma, Andries; Nogier, Marie-Béatrice; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J; Gansevoort, Ron T

2014-12-01

338

Autosomal Recessive Retinitis Pigmentosa and E150K Mutation in the Opsin Gene*S  

E-print Network

Autosomal Recessive Retinitis Pigmentosa and E150K Mutation in the Opsin Gene*S Received with an autosomal dominant (adRP), autosomal recessive (arRP), or X-linked pattern of inheritance. Although to be associated with autosomal recessive retinitis pigmentosa (arRP). The first reported case of arRP associated

Palczewski, Krzysztof

339

Over one-third of African-American MGUS and multiple myeloma patients are carriers of hyperphosphorylated paratarg-7, an autosomal dominantly inherited risk factor for MGUS/MM.  

PubMed

As hyperphosphorylated paratarg-7 (pP-7) carrier state was shown to be the first molecularly defined autosomal dominantly inherited risk factor for monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma (MM) in a European population, the prevalence of pP-7 carrier state among African-Americans who have a significantly higher incidence of MGUS/MM is of interest. We therefore determined pP-7 carrier state and paraproteins with specificity for P-7 in African-American, European and Japanese patients with MGUS/MM and healthy controls. By isoelectric focusing and ELISA, a paratarg-7-specific paraprotein and the associated pP-7 carrier state was observed in 30/81 (37.0%) African-American, 42/252 (16.7%) European and 7/176 (4.0%) Japanese MGUS/MM patients (p < 0.001). A pP-7 carrier state was found in 11/100 (11.0%) African-American, 8/550 (1.5%) European and 1/278 (0.4%) Japanese healthy controls (p < 0.001), resulting in an odds ratio for MGUS/MM of 4.8 (p < 0.001) among African-American, 13.6 among European (p < 0.001) and 11.5 (p = 0.023) among Japanese carriers of pP-7. We conclude that pP-7 carriers are most prevalent among African-Americans, but a pP-7 carrier state is the strongest molecularly defined single risk factor for MGUS/MM known to date in all three ethnic groups. The high prevalence of pP-7 carriers among African-American patients emphasizes a predominant role of this genetic factor in the pathogenesis of these diseases. The large number of pP7 African-American patients and controls should facilitate the identification of the SNP or mutation underlying the pP-7 carrier state. PMID:24443359

Zwick, Carsten; Held, Gerhard; Auth, Michaela; Bernal-Mizrachi, Leon; Roback, John D; Sunay, Susan; Iida, Shinsuke; Kuroda, Yoshiaki; Sakai, Akira; Ziepert, Marita; Ueda, Ryuzo; Pfreundschuh, Michael; Preuss, Klaus-Dieter

2014-08-15

340

Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father.  

PubMed

We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to confirm the clinical diagnoses. PMID:25118007

Loupe, Jacob; Sampath, Srirangan; Lacassie, Yves

2014-10-01

341

A new brachydactyly syndrome with similarities to Julia Bell types B and E  

Microsoft Academic Search

We report a family with some of the features of both types B and E Julia Bell brachydactyly. We feel therefore that this family may constitute a new syndrome and we would like to name this after the family involved, the Ballard syndrome.

P Pitt; I Williams

1985-01-01

342

Angel-shaped phalanges in brachydactyly C: a case report, and speculation on pathogenesis  

Microsoft Academic Search

We describe a woman and her daughter affected by brachydactyly type C. The unusual feature in the child included the striking ‘angel-shaped’ appearance of the proximal phalanges of the index and middle fingers of one hand, whereas more typical triangular epiphyses with elongation of their radial side were present at the same location in the opposite hand. It is suggested

Alessandro Castriota-Scanderbeg; Francesco Giuseppe Garaci; Giampiero Beluffi

2005-01-01

343

Spastic paraplegia, dysarthria, brachydactyly, and cone shaped epiphyses: confirmation of the Fitzsimmons syndrome.  

PubMed

A girl with slowly progressive difficulty in walking, dysarthria, growth retardation, brachydactyly, and cone shaped epiphyses is described. This constellation of symptoms was described in 1987 by Fitzsimmons and Guilbert. It probably represents a rare mendelian disorder of unknown cause. PMID:8014978

Hennekam, R C

1994-03-01

344

Autosomal recessive juvenile parkinsonism  

Microsoft Academic Search

Autosomal recessive juvenile parkinsonism (AR-JP) is a hereditary neurodegenerative disorder characterized by levodopa-responsive parkinsonism with onset before age 40 years and a slowly progressive course. Families with this condition have been described predominantly in Japanese population, occasionally under different names including an autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF) or a familial form of juvenile parkinsonism. Recently, the causative

Masaaki Saito; Mieko Maruyama; Ken Ikeuchi; Hiroshi Kondo; Atsushi Ishikawa; Tatsuhiko Yuasa; Shoji Tsuji

2000-01-01

345

The Deleted in Brachydactyly B Domain of ROR2 Is Required for Receptor Activation by Recruitment of Src  

E-print Network

The transmembrane receptor ‘ROR2 ’ resembles members of the receptor tyrosine kinase family of signalling receptors in sequence but its ’ signal transduction mechanisms remain enigmatic. This problem has particular importance because mutations in ROR2 are associated with two human skeletal dysmorphology syndromes, recessive Robinow Syndrome (RS) and dominant acting Brachydactyly type B (BDB). Here we show, using a constitutive dimerisation approach, that ROR2 exhibits dimerisation-induced tyrosine kinase activity and the ROR2 C-terminal domain, which is deleted in BDB, is required for recruitment and activation of the non-receptor tyrosine kinase Src. Native ROR2 phosphorylation is induced by the ligand Wnt5a and is blocked by pharmacological inhibition of Src kinase activity. Eight sites of Src-mediated ROR2 phosphorylation have been identified by mass spectrometry. Activation via tyrosine phosphorylation of ROR2 receptor leads to its internalisation into Rab5 positive endosomes. These findings show that BDB mutant receptors are defective in kinase activation as a result of failure to recruit Src.

unknown authors

2007-01-01

346

Brachydactyly type A2 associated with a defect in proGDF5 processing  

Microsoft Academic Search

We investigated a family with a brachydactyly type A2 and identified a heterozygous arginine to glutamine (R380Q) substitution in the growth\\/differentiation factor 5 (GDF5) in all affected individuals. The observed mutation is located at the processing site of the protein, at which the GDF5 precursor is thought to be cleaved releasing the mature molecule from the prodomain. In order to

Frank Ploger; Petra Seemann; Mareen Schmidt-von Kegler; Katarina Lehmann; Jorg Seidel; Klaus W. Kjaer; Jens Pohl; Stefan Mundlos

2008-01-01

347

Spherophakia, nanophthalmia, hypoplastic ciliary body and glaucoma in brachydactyly-associated syndromes  

Microsoft Academic Search

Three juvenile patients showing a systemic disorder associated with small stature, brachydactyly and glaucoma were discovered\\u000a to have spherophakia and a nanophthalmic axial length of the eye between 20.29 and 21.26 mm. According to clinical and radiological\\u000a criteria only one patient was classified as having Marchesani syndrome; one patient suffered from an acrofacial disorder,\\u000a and the third displayed typical ocular

Thomas S. Dietlein; Holger Mietz; Philipp C. Jacobi; Giinter K. Krieglstein

1996-01-01

348

Molecular cytogenetic analysis of five 2q37 deletions: refining the brachydactyly candidate region  

Microsoft Academic Search

Deletions of the 2q37 region are associated with a recognizable pattern of MCA\\/MR so-called the AHO-like syndrome. Brachydactyly is a variable but characteristic feature of this clinical entity. Here we report on five cases of cytogenetically visible de novo deletions of this 2q37 chromosome region. Using FISH, we characterized at the molecular level the breakpoints of these deletions using a

M. Chaabouni; M. Le Merrer; O. Raoul; M. Prieur; M. C. de Blois; A. Philippe; M. Vekemans; S. P. Romana

2006-01-01

349

Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity  

Microsoft Academic Search

ObjectiveThe autosomal-dominant form of the hyperimmunoglobulin E syndrome (AD-HIES) has been described as a multisystem disorder including immune, skeletal, and dental abnormalities. Variants of AD-HIES are known but not well defined.

Eleonore D. Renner; Jennifer M. Puck; Steven M. Holland; Markus Schmitt; Michael Weiss; Michael Frosch; Markus Bergmann; Joie Davis; Bernd H. Belohradsky; Bodo Grimbacher

2004-01-01

350

Deletions in 14q24.1q24.3 are associated with congenital heart defects, brachydactyly, and mild intellectual disability.  

PubMed

Interstitial deletions of chromosome band 14q24.1q24.3 are apparently very rare. We report on three unrelated patients with overlapping de novo deletions of sizes 5.4, 2.8, and 2.3?Mb in this region. While some clinical problems such as intestinal malrotation, cryptorchidism, and ectopic kidney were only observed in single patients, all three patients had mild intellectual disability, congenital heart defects (truncus arteriosus, pulmonary atresia, atrial septal defect, and/or ventricular septal defect), brachydactyly, hypertelorism, broad nasal bridge, and thin upper lips. Likely haploinsufficiency of one or several of the 19 genes in the common deleted interval (ACTN1, DCAF5, EXD2, GALNTL1, ERH, SLC39A9, PLEKHD1, CCDC177, KIAA0247, LOC100289511, SRSF5, SLC10A1, SMOC1, SLC8A3, ADAM21P1, COX16, SYNJ2BP, SYNJ2BP-COX16, ADAM21) was responsible for these manifestations, but apart from SMOC1, mutations in which cause autosomal recessive Waardenburg anophthalmia syndrome, and ACTN1, mutations in which are associated with congenital macrothrombocytopenia, no disease associations have so far been reported for the other genes. Functional studies and a systematic search for mutations or chromosome aberrations in this region will elucidate the role of individual genes in the clinical manifestations and will provide insight into the underlying biological mechanisms. PMID:24357125

Oehl-Jaschkowitz, Barbara; Vanakker, Olivier M; De Paepe, Anne; Menten, Björn; Martin, Thomas; Weber, Georg; Christmann, Alexander; Krier, Romain; Scheid, Simone; McNerlan, Susan E; McKee, Shane; Tzschach, Andreas

2014-03-01

351

A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2.  

PubMed

Heterozygous missense mutations in the serine-threonine kinase receptor BMPR1B result typically in brachydactyly type A2 (BDA2), whereas mutations in the corresponding ligand GDF5 cause brachydactyly type C (BDC). Mutations in the GDF inhibitor Noggin (NOG) or activating mutations in GDF5 cause proximal symphalangism (SYM1). Here, we describe a novel mutation in BMPR1B (R486Q) that is associated with either BDA2 or a BDC/SYM1-like phenotype. Functional investigations of the R486Q mutation were performed and compared with the previously reported BDA2-causing mutation R486W and WT BMPR1B. Overexpression of the mutant receptors in chicken micromass cultures resulted in a strong inhibition of chondrogenesis with the R486Q mutant, showing a stronger effect than the R486W mutant. To investigate the consequences of the BMPR1B mutations on the intracellular signal transduction, we used stably transfected C2C12 cells and measured the activity of SMAD-dependent and SMAD-independent pathways. SMAD activation after stimulation with GDF5 was suppressed in both mutants. Alkaline phosphatase induction showed an almost complete loss of activation by both mutants. Our data extend the previously known mutational and phenotypic spectrum associated with mutations in BMPR1B. Disturbances of NOG-GDF5-BMPR1B signaling cascade can result in similar clinical manifestations depending on the quantitative effect and mode of action of the specific mutations within the same functional pathway. PMID:16957682

Lehmann, Katarina; Seemann, Petra; Boergermann, Jan; Morin, Gilles; Reif, Silke; Knaus, Petra; Mundlos, Stefan

2006-12-01

352

Congenital anonychia and brachydactyly of the left foot - Cooks syndrome variant: Case report and review of literature  

PubMed Central

Cooks syndrome is characterized by familial congenital anonychia or onychodystrophy, hypoplasia or absence of distal phalanges of the hands and feet with brachydactyly of the fifth finger and digitalization of the thumb (triphalangism). It is listed as a “rare disease” by the Office of Rare Diseases of the National Institutes of Health. Here, we report a case of congenital anonychia and brachydactyly of the left foot, which possibly is a variant of Cooks syndrome with a positive family history of similar deformity. PMID:25400355

Chatterjee, Daipayan

2014-01-01

353

Congenital anonychia and brachydactyly of the left foot - Cooks syndrome variant: Case report and review of literature.  

PubMed

Cooks syndrome is characterized by familial congenital anonychia or onychodystrophy, hypoplasia or absence of distal phalanges of the hands and feet with brachydactyly of the fifth finger and digitalization of the thumb (triphalangism). It is listed as a "rare disease" by the Office of Rare Diseases of the National Institutes of Health. Here, we report a case of congenital anonychia and brachydactyly of the left foot, which possibly is a variant of Cooks syndrome with a positive family history of similar deformity. PMID:25400355

Chatterjee, Daipayan

2014-04-01

354

Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism  

Microsoft Academic Search

Growth\\/differentiation factor 5 (GDF5) is a secreted growth factor that plays a key regulatory role in embryonic skeletal\\u000a and joint development. Mutations in the GDF5 gene can cause different types of skeletal dysplasia, including brachydactyly\\u000a type C (BDC) and proximal symphalangism (SYM1). We report two novel mutations in the GDF5 gene in Chinese families with distinct limb malformations. In one

Wei Yang; Lihua Cao; Wenli Liu; Li Jiang; Miao Sun; Dai Zhang; Shusen Wang; Wilson H. Y. Lo; Yang Luo; Xue Zhang

2008-01-01

355

Brachydactyly A-1 mutations restricted to the central region of the N-terminal active fragment of Indian Hedgehog  

Microsoft Academic Search

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we

Ashley M Byrnes; Lemuel Racacho; Allison Grimsey; Louanne Hudgins; Andrea C Kwan; Michel Sangalli; Alexa Kidd; Yuval Yaron; Yu-Lung Lau; Sarah M Nikkel; Dennis E Bulman

2009-01-01

356

A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2  

Microsoft Academic Search

Background: Brachydactyly type A2 (OMIM 112600) is characterised by hypoplasia\\/aplasia of the second middle phalanx of the index finger and sometimes the little finger. BDA2 was first described by Mohr and Wriedt in a large Danish\\/Norwegian kindred and mutations in BMPR1B were recently demonstrated in two affected families.Methods: We found and reviewed Mohr and Wriedt’s original unpublished annotations, updated the

K W Kjaer; H Eiberg; L Hansen; C B van der Hagen; K Rosendahl; N Tommerup; S Mundlos

2006-01-01

357

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

Microsoft Academic Search

Missense or nonsense mutations of the rhodopsin gene have been implied in the pathogenesis of at least 3 different traits; autosomal dominant retinitis pigmentosa (adRP), congenital stationary night blindness (CSNB), and autosomal recessive retinitis pigmentosa (arRP). For the latter, a single patient has been reported with a nonsense mutation at codon 249 on both alleles. Heterozygous carriers of missense mutations

U. Orth; R. Oehlmann; A. Gal

1994-01-01

358

Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease  

Microsoft Academic Search

Osteogenesis imperfecta (OI) is a heritable disease of bone with low bone mass and bone fragility. The disease is generally classified into four types based on clinical features and disease severity, although recently fifth and sixth forms have also been reported. Most forms of OI are autosomal dominant. Rarely, autosomal recessive disease has been described. We report the clinical, radiological,

L. M Ward; F Rauch; R Travers; G Chabot; E. M Azouz; L Lalic; P. J Roughley; F. H Glorieux

2002-01-01

359

Autosomal recessive forms of hereditary motor and sensory neuropathy  

Microsoft Academic Search

Six families are described with hereditary motor and sensory neuropathy (HMSN) of probable autosomal recessive inheritance. Four of these were classified as HMSN type I and two as type II. The consanguinity rate in this series was high, suggesting that these recessive genes are rare. In comparison with the dominantly inherited forms of these disorders, the mean age of onset

A E Harding; P K Thomas

1980-01-01

360

Nonacidotic proximal tubulopathy transmitted as autosomal dominant trait  

Microsoft Academic Search

The family of a patient with a nonacidotic and hypercalciuric proximal tubulopathy was studied. The proband showed glycosuria, aminoaciduria, tubular proteinuria, renal hypophosphatemia, and urate tubular hyporeabsorption without bicarbonate loss. He also presented increased urine calcium excretion, plasma 1,25-dihydroxyvitamin D, and enteral calcium absorption. Clinical consequences of the tubulopathy were osteopenia and calcium kidney stones. Fifteen of the proband's relatives

Giuseppe Vezzoli; Simona Zerbi; Ivano Baragetti; Laura Soldati; Stefano Mora; Giacomo Dell'Antonio; Giuseppe Bianchi

1997-01-01

361

Regulation of cell proliferation in autosomal dominant polycystic kidney disease  

E-print Network

of PLAT domain may indicate its interaction with other proteins (32). The cytoplasmic tail of PC1 is found to bind heterotrimeric G proteins in vitro, activate the AP-1 transcription factor and take part in the regulation of Wnt signaling (33...). The cytoplasmic tail contains a coiled-coil domain with which it interacts with polycystin-2 (PC2), the protein product of the PKD2 gene (11). A sequence motif that is rich in proline, glutamic acid, serine and threonine (PEST), which facilitates ubiquitin...

Paul, Binu M.

2011-08-31

362

Autosomal dominant stationary night-blindness. A large family rediscovered.  

PubMed

In 1909, 2 years after the famous publication by Nettleship, a large family with congenital stationary night-blindness of the 'Nougaret type' was published by the Danish district surgeon, Sigurd Rambusch. In 1990 the 'Rambusch family', still resident in the original area, was sought out and rediscovered, at which time the reconstructed part of the pedigree comprised more than 200 affected persons in 11 generations. Dark adaptometry and electroretinography were performed on a few affected family members, including a descendant with a uniocular affection. The pedigree is presented and recordings of dark adaptation courses and electroretinographical responses from a few family members are demonstrated. PMID:1789082

Rosenberg, T; Haim, M; Piczenik, Y; Simonsen, S E

1991-12-01

363

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts and Leukoencephalopathy (CADASIL)  

MedlinePLUS

... few decades as the disease advances, strokes and dementia are common symptoms. Death generally occurs 10-20 years after the onset of strokes and dementia. The most common symptoms of CADASIL include: Migraine with aura: a migraine ...

364

Lamin B1 duplications cause autosomal dominant leukodystrophy  

Microsoft Academic Search

NOTE: The construct we described as moody-GAL4 has a name that was assigned to a different construct in a previously published paper. In this paper, it should be referred to as SPG-GAL4 (for 'sub-perineural-glia-GAL4'). This construct was a gift from R. Bainton (University of California San Francisco School of Medicine). The construction and activity of this promoter will be published

Quasar S Padiath; Kazumasa Saigoh; Raphael Schiffmann; Hideaki Asahara; Takeshi Yamada; Anulf Koeppen; Kirk Hogan; Louis J Ptá?ek; Ying-Hui Fu

2006-01-01

365

[Autosomal recessive forms of Charcot-Marie-Tooth disease].  

PubMed

In some countries with a high prevalence of consanguineous mariage, autosomal recessive inheritance probably accounts for the vast majority of all forms of CMT. Like dominant forms, autosomal recessive forms are generally subdivided into demyelinating forms (autosomal recessive CMT1: AR-CMT1 or CMT4) and axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has identified several novel CMT-related genes (GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin and lamin). Given the clinical, electrophysiological and histological heterogeneity of this disease, numerous culprit genes probably remain to be discovered, leading to an even more complex classification. Clinical and histological features often point to the involvement of a particular gene. Nerve biopsy and molecular studies can contribute to the diagnosis, but this approach is highly time-consuming and can only be performed in specialized laboratories. PMID:16119880

Vallat, Jean-Michel; Grid, Djamel; Magdelaine, Corinne; Sturtz, Franck; Levy, Nicolas; Tazir, Mériem

2005-01-01

366

Gonadal mosaicism as a rare cause of autosomal recessive inheritance.  

PubMed

Autosomal recessive diseases are typically caused by the biparental inheritance of familial mutant alleles. Unusual mechanisms by which the recessiveness of a mutant allele is unmasked include uniparental isodisomy and the occurrence of a de novo chromosomal rearrangement that disrupts the other allele. Gonadal mosaicism is a condition in which a postfertilization mutation is confined to the gamete precursors and is not detected in somatic tissues. Gonadal mosaicism is known to give the impression of autosomal recessive inheritance when recurrence of an autosomal-dominant condition among offspring of phenotypically normal parents is observed. Here, we report an extremely rare event in which maternal gonadal mosaicism for a recessive mutation in COL4A4 caused the recurrence of Alport syndrome within a consanguineous family. Such rare occurrence should be taken into account when analyzing pedigrees both for clinical and research purposes. PMID:23551117

Anazi, S; Al-Sabban, E; Alkuraya, F S

2014-03-01

367

Identical twins with mental retardation, dysarthria, progressive spastic paraplegia, and brachydactyly type E: a new syndrome or variant of Fitzsimmons-Guilbert syndrome?  

PubMed

We report on concordantly affected female identical twins with mental retardation, dysarthria, progressive spastic paraplegia, and brachydactyly type E. The most similar condition reported is the syndrome described by Fitzsimmons and Guilbert in uniovular twins characterized by progressive spastic paraplegia, dysarthria, brachydactyly type E, and cone-shaped epiphyses. During the last 11 years a report of only one other patient with this syndrome has been published; hence, its phenotypic delineation may be only partial. Although our patients might expand the phenotypic spectrum of this syndrome, they may represent a new disorder. PMID:10323731

Lacassie, Y; Arriaza, M I; Duncan, M C; Dijamco, C; McElveen, C; Stahls, P F

1999-05-21

368

Original article Autosomal recessive myotonia congenita  

E-print Network

Original article Autosomal recessive myotonia congenita in sheep GA Moore KR Dyer2 RM Dyer DP, which is consistent with the hypothesis of an autosomal recessive gene responsible for the condition is due to an autosomal recessive gene (Ptacek et al, 1993). Myotonic animals are consistently heavily

Paris-Sud XI, Université de

369

The Population Genetics of X-Autosome Synthetic Lethals and Steriles  

PubMed Central

Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation–selection balance conditions for X–autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X–autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane’s rule. PMID:21900269

Lachance, Joseph; Johnson, Norman A.; True, John R.

2011-01-01

370

Retinitis pigmentosa, metaphyseal chondrodysplasia, and brachydactyly: an affected brother and sister  

Microsoft Academic Search

A brother and sister, children of normal parents are described. They had retinitis pigmentosa, causing near-blindness as a result of very narrow fields of vision, associated with metaphyseal chondrodysplasia and marked shortening of the metacarpals and terminal phalanges. Autosomal recessive inheritance is suggested with a common biochemical cause for all these defects. This apparently new association of retinitis pigmentosa with

C I Phillips; R Wynne-Davies; N L Stokoe; M Newton

1981-01-01

371

Identification of a GDF5 mutation in a Korean patient with brachydactyly type C without foot involvement.  

PubMed

Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little fingers. Hyperphalangy of the index and middle finger and shortening of the first metacarpal can also be observed. BDC is a rare genetic condition associated with the GDF5 gene, and this condition has not been confirmed by genetic analysis so far in the Korean population. Herein, we present a case of a 6-yr-old girl diagnosed with BDC confirmed by molecular genetic analysis. The patient presented with shortening of the second and third digits of both hands. Sequence analysis of the GDF5 gene was performed and the pathogenic mutation, c.1312C>T (p.Arg438Cys), was identified. Interestingly, this mutation was previously described in a patient who presented with the absence of the middle phalanges in the second through fifth toes. However, our patient showed no involvement of the feet. Considering intrafamilial and interfamilial variability, molecular analysis of isolated brachydactyly is warranted to elucidate the genetic origin and establish a diagnosis. PMID:23483675

Seo, Soo Hyun; Park, Mi Jung; Kim, Shin-Hye; Kim, Ok-Hwa; Park, Seungman; Cho, Sung Im; Park, Sung Sup; Seong, Moon-Woo

2013-03-01

372

Identification of a GDF5 Mutation in a Korean Patient with Brachydactyly Type C without Foot Involvement  

PubMed Central

Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little fingers. Hyperphalangy of the index and middle finger and shortening of the first metacarpal can also be observed. BDC is a rare genetic condition associated with the GDF5 gene, and this condition has not been confirmed by genetic analysis so far in the Korean population. Herein, we present a case of a 6-yr-old girl diagnosed with BDC confirmed by molecular genetic analysis. The patient presented with shortening of the second and third digits of both hands. Sequence analysis of the GDF5 gene was performed and the pathogenic mutation, c.1312C>T (p.Arg438Cys), was identified. Interestingly, this mutation was previously described in a patient who presented with the absence of the middle phalanges in the second through fifth toes. However, our patient showed no involvement of the feet. Considering intrafamilial and interfamilial variability, molecular analysis of isolated brachydactyly is warranted to elucidate the genetic origin and establish a diagnosis. PMID:23483675

Seo, Soo Hyun; Park, Mi Jung; Kim, Shin-Hye; Kim, Ok-Hwa; Park, Seungman; Cho, Sung Im; Park, Sung Sup

2013-01-01

373

De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly  

Microsoft Academic Search

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.

Yoshimitsu Fukushima; Hirofumi Ohashi; Keiko Wakui; Hiroshi Nishimoto; Masato Sato; Toshinori Aihara

1995-01-01

374

A novel TECTA mutation confirms the recognizable phenotype among autosomal recessive hearing impairment families  

Microsoft Academic Search

Mutations in the TECTA gene result in sensorineural non-syndromic hearing impairment. TECTA-related deafness can be inherited autosomal dominantly (designated as DFNA8\\/12) or autosomal recessively (as DFNB21). The alpha-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Six mutations in the TECTA gene have already been reported

Fatemeh Alasti; Mohammad Hossein Sanati; Amir Hossein Behrouzifard; Abdorrahim Sadeghi; Arjan P. M. de Brouwer; Hannie Kremer; Richard J. H. Smith; Guy Van Camp

2008-01-01

375

Autosomal recessive Alport syndrome: Immunohistochemical study of type IV collagen chain distribution  

Microsoft Academic Search

Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution. Alport syndrome (AS) is an hereditary disease of basement membrane collagen. It is mainly transmitted as a dominant X-linked trait and caused by mutations in the COL4A5 gene encoding the ?5 chain of type IV collagen. However, autosomal recessive AS due to mutations in the COL4A3 or COL4A4

Marie-Claire Gubler; Bertrand Knebelmann; Agnès Beziau; Michel Broyer; Yves Pirson; Farid Haddoum; Mary M Kleppel; Corinne Antignac

1995-01-01

376

Targeted loss of the ATR-X syndrome protein in the limb mesenchyme of mice causes brachydactyly.  

PubMed

ATR-X syndrome is a rare genetic disorder caused by mutations in the ATRX gene. Affected individuals are cognitively impaired and display a variety of developmental abnormalities, including skeletal deformities. To investigate the function of ATRX during skeletal development, we selectively deleted the gene in the developing forelimb mesenchyme of mice. The absence of ATRX in the limb mesenchyme resulted in shorter digits, or brachydactyly, a defect also observed in a subset of ATR-X patients. This phenotype persisted until adulthood, causing reduced grip strength and altered gait in mutant mice. Examination of the embryonic ATRX-null forelimbs revealed a significant increase in apoptotic cell death, which could explain the reduced digit length. In addition, staining for the DNA damage markers ?-histone 2A family member X (?-H2AX) and 53BP1 demonstrated a significant increase in the number of cells with DNA damage in the embryonic ATRX-null forepaw. Strikingly, only one large bright DNA damage event was observed per nucleus in proliferating cells. These large ?-H2AX foci were located in close proximity to the nuclear lamina and remained largely unresolved after cell differentiation. In addition, ATRX-depleted forelimb mesenchymal cells did not exhibit hypersensitivity to DNA fork-stalling compounds, suggesting that the nature as well as the response to DNA damage incurred by loss of ATRX in the developing limb fundamentally differs from other tissues. Our data suggest that DNA damage-induced apoptosis is a novel cellular mechanism underlying brachydactyly that might be relevant to additional skeletal syndromes. PMID:23892236

Solomon, Lauren A; Russell, Bailey A; Watson, L Ashley; Beier, Frank; Bérubé, Nathalie G

2013-12-15

377

The cytogenetics of mammalian autosomal rearrangements  

SciTech Connect

Combining data from animal and clinical studies with classical cytogenetic observations, the volume provides information on various aspects of mammalian autosomal rearrangements. Topics range from the reproductive consequences to carriers of autosomal rearrangements to the application of structural rearrangements and DNA probes to gene mapping. In addition, the book presents an overview of new perspectives and future directions for research.

Daniel, A.

1988-01-01

378

Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death, dilated cardiomyopathy, and brachydactyly. A new type of heart-hand syndrome?  

PubMed

We identified a family with 10 affected members in four generations suffering from adult-onset progressive sinoatrial and atrioventricular conduction disease, sudden death due to ventricular tachyarrhythmia, dilated cardiomyopathy, and a unique type of brachydactyly with mild hand involvement (short distal, middle, proximal phalanges and clinodactyly) and more severe foot involvement (short distal, proximal phalanges and metatarsal bones, short or absent middle phalanges, terminal symphalangism, duplication of the bases of the second metatarsals, extra ossicles, and syndactyly). The phenotype differences from other reported genetic abnormalities and linkage exclusion of Holt-Oram syndrome, ulnar-mammary syndrome, brachydactyly type B or Robinow syndrome, and cardiac conduction disease or Brugada syndrome loci suggest that we report on a new hereditary heart-hand syndrome. PMID:15996213

Sinkovec, M; Petrovic, D; Volk, M; Peterlin, B

2005-08-01

379

What's Dominant?  

NSDL National Science Digital Library

In a class discussion format, the teacher presents background information about basic human genetics. The number of chromosomes in both body cells and egg and sperm cells is covered, as well as the concept of dominant and recessive alleles. Students determine whether or not they possess the dominant allele for the tongue-rolling gene as an example.

Engineering K-Ph.d. Program

380

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

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...

Davidson, Ashley Greene

2009-05-15

381

A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.  

PubMed

Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients. In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface. PMID:17668388

Lehmann, K; Seemann, P; Silan, F; Goecke, T O; Irgang, S; Kjaer, K W; Kjaergaard, S; Mahoney, M J; Morlot, S; Reissner, C; Kerr, B; Wilkie, A O M; Mundlos, S

2007-08-01

382

Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism.  

PubMed

Growth/differentiation factor 5 (GDF5) is a secreted growth factor that plays a key regulatory role in embryonic skeletal and joint development. Mutations in the GDF5 gene can cause different types of skeletal dysplasia, including brachydactyly type C (BDC) and proximal symphalangism (SYM1). We report two novel mutations in the GDF5 gene in Chinese families with distinct limb malformations. In one family affected with BDC, we identified a novel nonsense mutation, c.1461T > G (p.Y487X), which is predicted to truncate the GDF5 precursor protein by deleting 15 amino acids at its C-terminus. In one family with SYM1, we found a novel missense mutation, c.1118T > G (p.L373R), which changes a highly conserved amino acid in the prodomain of GDF5. We transfected COS-7 cells with retroviral constructs to express human wild-type or mutant GDF5 cDNAs. The mature GDF5 protein was detected, as in the wild-type, in supernatant derived from the p.L373R mutant GDF5 transfected cells, but not in the supernatant from the p.Y487X mutant transfected cells, indicating that the two mutations led to different fates of the mutant GDF5 proteins, thereby producing distinct limb phenotypes. PMID:18283415

Yang, Wei; Cao, Lihua; Liu, Wenli; Jiang, Li; Sun, Miao; Zhang, Dai; Wang, Shusen; Lo, Wilson H Y; Luo, Yang; Zhang, Xue

2008-01-01

383

PARK7, a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, on Chromosome 1p36  

Microsoft Academic Search

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome

C. M. van Duijn; M. C. J. Dekker; V. Bonifati; R. J. Galjaard; J. J. Houwing-Duistermaat; P. J. L. M. Snijders; L. Testers; G. J. Breedveld; M. Horstink; L. A. Sandkuijl; J. C. van Swieten; B. A. Oostra; P. Heutink

2001-01-01

384

A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease  

Microsoft Academic Search

Charcot-Marie-Tooth (CMT) disease is a hetero- geneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities. Inheritance can be autosomal dominant, X-linked or autosomal recessive (ARCMT). Recently, a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in

Angèle Guilbot; Anna Williams; Nicole Ravisé; Christophe Verny; Alexis Brice; Diane L. Sherman; Peter J. Brophy; Eric LeGuern

2001-01-01

385

The ABCR Gene in Recessive and Dominant Stargardt Diseases: A Genetic Pathway in Macular Degeneration  

Microsoft Academic Search

Stargardt disease (STGD) is a juvenile-onset macular dystrophy and can be inherited in an autosomal recessive or in an autosomal dominant manner. Genes involved in dominant STDG have been mapped to human chromosomes 13q (STGD2) and 6q (STGD3). Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus. Because of a more severe

Kang Zhang; Marina Kniazeva; Amy Hutchinson; Min Han; Michael Dean; Rando Allikmets

1999-01-01

386

Impact of Genetic Architecture on the Relative Rates of X versus Autosomal Adaptive Substitution  

PubMed Central

Molecular evolutionary theory predicts that the ratio of autosomal to X-linked adaptive substitution (KA/Kx) is primarily determined by the average dominance coefficient of beneficial mutations. Although this theory has profoundly influenced analysis and interpretation of comparative genomic data, its predictions are based upon two unverified assumptions about the genetic basis of adaptation. The theory assumes that 1) the rate of adaptively driven molecular evolution is limited by the availability of beneficial mutations, and 2) the scaling of evolutionary parameters between the X and the autosomes (e.g., the beneficial mutation rate, and the fitness effect distribution of beneficial alleles, per X-linked versus autosomal locus) is constant across molecular evolutionary timescales. Here, we show that the genetic architecture underlying bouts of adaptive substitution can influence both assumptions, and consequently, the theoretical relationship between KA/Kx and mean dominance. Quantitative predictions of prior theory apply when 1) many genomically dispersed genes potentially contribute beneficial substitutions during individual steps of adaptive walks, and 2) the population beneficial mutation rate, summed across the set of potentially contributing genes, is sufficiently small to ensure that adaptive substitutions are drawn from new mutations rather than standing genetic variation. Current research into the genetic basis of adaptation suggests that both assumptions are plausibly violated. We find that the qualitative positive relationship between mean dominance and KA/Kx is relatively robust to the specific conditions underlying adaptive substitution, yet the quantitative relationship between dominance and KA/Kx is quite flexible and context dependent. This flexibility may partially account for the puzzlingly variable X versus autosome substitution patterns reported in the empirical evolutionary genomics literature. The new theory unites the previously separate analysis of adaptation using new mutations versus standing genetic variation and makes several useful predictions about the interaction between genetic architecture, evolutionary genetic constraints, and effective population size in determining the ratio of adaptive substitution between autosomal and X-linked genes. PMID:22319138

Connallon, Tim; Singh, Nadia D.; Clark, Andrew G.

2012-01-01

387

Identification of Duplication Downstream of BMP2 in a Chinese Family with Brachydactyly Type A2 (BDA2)  

PubMed Central

Brachydactyly type A2 (BDA2, MIM 112600) is characterized by the deviation and shortening of the middle phalange of the index finger and the second toe. Using genome-wide linkage analysis in a Chinese BDA2 family, we mapped the maximum candidate interval of BDA2 to a ?1.5 Mb region between D20S194 and D20S115 within chromosome 20p12.3 and found that the pairwise logarithm of the odds score was highest for marker D20S156 (Zmax?=?6.09 at ??=?0). Based on functional and positional perspectives, the bone morphogenetic protein 2 (BMP2) gene was identified as the causal gene for BDA2 in this region, even though no point mutation was detected in BMP2. Through further investigation, we identified a 4,671 bp (Chr20: 6,809,218–6,813,888) genomic duplication downstream of BMP2. This duplication was located within the linked region, co-segregated with the BDA2 phenotype in this family, and was not found in the unaffected family members and the unrelated control individuals. Compared with the previously reported duplications, the duplication in this family has a different breakpoint flanked by the microhomologous sequence GATCA and a slightly different length. Some other microhomologous nucleotides were also found in the duplicated region. In summary, our findings support the conclusions that BMP2 is the causing gene for BDA2, that the genomic location corresponding to the duplication region is prone to structural changes associated with malformation of the digits, and that this tendency is probably caused by the abundance of microhomologous sequences in the region. PMID:24710560

Zhao, Aman; Zhang, Rui; Ji, Baohu; Wang, Lei; Zheng, Yonglan; Zeng, Bingfang; Valenzuela, Robert K.; He, Lin; Ma, Jie

2014-01-01

388

Identification of duplication downstream of BMP2 in a Chinese family with brachydactyly type A2 (BDA2).  

PubMed

Brachydactyly type A2 (BDA2, MIM 112600) is characterized by the deviation and shortening of the middle phalange of the index finger and the second toe. Using genome-wide linkage analysis in a Chinese BDA2 family, we mapped the maximum candidate interval of BDA2 to a ?1.5 Mb region between D20S194 and D20S115 within chromosome 20p12.3 and found that the pairwise logarithm of the odds score was highest for marker D20S156 (Zmax?=?6.09 at ??=?0). Based on functional and positional perspectives, the bone morphogenetic protein 2 (BMP2) gene was identified as the causal gene for BDA2 in this region, even though no point mutation was detected in BMP2. Through further investigation, we identified a 4,671 bp (Chr20: 6,809,218-6,813,888) genomic duplication downstream of BMP2. This duplication was located within the linked region, co-segregated with the BDA2 phenotype in this family, and was not found in the unaffected family members and the unrelated control individuals. Compared with the previously reported duplications, the duplication in this family has a different breakpoint flanked by the microhomologous sequence GATCA and a slightly different length. Some other microhomologous nucleotides were also found in the duplicated region. In summary, our findings support the conclusions that BMP2 is the causing gene for BDA2, that the genomic location corresponding to the duplication region is prone to structural changes associated with malformation of the digits, and that this tendency is probably caused by the abundance of microhomologous sequences in the region. PMID:24710560

Liu, Xudong; Gao, Linghan; Zhao, Aman; Zhang, Rui; Ji, Baohu; Wang, Lei; Zheng, Yonglan; Zeng, Bingfang; Valenzuela, Robert K; He, Lin; Ma, Jie

2014-01-01

389

Autosomal recessive forms of Charcot-Marie-Tooth disease.  

PubMed

In some countries with a high prevalence of consanguineous marriages, autosomal recessive inheritance is likely to account for the great majority of all forms of Charcot-Marie-Tooth (CMT) disease. As with the dominant forms, it is usual to differentiate the demyelinating forms (autosomal recessive -CMT1 or AR-CMT4) from the axonal forms (AR-CMT2). Genetic analysis of large families with recessive transmission has proved to be an efficient mean of discovering novel CMT genotypes (eg, the genes GDAP1, MTMR2, MTMR13, KIAA1985, NDGR1, periaxin, and lamin). Because of the clinical, electrophysiologic, and histologic heterogeneity of these patients, it is likely that there are numerous genes that remain to be discovered, which will probably make classification even more complex. Clinical, and especially histologic, phenotypes often lead to a suspicion that a specific gene is implicated. There is, therefore, an indication for nerve biopsy to orient diagnostic research in molecular biology, which is presently very time consuming and can only be performed in highly specialized laboratories. PMID:15324608

Vallat, J M; Grid, D; Magdelaine, C; Sturtz, F; Tazir, M

2004-09-01

390

Brachydactylia with symphalangism, probably autosomal recessive  

Microsoft Academic Search

Association, in one patient, of the following malformations: brachydactylia of all segments but terminal phalanges; proximal symphalangism of many fingers and toes; abnormalities of carpal and tarsal bones; partial duplication of both big toes; mild hypertelorism. Genetic transmission seems to be recessive autosomal.

Roland Walbaum; Claude Hazard; Roger Cordier

1976-01-01

391

Autosomal monoallelic expression in the mouse  

PubMed Central

Background Random monoallelic expression defines an unusual class of genes displaying random choice for expression between the maternal and paternal alleles. Once established, the allele-specific expression pattern is stably maintained and mitotically inherited. Examples of random monoallelic genes include those found on the X-chromosome and a subset of autosomal genes, which have been most extensively studied in humans. Here, we report a genome-wide analysis of random monoallelic expression in the mouse. We used high density mouse genome polymorphism mapping arrays to assess allele-specific expression in clonal cell lines derived from heterozygous mouse strains. Results Over 1,300 autosomal genes were assessed for allele-specific expression, and greater than 10% of them showed random monoallelic expression. When comparing mouse and human, the number of autosomal orthologs demonstrating random monoallelic expression in both organisms was greater than would be expected by chance. Random monoallelic expression on the mouse autosomes is broadly similar to that in human cells: it is widespread throughout the genome, lacks chromosome-wide coordination, and varies between cell types. However, for some mouse genes, there appears to be skewing, in some ways resembling skewed X-inactivation, wherein one allele is more frequently active. Conclusions These data suggest that autosomal random monoallelic expression was present at least as far back as the last common ancestor of rodents and primates. Random monoallelic expression can lead to phenotypic variation beyond the phenotypic variation dictated by genotypic variation. Thus, it is important to take into account random monoallelic expression when examining genotype-phenotype correlation. PMID:22348269

2012-01-01

392

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 ...

393

Novel indel Mutation in the GDF5 Gene Is Associated with Brachydactyly Type C in a Four-Generation Turkish Family  

PubMed Central

Heterozygous loss-of-function mutations of GDF5 are reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly), and heterozygous gain-of-function mutations, occurring either on the gene itself or through the loss of its inhibitor noggin, result in joint fusion (symphalangism). We present here the clinical and molecular investigation of a family with disproportionate shortness of the second and third fingers which comprises 9 variably affected members spanning 4 generations. In this study, we performed clinical and radiographical examinations of 2 patients of this family, sequencing of GDF5 and 3D protein modeling of the wildtype and mutated polypeptide to predict the structural alteration. Diagnoses were compatible with familial brachydactyly type C. GDF5 analysis revealed a novel heterozygous in-frame indel mutation (c.803_ 827del25ins25), involving the propeptide domain of GDF5 that alters the number of random coil and beta-strand structures, creating a 1-turn-helix at the mutated site. The mutation described here is the second indel reported in GDF5. The previously published homozygous indel mutation affected the TGF-beta like domain and was associated with Du Pan syndrome. The novel mutation reported here presents further allelic heterogeneity and a probable intrafamilial variable clinical expressivity of GDF5. PMID:24715855

Uyguner, Z.O.; Kocao?lu, M.; Toksoy, G.; Basaran, S.; Kayserili, H.

2014-01-01

394

Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4.  

PubMed

Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance. PMID:23188045

Villavicencio-Lorini, Pablo; Klopocki, Eva; Trimborn, Marc; Koll, Randi; Mundlos, Stefan; Horn, Denise

2013-07-01

395

Novel indel Mutation in the GDF5 Gene Is Associated with Brachydactyly Type C in a Four-Generation Turkish Family.  

PubMed

Heterozygous loss-of-function mutations of GDF5 are reported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly), and heterozygous gain-of-function mutations, occurring either on the gene itself or through the loss of its inhibitor noggin, result in joint fusion (symphalangism). We present here the clinical and molecular investigation of a family with disproportionate shortness of the second and third fingers which comprises 9 variably affected members spanning 4 generations. In this study, we performed clinical and radiographical examinations of 2 patients of this family, sequencing of GDF5 and 3D protein modeling of the wildtype and mutated polypeptide to predict the structural alteration. Diagnoses were compatible with familial brachydactyly type C. GDF5 analysis revealed a novel heterozygous in-frame indel mutation (c.803_ 827del25ins25), involving the propeptide domain of GDF5 that alters the number of random coil and beta-strand structures, creating a 1-turn-helix at the mutated site. The mutation described here is the second indel reported in GDF5. The previously published homozygous indel mutation affected the TGF-beta like domain and was associated with Du Pan syndrome. The novel mutation reported here presents further allelic heterogeneity and a probable intrafamilial variable clinical expressivity of GDF5. PMID:24715855

Uyguner, Z O; Kocao?lu, M; Toksoy, G; Basaran, S; Kayserili, H

2014-02-01

396

Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4  

PubMed Central

Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance. PMID:23188045

Villavicencio-Lorini, Pablo; Klopocki, Eva; Trimborn, Marc; Koll, Randi; Mundlos, Stefan; Horn, Denise

2013-01-01

397

CASE REPORT Open Access Autosomal recessive cerebellar ataxia caused  

E-print Network

CASE 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 is warranted in children and adults with ARCA. Background Main causes of autosomal recessive cerebellar ataxia

Paris-Sud XI, Université de

398

Autosomal recessive cutis laxa syndrome revisited  

PubMed Central

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

Morava, Eva; Guillard, Mailys; Lefeber, Dirk J; Wevers, Ron A

2009-01-01

399

HOXA2 Haploinsufficiency in Dominant Bilateral Microtia and Hearing Loss  

PubMed Central

Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia. PMID:23775976

Brown, Kerry K.; Viana, Lucas M.; Helwig, Cecilia C.; Artunduaga, Maria A.; Quintanilla-Dieck, Lourdes; Jarrin, Patricia; Osorno, Gabriel; McDonough, Barbara; DePalma, Steven R.; Eavey, Roland D.; Seidman, Jonathan G.; Seidman, Christine E.

2013-01-01

400

Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral ectopia lentis.  

PubMed

Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis. PMID:20141359

Greene, V Bennouna; Stoetzel, C; Pelletier, V; Perdomo-Trujillo, Y; Liebermann, L; Marion, V; De Korvin, H; Boileau, C; Dufier, J L; Dollfus, H

2010-03-01

401

Homozygosity haplotype allows a genomewide search for the autosomal segments shared among patients.  

PubMed

A promising strategy for identifying disease susceptibility genes for both single- and multiple-gene diseases is to search patients' autosomes for shared chromosomal segments derived from a common ancestor. Such segments are characterized by the distinct identity of their haplotype. The methods and algorithms currently available have only a limited capability for determining a high-resolution haplotype genomewide. We herein introduce the homozygosity haplotype (HH), a haplotype described by the homozygous SNPs that are easily obtained from high-density SNP genotyping data. The HH represents haplotypes of both copies of homologous autosomes, allowing for direct comparisons of the autosomes among multiple patients and enabling the identification of the shared segments. The HH successfully detected the shared segments from members of a large family with Marfan syndrome, which is an autosomal dominant, single-gene disease. It also detected the shared segments from patients with model multigene diseases originating with common ancestors who lived 10-25 generations ago. The HH is therefore considered to be useful for the identification of disease susceptibility genes in both single- and multiple-gene diseases. PMID:17503327

Miyazawa, Hitoshi; Kato, Masaaki; Awata, Takuya; Kohda, Masakazu; Iwasa, Hiroyasu; Koyama, Nobuyuki; Tanaka, Tomoaki; Huqun; Kyo, Shunei; Okazaki, Yasushi; Hagiwara, Koichi

2007-06-01

402

When Is Dominance Related to Smiling? Assigned Dominance, Dominance Preference, Trait Dominance, and Gender as Moderators  

Microsoft Academic Search

We investigated gender and different types of dominance measures as potential moderators of the relation between dominance and smiling. We asked participants about their preference for either a dominant or a subordinate role (dominance preference), randomly assigned one of these roles to them (assigned dominance), and assessed trait dominance, felt dominance, and perceived dominance. Participants had two 8-min dyadic interactions

MarianneSchmid Mast; Judith A. Hall

2004-01-01

403

A contribution to the relation of the gene loci involved in the isoagglutinin reaction, taste blindness, Friedreich’s ataxia and major brachydactyly of man  

Microsoft Academic Search

Conclusions  The following conclusions may now be stated:\\u000a \\u000a \\u000a (1) \\u000a \\u000a Friedreich’s ataxia is determined by a single recessive gene substitution (f).\\u000a \\u000a \\u000a \\u000a \\u000a (2) \\u000a \\u000a The locusF-f is not strongly linked toT-t (phenyl-thio-urea taste blindness) orA-B-R (isoagglutinin reaction). As far as the present evidence permits any inference it appears to segregate independently.\\u000a \\u000a \\u000a \\u000a \\u000a (3) \\u000a \\u000a The locusBr-br (brachydactyly) is not strongly linked toT-t, neither isA-B-R. The data

Lancelot Hogben; Ray Pollack

1935-01-01

404

The phenotypic manifestations of autosomal recessive axonalCharcot–Marie–Tooth due to a mutation in Lamin A\\/C gene  

Microsoft Academic Search

Charcot–Marie–Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot–Marie–Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot–Marie–Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot–Marie–Tooth type 2 due to a recently-described mutation (c.892C>T–p.R298C)

M. Chaouch; Y. Allal; A. De Sandre-Giovannoli; J. M. Vallat; A. Amer-el-Khedoud; N. Kassouri; A. Chaouch; P. Sindou; T. Hammadouche; M. Tazir; N. Lévy; D. Grid

2003-01-01

405

Characterization of a novel missense mutation in the prodomain of GDF5, which underlies brachydactyly type C and mild Grebe type chondrodysplasia in a large Pakistani family.  

PubMed

All TGF-beta family members have a prodomain that is important for secretion. Lack of secretion of a TGF-beta family member GDF5 is known to underlie some skeletal abnormalities, such as brachydactyly type C that is characterized by a huge and unexplained phenotypic variability. To search for potential phenotypic modifiers regulating secretion of GDF5, we compared cells overexpressing wild type (Wt) GDF5 and GDF5 with a novel mutation in the prodomain identified in a large Pakistani family with Brachydactyly type C and mild Grebe type chondrodyslplasia (c527T>C; p.Leu176Pro). Initial in vitro expression studies revealed that the p.Leu176Pro mutant (Mut) GDF5 was not secreted outside the cells. We subsequently showed that GDF5 was capable of forming a complex with latent transforming growth factor binding proteins, LTBP1 and LTBP2. Furthermore, secretion of LTBP1 and LTBP2 was severely impaired in cells expressing the Mut-GDF5 compared to Wt-GDF5. Finally, we demonstrated that secretion of Wt-GDF5 was inhibited by the Mut-GDF5, but only when LTBP (LTBP1 or LTBP2) was co-expressed. Based on these findings, we suggest a novel model, where the dosage of secretory co-factors or stabilizing proteins like LTBP1 and LTBP2 in the microenvironment may affect the extent of GDF5 secretion and thereby function as modifiers in phenotypes caused by GDF5 mutations. PMID:23812741

Farooq, Muhammad; Nakai, Hiroyuki; Fujimoto, Atsushi; Fujikawa, Hiroki; Kjaer, Klaus Wilbrandt; Baig, Shahid Mahmood; Shimomura, Yutaka

2013-11-01

406

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.  

PubMed

The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8?Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1. PMID:23073310

Leroy, Camille; Landais, Emilie; Briault, Sylvain; David, Albert; Tassy, Olivier; Gruchy, Nicolas; Delobel, Bruno; Grégoire, Marie-José; Leheup, Bruno; Taine, Laurence; Lacombe, Didier; Delrue, Marie-Ange; Toutain, Annick; Paubel, Agathe; Mugneret, Francine; Thauvin-Robinet, Christel; Arpin, Stéphanie; Le Caignec, Cedric; Jonveaux, Philippe; Beri, Mylène; Leporrier, Nathalie; Motte, Jacques; Fiquet, Caroline; Brichet, Olivier; Mozelle-Nivoix, Monique; Sabouraud, Pascal; Golovkine, Nathalie; Bednarek, Nathalie; Gaillard, Dominique; Doco-Fenzy, Martine

2013-06-01

407

Late infantile autosomal recessive myotonia, mental retardation, and skeletal abnormalities: a new autosomal recessive syndrome.  

PubMed Central

Four sibs of non-consanguineous parents who had myotonia from late infancy are described. Mild to moderate mental retardation, severe bone abnormalities of the vertebral column (mainly in the thoracolumbar region), and short stature were also observed. Autosomal recessive inheritance is demonstrated. These cases are compared with reported cases of the Schwartz-Jampel syndrome. Images PMID:6716408

Richieri-Costa, A; Garcia da Silva, S M; Frota-Pessoa, O

1984-01-01

408

Autosomal recessive nonsyndromic deafness genes: a review  

PubMed Central

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

Duman, Duygu; Tekin, Mustafa

2013-01-01

409

Confirmation of the autosomal recessive syndrome of ectopia lentis and distinctive craniofacial appearance.  

PubMed

We report four members of a Lebanese Druze family with the syndrome of lens dislocation, spontaneous filtering blebs, anterior segment abnormalities, and a distinctive facial appearance. The constellation of clinical abnormalities in these patients is not suggestive of the Marfan syndrome or other connective tissue disorders associated with ectopia lentis. We previously described this syndrome in another presumably unrelated and highly inbred Druze family from the mountains of Lebanon. We postulated autosomal recessive inheritance in a pseudo-dominant pedigree. A few isolated reports of similar cases are scattered in the world literature. We now confirm that this is a distinct autosomal recessive syndrome whose gene mutation is enriched in the Lebanese Druze community. PMID:11241487

Haddad, R; Uwaydat, S; Dakroub, R; Traboulsi, E I

2001-03-15

410

[Epilepsy in patient with structural autosomal abnormality].  

PubMed

Few cases have been reported on the structural autosomal abnormality (SAA) focusing on epilepsy excluding those of Down syndrome and Klinefelter syndrome. We investigated patients who had SAA with special reference to epilepsy. Various types of epilepsy were observed in its severity in our cases as well as previously reported cases. There was no correlation between the degree of mental retardation, motor dysfunction, brain damage on CT scan, and severity of epilepsy. Some cases had brain dysplasia, such as agenesis of corpus callosum, pachygyria, and mega cisterna magna. No correlation was found between these brain dysplasia and severity of epilepsy. It is important for a pediatrician to find a common epileptic syndrome or EEG abnormality in a SAA. An observation of symptoms in patients with the same chromosomal deletion or duplication will lead to identification of responsible gene for an epileptic symptom. PMID:7803078

Sugama, S; Atsukawa, K; Kusano, K; Akatsuka, A; Ochiai, Y; Tsuzura, S; Maekawa, K

1994-11-01

411

Familial Segregation of Hemangiomas and Vascular Malformations as an Autosomal Dominant Trait  

Microsoft Academic Search

Background: The pathogenesis of infantile hemangio- mas is not yet understood. Growth factors and hor- monal and mechanical influences have been thought to affect the focal abnormal growth of endothelial cells in these lesions. However, these influences may represent secondary responses to an underlying primary molecu- lar event leading to the development of hemangiomas. Observations: We report the rare familial

Francine Blei; Jeffrey Walter; Seth J. Orlow; Douglas A. Marchuk

1998-01-01

412

The Autosomal Dominant Trait of Obesity, Acanthosis nigricans, Hypertension, Ischemic Heart Disease and Diabetes Type 2  

Microsoft Academic Search

Objective: Among obese subjects, acanthosis nigricans in both males and females is not as uncommon as previously thought. Whereas this finding was extensively evaluated in females, mostly in the context of polycystic ovaries syndrome, little attention has been paid to obese males with acanthosis nigricans. As acanthosis seems to be a marker for insulin resistance, the present study was designed

Nogah Kerem; Hadassah Guttmann; Ze’ev Hochberg

2001-01-01

413

The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract.  

PubMed

Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles in this region, in ACACA and UNC45B. As alterations of the UNC45B protein have been shown to affect eye development in model organisms, effort was focused on the heterozygous UNC45B missense mutation. UNC45B encodes a myosin-specific chaperone that, together with the general heat shock protein HSP90, is involved in myosin assembly. The mutation changes p.Arg805 to Trp in the UCS domain, an amino acid that is highly conserved from yeast to human. UNC45B is strongly expressed in the heart and skeletal muscle tissue, but here we show expression in human embryo eye and zebrafish lens. The zebrafish mutant steif, carrying an unc45b nonsense mutation, has smaller eyes than wild-type embryos and shows accumulation of nuclei in the lens. Injection of RNA encoding the human wild-type UNC45B protein into the steif homozygous embryo reduced the nuclei accumulation and injection of human mutant UNC45B cDNA in wild-type embryos resulted in development of a phenotype similar to the steif mutant. The p.Arg805Trp alteration in the mammalian UNC45B gene suggests that developmental cataract may be caused by a defect in non-muscle myosin assembly during maturation of the lens fiber cells. PMID:24549050

Hansen, Lars; Comyn, Sophie; Mang, Yuan; Lind-Thomsen, Allan; Myhre, Layne; Jean, Francesca; Eiberg, Hans; Tommerup, Niels; Rosenberg, Thomas; Pilgrim, David

2014-11-01

414

Treatment of autosomal dominant polycystic kidney disease (ADPKD): the new horizon for children with ADPKD  

Microsoft Academic Search

Polycystic kidney disease (PKD) is the most common inherited renal disorder. Patients with PKD remain clinically asymptomatic\\u000a for decades, while significant anatomic and physiologic systemic changes take place. Sequencing of the responsible genes and\\u000a identification of their protein products have significantly expanded our understanding of the pathophysiology of PKD. The\\u000a molecular basis for cystogenesis is being unraveled, leading to new

Dana Rizk; Arlene Chapman

2008-01-01

415

Potential Deleterious Effects of Vasopressin in Chronic Kidney Disease and Particularly Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin

E. Meijer; W. E. Boertien; R. Zietse; R. T. Gansevoort

2011-01-01

416

Linkage studies in Spanish autosomal dominant polycystic kidney disease-type 2 (ADPKD-2) families  

SciTech Connect

ADPKD results from mutations in at least two genetically distinct loci. Most of the cases (ADPKD-1) are due to mutations in the locus PKD1, on the short arm of chromosome 16. ADPKD-2 accounts for 15% of ADPKD in Spanish population. Previous linkage studies have localized the gene for ADPKD-2 (PKD2) in the chromosome region 4q13-q23, and the distance between the flanking markers, D4S231 and D4S423/D4S414, was 7 cM. We have analyzed seven unrelated families with ADPKD not linked to PKD1 by using eight microsatellite markers that map within the candidate region. All the families did show linkage to any of the markers for which they were informative. Pairwise linkage analysis revealed that loci D4S414 and D4S423 are tightly linked to the disease with lod scores of 3.12 and 6.50, respectively, at a recombination fraction of 0.00. Multilocus linkage analysis indicates that the most likely location for PKD2 is distal to D4S1542, with odds of 1000:1 over the location proximal to D4S1542. Two recombination events involving PKD2 chromosomes have been identified in our seven families. These results provide a proximal boundary for the PKD2 locus and, considering previous studies, its localization is further refined to a 3 cM interval flanked by markers D4S1542 and D4S414/D4S423.

San Millan, J.L.; Viribay, M.; Perral, B. [Hospital Ramon y Cajal, Madrid (Spain)] [and others

1994-09-01