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1

Autosomal dominant pseudoxanthoma elasticum  

Microsoft Academic Search

Two families are described, each with a unique clinical variant of pseudoxanthoma elasticum (PXE) inherited in autosomal dominant fashion. Dominant type I PXE is characterized by a classical flexurally distributed rash, severe and frequent angina of effort, intermittent claudication and hypertension, and a very severe choroidoretinitis, often complicated by blindness. Dominant type II PXE, on the other hand, is a

F. M. Pope

1974-01-01

2

Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?  

PubMed

Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?: We report on two sibs, a boy and a girl, with syndromic brachydactyly type E. Parents were first cousins. Facial dysmorphia was characterized by a flat occiput, a large forehead, hypertelorism, a long triangular nose, an everted lower lip, downslanting palpebral fissures and strabismus. They had marked shortening of the third, fourth and fifth fingers and of the third, fourth, and fifth toes. IQ was 16 in the boy, 63 in the girl. In both sibs ophtalmologic examination showed strabismus, absence of cataract and normal fundus and radiological findings disclosed increased bone density involving the skull, the vertebrae and the corticalis of the long bones. Neither ectopic calcifications, nor exostosic, nor osteomalacia, and nor osteotis fibrosa cystica were present. Investigations revealed that plasma calcium, phosphate, vitamine D, parathyroid hormone (PTH), response to exogenous PTH, and Gs activity were normal as well as renal and thyroid function. Molecular genetic studies failed to identify mutations in the GNAS 1 gene, in the PTH receptor gene and in the HOX D13 gene. Analysis of 2q showed that there was no deletion 2q37. Other known syndromes with brachydactyly type E and mental retardation were excluded. In conclusion we suggest that these two sibs with a combination of brachydactyly, mental retardation and increased bone density have a specific autosomal recessive syndrome. PMID:15658617

Stoll, C; Alembik, Y

2004-01-01

3

Arterial hypertension with brachydactyly in a 15-year-old boy  

Microsoft Academic Search

Autosomal dominant brachydactyly with hypertension is the only form of monogenic hypertension which is not sodium dependent. The disease is characterized by brachydactyly type E, short stature, arterial hypertension and aberrant loop of posterior inferior cerebellar artery (PICA) causing neurovascular conflict. So far the syndrome was described in one family in Turkey and two in Canada. We report a case

Mieczyslaw Litwin; Elzbieta Jurkiewicz; Katarzyna Nowak; Andrzej Kosciesza; Ryszard Grenda; Katarzyna Malczyk; Iwona Kosciesza

2003-01-01

4

Autosomal dominant precalcaneal congenital fibrolipomatous hamartoma.  

PubMed

Precalcaneal congenital fibrolipomatous hamartoma is a rare minor malformation previously reported only as sporadic. We report this finding in three family members from two generations, suggesting autosomal dominant inheritance. PMID:16060876

Meyer, Peter; Soennichsen, Karsten; Buchenau, Wolfgang

2005-01-01

5

Sulcus vocalis: evidence for autosomal dominant inheritance.  

PubMed

We found evidence of autosomal dominant hereditary transmission of sulcus vocalis. Four dysphonic patients from three generations of the same family were submitted to videolaryngoscopic examination (three patients) and to direct laryngoscopy (one patient) to diagnose the hoarseness. Sulcus vocalis was diagnosed in all four patients. The finding of four affected individuals in three generations, with vertical transmission affecting man and women, is more consistent with autosomal dominant inheritance pattern; it is an etiological model that we propose for the sulcus vocalis in this pedigree. PMID:22194172

Martins, R H G; Gonçalves, T M; Neves, D S; Fracalossi, T A; Tavares, E L M; Moretti-Ferreira, D

2011-01-01

6

Autosomal dominant juvenile amyotrophic lateral sclerosis  

Microsoft Academic Search

Summary Juvenile amyotrophic lateral sclerosis (ALS) is a form of chronic motor neuron disease characterized by combined upper and lower motor neuron symptoms and signs with onset prior to age 25 years. We report the clinical and electrodiagnostic findings in 49 affected family members and neuropathological findings from two autopsies of a Maryland kindred with autosomal dominant juvenile ALS linked

Bruce A. Rabin; John W. Griffin; Barbara J. Crain; Mena Scavina; Philip F. Chance; David R. Cornblath

1999-01-01

7

Rhodopsin mutations in autosomal dominant retinitis pigmentosa.  

PubMed Central

DNA samples from 161 unrelated patients with autosomal dominant retinitis pigmentosa were screened for point mutations in the rhodopsin gene by using the polymerase chain reaction and denaturing gradient gel electrophoresis. Thirty-nine patients were found to carry 1 of 13 different point mutations at 12 amino acid positions. The presence or absence of the mutations correlated with the presence or absence of retinitis pigmentosa in 174 out of 179 individuals tested in 17 families. The mutations were absent from 118 control subjects with normal vision. Images PMID:1862076

Sung, C H; Davenport, C M; Hennessey, J C; Maumenee, I H; Jacobson, S G; Heckenlively, J R; Nowakowski, R; Fishman, G; Gouras, P; Nathans, J

1991-01-01

8

Genetics Home Reference: Autosomal dominant congenital stationary night blindness  

MedlinePLUS

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

9

Cleidocranial dysplasia with autosomal dominant inheritance pattern.  

PubMed

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

2014-07-01

10

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

11

Autosomal dominant juvenile amyotrophic lateral sclerosis.  

PubMed

Juvenile amyotrophic lateral sclerosis (ALS) is a form of chronic motor neuron disease characterized by combined upper and lower motor neuron symptoms and signs with onset prior to age 25 years. We report the clinical and electrodiagnostic findings in 49 affected family members and neuropathological findings from two autopsies of a Maryland kindred with autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4). Patients ranged in age from 12 to 85 years (mean 45 years) and the mean age of onset was 17 years. Distal weakness and atrophy was associated with pyramidal signs (43/49) and normal sensation (44/49). Motor conduction studies (n = 8) showed reduced evoked amplitudes and normal conduction parameters. Sensory conduction studies (n = 8), quantitative sensory testing (n = 4) and intracutaneous sensory fibres in skin biopsies (n = 6) were normal in all patients tested. Electromyography showed distal more than proximal chronic partial denervation and reinnervation (n = 8). Post-mortem spinal cord tissue demonstrated atrophic spinal cords with marked loss of anterior horn cells and degeneration of corticospinal tracts, as well as loss of neurons in the dorsal root ganglia and degeneration of the posterior columns. Axonal spheroids were present in the grey matter of the spinal cord, the dorsal root entry zones and the peripheral nerves. Motor and sensory roots, as well as peripheral nerves, showed significant axonal loss. Swellings were prominent around motor neurons, probably representing changes in presynaptic terminals. These studies define autosomal dominant juvenile ALS linked to the chromosome 9q34 region (ALS4) and extend the clinical, pathological and genetic heterogeneity of familial ALS and juvenile ALS. PMID:10430837

Rabin, B A; Griffin, J W; Crain, B J; Scavina, M; Chance, P F; Cornblath, D R

1999-08-01

12

Non-syndromic autosomal-dominant deafness.  

PubMed

Non-syndromic deafness is a paradigm of genetic heterogeneity. More than 70 loci have been mapped, and 25 of the nuclear genes responsible for non-syndromic deafness have been identified. Autosomal-dominant genes are responsible for about 20% of the cases of hereditary non-syndromic deafness, with 16 different genes identified to date. In the present article we review these 16 genes, their function and their contribution to deafness in different populations. The complexity is underlined by the fact that several of the genes are involved in both dominant and recessive non-syndromic deafness or in both non-syndromic and syndromic deafness. Mutations in eight of the genes have so far been detected in only single dominant deafness families, and their contribution to deafness on a population base might therefore be limited, or is currently unknown. Identification of all genes involved in hereditary hearing loss will help in the understanding of the basic mechanisms underlying normal hearing, will facilitate early diagnosis and intervention and might offer opportunities for rational therapy. PMID:12123480

Petersen, M B

2002-07-01

13

Symptom onset in autosomal dominant Alzheimer disease  

PubMed Central

Objective: To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD. Methods: We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study. Results: We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10?16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex. Conclusions: Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research. PMID:24928124

Acosta-Baena, Natalia; Aisen, Paul S.; Bird, Thomas; Danek, Adrian; Fox, Nick C.; Goate, Alison; Frommelt, Peter; Ghetti, Bernardino; Langbaum, Jessica B.S.; Lopera, Francisco; Martins, Ralph; Masters, Colin L.; Mayeux, Richard P.; McDade, Eric; Moreno, Sonia; Reiman, Eric M.; Ringman, John M.; Salloway, Steve; Schofield, Peter R.; Sperling, Reisa; Tariot, Pierre N.; Xiong, Chengjie; Morris, John C.; Bateman, Randall J.

2014-01-01

14

Autosomal dominant inheritance of Brachmann-de Lange syndrome  

SciTech Connect

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

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

1996-12-30

15

A new mutation in the gene ROR2 causes brachydactyly type B1.  

PubMed

Brachydactyly type B, an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails, can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is caused by mutations in the receptor tyrosine kinase gene ROR2, which maps to chromosome 9q22, whereas BDB2 is caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Here, we report a three-generation Chinese family with dominant inheritance of the BDB1 limb phenotype. Sequence analysis identified a novel heterozygous base deletion (c.1396-1398delAA) in the gene ROR2 in all affected family members. This new deletion is expected to produce a truncated Ror2 protein with a new polypeptide of 57 amino acids at the C-terminal. PMID:24954533

Huang, Dan; Jiang, Shujuan; Zhang, Yuanyuan; Liu, Xiaoliang; Zhang, Jiubin; He, Rong

2014-08-15

16

AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome.  

PubMed

We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Trp663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2, as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2-associated ectodermal dysplasia and neoplastic syndrome. PMID:21416598

Marvin, Monica L; Mazzoni, Serina M; Herron, Casey M; Edwards, Sean; Gruber, Stephen B; Petty, Elizabeth M

2011-04-01

17

AXIN2-Associated Autosomal Dominant Ectodermal Dysplasia and Neoplastic Syndrome  

PubMed Central

We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Tyr663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2, as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2-associated ectodermal dysplasia and neoplastic syndrome. PMID:21416598

Marvin, Monica L.; Mazzoni, Serina; Herron, Casey M.; Edwards, Sean; Gruber, Stephen B.; Petty, Elizabeth M.

2011-01-01

18

PROGRESSIVE WHITE MATTER ABNORMALITIES IN AUTOSOMAL-DOMINANT  

E-print Network

P4-154 PROGRESSIVE WHITE MATTER ABNORMALITIES IN AUTOSOMAL-DOMINANT ALZHEIMER'S DISEASE: RESULTS, Reisa Sperling8, Stephen Salloway9, Keith Johnson10, Steve Correia11, Peter Schofield12, Nick Fox13 onset AD it is often difficult to separate white matter disease associated with aging and diseases

Thompson, Paul

19

Regulation of cell proliferation in autosomal dominant polycystic kidney disease  

E-print Network

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disorder characterized by the presence of fluid-filled cysts primarily in the kidneys. Mutations in either the PKD1 or PKD2 genes are the underlying cause of ADPKD...

Paul, Binu M.

2011-08-31

20

[Autosome dominant vitreoretinal dystrophy with skeletal dysplasia in one generation].  

PubMed

We report on ten patients of four generations with autosomal dominant vitreoretinal dystrophy with different manifestation. The ophthalmological findings are retinal detachment, retinal holes, retinoschisis, lattice and snowflake degeneration, vitreoretinal adhesions, chorioretinal atrophy and peripheral pigment epithelial changes. Two sisters show growth retardation with skeletal anomalies most likely brachyolmia. PMID:2056740

Lang, G E; Laudi, B; Pfeiffer, R A

1991-03-01

21

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy  

Microsoft Academic Search

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a recently described genetic disease characterized by recurrent subcortical infarcts and dementia. Based on linkage analysis its gene has been assigned to chromosome 19p13. We report an Australian kindred with typical clinical features of CADASIL, the diagnosis being supported by linkage analysis. No expansion was detected on repeat expansion

Alice-Ann Sullivan; Bin Tean Teh; Sue Jeavons; Martin Schalling; Peter Silburn; Catharina Larsson; Richard Boyle

1997-01-01

22

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

23

Autosomal dominant muscle cramp syndrome in a Japanese family  

PubMed Central

OBJECTIVES—To identify the clinical, electrophysiological, histological, and genetic characteristics of a Japanese family with a muscle cramp syndrome.?METHODS—Fourteen patients (eight men, six women) were studied in four generations of a single family. Electrophysiological examinations were performed in four cases and muscle and nerve biopsies were performed on the propositus.?RESULTS—The mode of inheritance seemed to be autosomal dominant. The cramps occurred during both exertion and at rest, and during sleep. Electromyographic examination indicated a neurogenic aetiology. There was a decreased number of large myelinated fibres in the sural nerve, and fibre type grouping in the quadriceps femoris muscle biopsy.?CONCLUSIONS—The autosomal dominant muscle cramp syndrome in this family is probably caused by a polyneuropathy.?? PMID:10369837

Chiba, S; Saitoh, M; Hatanaka, Y; Kashiwagi, M; Imai, T; Matsumoto, H; Minami, R

1999-01-01

24

Autosomal dominant polycystic kidney disease: molecular genetics and molecular pathogenesis  

Microsoft Academic Search

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

Michael Koptides; C. Constantinou Deltas

2000-01-01

25

Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease  

Microsoft Academic Search

Segawa disease is a rare dystonia due to autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency,\\u000a affecting dopamine and serotonin biosynthesis. Recently, the clinical phenotype was expanded to include psychiatric manifestations,\\u000a such as depression, anxiety, obsessive–compulsive disorder, and sleep disturbances. Although cognitive and neuropsychiatric\\u000a symptoms may be attributable to dopamine deficiency in the prefrontal cortex and frontostriatal circuitry, intelligence is

Eduardo Lopez-LasoAraceli; Araceli Sánchez-Raya; Juan Antonio Moriana; Eduardo Martínez-Gual; Rafael Camino-León; María Elena Mateos-González; Juan Luis Pérez-Navero; Juan José Ochoa-Sepúlveda; Aida Ormazabal; Thomas Opladen; Christine Klein; José Ignacio Lao-Villadóniga; Katrin Beyer; Rafael Artuch

26

PENCALC: A program for penetrance estimation in autosomal dominant diseases  

PubMed Central

We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows) and web versions (PenCalcWeb) of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm. PMID:21637415

2010-01-01

27

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

28

GCAP1 mutations associated with autosomal dominant cone dystrophy  

PubMed Central

We discuss the heterogeneity of autosomal dominant cone and cone-rod dystrophies (adCD, and adCORD, respectively). As one of the best characterized adCD genes, we focus on the GUCA1A gene encoding guanylate cyclase activating protein 1 (GCAP1), a protein carrying three high affinity Ca2+ binding motifs (EF hands). GCAP1 senses changes in cytoplasmic free [Ca2+] and communicates these changes to GC1, by either inhibiting it (at high free [Ca2+]), or stimulating it (at low free [Ca2+]). A number of missense mutations altering the structure and Ca2+ affinity of EF hands have been discovered. These mutations are associated with a gain of function, producing dominant cone and cone rod dystrophy phenotypes. In this article we review these mutations and describe the consequences of specific mutations on GCAP1 structure and GC stimulation. PMID:20238026

Jiang, Li; Baehr, Wolfgang

2010-01-01

29

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

30

Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis  

PubMed Central

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

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

2013-01-01

31

[Autosomal dominant polycystic kidney disease: Is the treatment for tomorrow?].  

PubMed

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent Mendelian inherited disorder. It covers 6.1% of incident ESRD patients in France in 2011. Long left untreated, this disease will soon benefit from targeted therapies currently under evaluation. Several molecules have already reached the stage of clinical trials: the evaluation of mTOR inhibitors yielded deceiving results and, more recently, 2 different molecules demonstrated a slight impact on the progression of total kidney volume (TKV): tolvaptan, vasopressin receptor-V2 inhibitor and somatostatin analogues; both of these molecules acting throughout the decrease of intracellular AMPc. The purpose of this review is to briefly describe the signaling pathways involved, then to present both the published and ongoing clinical trials and the promising molecules evaluated in murine models. PMID:25086476

Cornec-Le Gall, Emilie; Le Meur, Yannick

2014-11-01

32

Mitochondrial anomalies in a Swiss family with autosomal dominant myoglobinuria  

SciTech Connect

We report on a Swiss family in which 10 individuals of both sexes in 4 successive generations suffered from myoglobinuria, precipitated by febrile illness. It is the second family described with autosomal dominant inheritance of myoglobinuria. Four individuals suffered acute renal failure, which in two was reversible only after dialysis. In a recent case, a mitochondrial disorder was suspected because of an abnormal increase in lactate levels during an exercise test and because of a subsarcolemmal accumulation of mitochondria in a muscle biopsy, associated with a lack of cytochrome C oxidase in some muscle fibers. No mutation in the mitochondrial DNA was identified. Along with the inheritance pattern, these findings suggest that the myoglobinuria in this family is caused by a nuclear-encoded mutation affecting the respiratory chain. 22 refs., 2 figs.

Martin-du Pan, R.C. [Univ. Hospital, Geneva (Switzerland)] [Univ. Hospital, Geneva (Switzerland); Favre, H.; Junod, A. [Univ. Hospital, Geneva (Switzerland)] [and others] [Univ. Hospital, Geneva (Switzerland); and others

1997-04-14

33

Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2.  

PubMed

We report the clinical features of 12 families with autosomal dominant spastic paraplegia (ADSP) linked to the SPG4 locus on chromosome 2p, the major locus for this disorder that accounts for approximately 40% of the families. Among 93 gene carriers, 32 (34%) were unaware of symptoms but were clinically affected. Haplotype reconstruction showed that 90% of the asymptomatic gene carriers presented increased reflexes and/or extensor plantar responses independent of age at examination. The mean age at onset was 29 years, ranging from 1 to 63 years. Intra- as well as inter-familial variability of age at onset was important, but did not result from anticipation. Phenotype-genotype correlations and comparison with SPG3 and SPG5 families indicated that despite the variability of age at onset, SPG4 is a single genetic entity but no clinical features distinguish individual SPG4 patients from those with SPG3 or SPG5 mutations. PMID:8931574

Dürr, A; Davoine, C S; Paternotte, C; von Fellenberg, J; Cogilinicean, S; Coutinho, P; Lamy, C; Bourgeois, S; Prud'homme, J F; Penet, C; Mas, J L; Burgunder, J M; Hazan, J; Weissenbach, J; Brice, A; Fontaine, B

1996-10-01

34

Genetic aspects of autosomal dominant late onset cerebellar ataxia.  

PubMed Central

The genetic features of eight families with autosomal dominant late onset cerebellar ataxia with randomly distributed associated clinical features are described. The ratio of affected to unaffected offspring of affected subjects was not significantly different from 1:1. The mutant gene was fully penetrant when cases who died before the period of risk of developing the disease were excluded. The proportion of new mutants with this disorder appears to be low. Biological fitness was not impaired. Affected females tended to have large families than affected males. The ages of onset of females and males were not significantly different, but the offspring of affected males had earlier ages of onset and death than those of affected females. A cumulative age of onset curve is presented which should aid genetic counselling of subjects at risk and their children. PMID:7334501

Harding, A E

1981-01-01

35

Novel MSX1 Frameshift Causes Autosomal-dominant Oligodontia  

PubMed Central

Can kindreds with tooth agenesis caused by MSX1 or PAX9 mutations be distinguished by their phenotypes? We have identified an MSX1 frameshift mutation (g.62dupG, p.G22RfsX168) that causes non-syndromic autosomal-dominant oligodontia, featuring the absence of multiple permanent teeth, including all second bicuspids and mandibular central incisors. The dominant phenotype is apparently due to haploinsufficiency. We analyzed patterns of partial tooth agenesis in seven kindreds with defined MSX1 mutations and ten kindreds with defined PAX9 mutations. The probability of missing a particular type of tooth is always bilaterally symmetrical, but differences exist between the maxilla and mandible. MSX1-associated oligodontia typically includes missing maxillary and mandibular second bicuspids and maxillary first bicuspids. The most distinguishing feature of MSX1-associated oligodontia is the frequent (75%) absence of maxillary first bicuspids, while the most distinguishing feature of PAX9-associated oligodontia is the frequent (> 80%) absence of the maxillary and mandibular second molars. PMID:16498076

Kim, J.-W.; Simmer, J.P.; Lin, B.P.-J.; Hu, J.C.-C.

2008-01-01

36

Mechanisms of emphysema in autosomal dominant cutis laxa.  

PubMed

Heterozygous elastin gene mutations cause autosomal dominant cutis laxa associated with emphysema and aortic aneurysms. To investigate the molecular mechanisms leading to cutis laxa in vivo, we generated transgenic mice by pronuclear injection of minigenes encoding normal human tropoelastin (WT) or tropoelastin with a cutis laxa mutation (CL). Three independent founder lines of CL mice showed emphysematous pulmonary airspace enlargement. No consistent dermatological or cardiovascular pathologies were observed. One CL and one WT line were selected for detailed studies. Both mutant and control transgenic animals showed elastin deposition into pulmonary elastic fibers, indicated by increased desmosine levels in the lung and by colocalization of transgenic and endogenous elastin by immunostaining. CL mice showed increased static lung compliance and decreased stiffness of lung tissue. In addition, markers of transforming growth factor-? (TGF?) signaling and the unfolded protein response (UPR) were elevated together with increased apoptosis in the lungs of CL animals. We conclude that the synthesis of mutant elastin in CL activates multiple downstream disease pathways by triggering a UPR, altered mechanical signaling, increased release of TGF? and apoptosis. We propose that the combined effects of these processes lead to the development of an emphysematous pulmonary phenotype in CL. PMID:20600892

Hu, Qirui; Shifren, Adrian; Sens, Carla; Choi, Jiwon; Szabo, Zoltan; Starcher, Barry C; Knutsen, Russell H; Shipley, J Michael; Davis, Elaine C; Mecham, Robert P; Urban, Zsolt

2010-09-01

37

Urine proteome of autosomal dominant polycystic kidney disease patients  

PubMed Central

Background Autosomal dominant polycystic kidney disease (ADPKD) is responsible for 10% of cases of the end stage renal disease. Early diagnosis, especially of potential fast progressors would be of benefit for efficient planning of therapy. Urine excreted proteome has become a promising field of the search for marker patterns of renal diseases including ADPKD. Up to now however, only the low molecular weight fraction of ADPKD proteomic fingerprint was studied. The aim of our study was to characterize the higher molecular weight fraction of urinary proteome of ADPKD population in comparison to healthy controls as a part of a general effort aiming at exhaustive characterization of human urine proteome in health and disease, preceding establishment of clinically useful disease marker panel. Results We have analyzed the protein composition of urine retentate (>10?kDa cutoff) from 30 ADPKD patients and an appropriate healthy control group by means of a gel-free relative quantitation of a set of more than 1400 proteins. We have identified an ADPKD-characteristic footprint of 155 proteins significantly up- or downrepresented in the urine of ADPKD patients. We have found changes in proteins of complement system, apolipoproteins, serpins, several growth factors in addition to known collagens and extracellular matrix components. For a subset of these proteins we have confirmed the results using an alternative analytical technique. Conclusions Obtained results provide basis for further characterization of pathomechanism underlying the observed differences and establishing the proteomic prognostic marker panel. PMID:23228063

2012-01-01

38

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

39

Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease.  

PubMed

Segawa disease is a rare dystonia due to autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, affecting dopamine and serotonin biosynthesis. Recently, the clinical phenotype was expanded to include psychiatric manifestations, such as depression, anxiety, obsessive-compulsive disorder, and sleep disturbances. Although cognitive and neuropsychiatric symptoms may be attributable to dopamine deficiency in the prefrontal cortex and frontostriatal circuitry, intelligence is considered normal in Segawa disease. Our aim was to investigate neuropsychiatric symptoms and intelligence quotients (IQ) in a series of individuals with adGTPCH deficiency. The assessment included a structured clinical interview following the DSM-IV-TR's guidelines, Beck's Depression Inventory, the State-Trait Anxiety Inventory, the Maudsley Obsessive-Compulsive Questionnaire, the Barratt Impulsiveness Scale-11 (BIS-11), the Oviedo Sleep Questionnaire, the Pittsburgh Sleep Quality Index, and the Wechsler Adult Intelligence Scale-Third Edition. Equivalent tests were applied to pediatric patients as appropriate for their age group. Fourteen patients with adGTPCH deficiency were evaluated (seven adult and seven pediatric patients). Depression, anxiety, and obsessive-compulsive symptoms were not more common than expected in the general population. However, the seven adults showed impulsivity in the BIS-11; nine individuals had an IQ in the range of borderline intellectual functioning to mild mental retardation, and sleep disturbances were found in four individuals. We found no differences between these results and the motor impairment. In conclusion, our findings would suggest that cognitive impairment, and impulsivity in adults, may be associated with Segawa disease. PMID:21556877

López-Laso, Eduardo; Sánchez-Raya, Araceli; Moriana, Juan Antonio; Martínez-Gual, Eduardo; Camino-León, Rafael; Mateos-González, María Elena; Pérez-Navero, Juan Luis; Ochoa-Sepúlveda, Juan José; Ormazabal, Aida; Opladen, Thomas; Klein, Christine; Lao-Villadóniga, José Ignacio; Beyer, Katrin; Artuch, Rafael

2011-12-01

40

Vestibular function in families with inherited autosomal dominant hearing loss  

PubMed Central

The inner ear contains the developmentally related cochlea and peripheral vestibular labyrinth. Given the similar physiology between these two organs, hearing loss and vestibular dysfunction may be expected to occur simultaneously in individuals segregating mutations in inner ear genes. Twenty-two different genes have been discovered that when mutated lead to non-syndromic autosomal dominant hearing loss. A review of the literature indicates that families segregating mutations in 13 of these 22 genes have undergone formal clinical vestibular testing. Formal assessment revealed vestibular dysfunction in families with mutations in ten of these 13 genes. Remarkably, only families with mutations in the COCH and MYO7A genes self-report considerable vestibular challenges. Families segregating mutations in the other eight genes do not self-report significant balance problems and appear to compensate well in everyday life for vestibular deficits discovered during formal clinical vestibular assessment. An example of a family (referred to as the HL1 family) with progressive hearing loss and clinically-detected vestibular hypofunction that does not report vestibular symptoms is described in this review. Notably, one member of the HL1 family with clinically-detected vestibular hypofunction reached the summit of Mount Kilimanjaro. PMID:18776598

Street, Valerie A.; Kallman, Jeremy C.; Strombom, Paul D.; Bramhall, Naomi F.; Phillips, James O.

2008-01-01

41

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

42

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

SciTech Connect

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

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

1996-12-30

43

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

E-print Network

subunit mutation, A322D (AD), causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJMEGABAA Receptor 1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors*S Received

Palmeri, Thomas

44

Diagnosis and Screening of Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and accounts for ?5% of end-stage renal disease (ESRD) population in the United States. The disorder is characterized by the focal and sporadic development of renal cysts, which increase in size and number with age. Mutations of PKD1 and PKD2 account for most of the cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with larger kidneys and earlier onset of ESRD. In general, renal ultrasonography is commonly used for the diagnosis of ADPKD and age-dependent criteria have been defined for subjects at-risk of PKD1. However, the utility of the PKD1 ultrasound criteria in the clinic setting is unclear since their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. Additionally, both DNA linkage or gene-based direct sequencing are now available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, a negative or indeterminate family history, or in younger at-risk individuals being evaluated as potential living-related kidney donors. Here, we review the clinical utilities and limitations of both imaging- and molecular-based diagnostic tests, and outline our approach for the evaluation of individuals suspected to have ADPKD. PMID:20219617

Pei, York; Watnick, Terry

2010-01-01

45

Association of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease  

Microsoft Academic Search

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

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

1993-01-01

46

Clinical and Radiological Findings of Autosomal Dominant Osteopetrosis Type II: A Case Report  

PubMed Central

Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton caused by the absence or malfunction of osteoclasts. Three distinct forms of the disease have been recognized, autosomal dominant osteopetrosis being the most common. Autosomal dominant osteopetrosis exhibits a heterogeneous trait with milder symptoms, often at later childhood or adulthood. The aim of this case report is to present the clinical and radiographic features of a 35-year-old female patient with autosomal dominant osteopetrosis type II who exhibited features of chronic generalised periodontitis, and the radiographs revealed generalised osteosclerosis and hallmark radiographic features of ADO type II, that is, “bone-within-bone appearance” and “Erlenmeyer-flask deformity.” PMID:24260721

Kant, Priyanka; Sharda, Neelkamal; Bhowate, Rahul R.

2013-01-01

47

Midtrimester diagnosis of severe deforming osteogenesis imperfecta with autosomal dominant inheritance.  

PubMed

Sonographic examination of a fetus whose father had severe deforming osteogenesis imperfecta (OI) was performed. The father had multiple congenital rib and extremity fractures. Subsequent fracture and deformity had suggested an autosomal recessive OI syndrome. However, fetal sonography at 18 weeks gestational age showed foreshortening of long bones in both legs and a reduced thoracic circumference, recapitulating, in part, the father's phenotype. This third reported case of early fetal diagnosis of autosomal dominant OI suggests that the fetal sonographic phenotype reflects that of the affected parent. Implications of this case for the application of fetal sonography in dominant OI syndromes are discussed. PMID:3516171

Carpenter, M W; Abuelo, D; Neave, C

1986-04-01

48

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

SciTech Connect

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

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

1994-07-01

49

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; Göpel, Karl Heinrich; Rothammer, Sophie; Förster, Martin; Krebs, Stefan

2012-01-01

50

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 kidney dis- ease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery and therapeutic strategies. Key words. PKD1; PKD2; polycystin-1; polycystin-2; ADPKD; polycystic kidney disease

Witzgall, Ralph - Naturwissenschaftliche Fakultät III

51

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

52

Evaluation and Management of Pain in Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Transient episodes of pain are common in autosomal dominant polycystic kidney disease (ADPKD). A small fraction of patients have disabling chronic pain. In this review, we discuss the etiologies of pain in ADPKD; review how ADPKD patients should be assessed; and discuss medical, surgical, and other management options. PMID:20439087

Hogan, Marie C.; Norby, Suzanne M.

2014-01-01

53

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

54

SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy  

Microsoft Academic Search

Autosomal dominant proximal spinal muscular atrophy (ADSMA) is a rare disorder with unknown gene defects in the majority of families. Here we describe a family where the diagnosis of juvenile and adult onset ADSMA was made in three individuals. Because of retained tendon reflexes an atypical course of juvenile amyotrophic lateral sclerosis (ALS4) was considered. SETX gene sequencing revealed the

Sabine Rudnik-Schöneborn; Larissa Arning; Jörg T. Epplen; Klaus Zerres

55

Familial Paroxysmal Exercise-Induced Dystonia: Atypical Presentation of Autosomal Dominant GTP-Cyclohydrolase 1 Deficiency  

ERIC Educational Resources Information Center

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced…

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

2010-01-01

56

Inheritance of Human Breast Cancer: Evidence for Autosomal Dominant Transmission in High-Risk Families  

Microsoft Academic Search

Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a population-based series of probands, an autosomal dominant model with a

Beth Newman; Melissa A. Austin; Ming Lee; Mary-Claire King

1988-01-01

57

More Adverse Renal Prognosis of Autosomal Dominant Polycystic Kidney Disease in Families With Primary rt1  

Microsoft Academic Search

Marked variability of age at renal death is noted in autosomal dominant polycystic kidney disease (AD- PKD). The hypothesis that the coexistence of primary hypertension and ADPKD within families is associated with earlier renal death was tested. Of a total of 162 ADPKD patients treated in one Austrian and three German centers, 57 propositi were identified whose families provided (

S. Geberth; E. Stier; M. Zeier; G. Mayer; M. Rambausek; E. Ritz; M. Zeler

1995-01-01

58

Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q  

SciTech Connect

Amelogenesis imperfecta (AI), a disorder affecting the formation of enamel, is significantly more common in Northern Sweden than in other parts of the world. The disease is genetically and clinically heterogenous, and autosomal dominant, autosomal recessive and X-linked inheritance patterns have been recognized. Linkage analysis has identified two different loci for X-linked AI, one of which is identical to the gene encoding the enamel protein amelogenin. However, in families with an autosomal inheritance pattern for AI, the genetic basis of the disease still remains unknown. We report a linkage analysis study performed on three Swedish families where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained, with a maximum lod score of 5.55 for the marker D4S428. Recombinations in the family localized the ADAI locus to the interval between D4S392 and D4S395. This chromosome region contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease.

Forsman, K.; Lind. L.; Westermark, E. [Univ. of Umea (Sweden)] [and others

1994-09-01

59

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

PubMed Central

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

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

1999-01-01

60

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

PubMed Central

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

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

1999-01-01

61

Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11  

Microsoft Academic Search

Idiopathic scoliosis (IS) is a spine deformity of unknown etiology. Family studies have suggested that IS may be inherited as a mendelian autosomal dominant trait. We have performed linkage analysis on a three-generation IS Italian family. A positive LOD score value of 3.20 at /=0.00 was detected with marker D17S799 after a genome-wide scanning. Analysis of six flanking microsatellites confirmed

Leila Baghernajad Salehi; Massimo Mangino; Salvatore De Serio; Domenico De Cicco; Francesca Capon; Sabrina Semprini; Antonio Pizzuti; Giuseppe Novelli; Bruno Dallapiccola

2002-01-01

62

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

63

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

64

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

65

Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model  

Microsoft Academic Search

Background  Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion,\\u000a resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported\\u000a to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the\\u000a early stage of ADPKD is necessary to clarify its

Takafumi Toyohara; Takehiro Suzuki; Yasutoshi Akiyama; Daisuke Yoshihara; Yoichi Takeuchi; Eikan Mishima; Koichi Kikuchi; Chitose Suzuki; Masayuki Tanemoto; Sadayoshi Ito; Shizuko Nagao; Tomoyoshi Soga; Takaaki Abe

66

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

67

A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree  

Microsoft Academic Search

Familial hypercholesterolemia results from mutations in the low-density lipoprotein (LDL) receptor or apolipoprotein B genes. We have previously reported the identification of a Utah autosomal-dominant hypercholesterolemia pedigree (kindred 1173) that did not show linkage to either of these loci (Hunt et al. 2000). Expansion of the pedigree and increased marker density within the region of interest have resulted in a multipoint

Kirsten M. Timms; Susanne Wagner; Mark E. Samuels; Kristian Forbey; Howard Goldfine; Srikanth Jammulapati; Mark H. Skolnick; Paul N. Hopkins; Steve C. Hunt; Donna M. Shattuck

2004-01-01

68

Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent inherited disorders. The majority of cases\\u000a are due to mutation of the PKD1 gene, on 16p13.3, while in most of the remainder the disease maps to the PKD2 locus, at chromosome\\u000a 4q21-q23. Recently, the PKD2 gene has been positionally cloned and three nonsense mutations within the coding sequence

Miguel Viribay; Tomohito Hayashi; Dolores Tellería; Toshio Mochizuki; David M. Reynolds; Rafael Alonso; Xose M. Lens; Felipe Moreno; Peter C. Harris; Stefan Somlo; José L. San Millán

1997-01-01

69

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME): Probable first family from India  

PubMed Central

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME) is an extremely rare syndrome characterized by familial occurrence of postural and action-induced tremors of the hands but showing electrophysiologic findings of cortical reflex myoclonus. Patients also have cognitive decline and tonic-clonic seizures, often precipitated by sleep deprivation or photic stimulation. We describe probably the first family from India of this ill-defined syndrome. PMID:25506167

Sharma, Chandra Mohan; Nath, Kunal; Kumawat, Bansi Lal; Khandelwal, Dinesh

2014-01-01

70

A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3  

Microsoft Academic Search

Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel\\u000a development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that\\u000a are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant\\u000a form of AI and mapped

Gustavo Mendoza; Trevor J. Pemberton; Kwanghyuk Lee; Raquel Scarel-Caminaga; Ruty Mehrian-Shai; Catalina Gonzalez-Quevedo; Vasiliki Ninis; Jaana Hartiala; Hooman Allayee; Malcolm L. Snead; Suzanne M. Leal; Sergio R. P. Line; Pragna I. Patel

2007-01-01

71

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

72

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

73

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

PubMed Central

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 the presence, distribution, and appearance of keloids, together with the timing of keloid onset and provocative factors. The clinical trial was registered at clinicaltrials.gov (NCT 00005802). Results Age of keloid onset varied considerably within families, but commonly occurred by the second decade. The fraction of affected individuals was 38%, 45%, 62%, 67% and 73% among the five families respectively. Keloid severity and morphology differed within and between families. A novel finding is that certain families manifest keloids in distinct locations, with one family showing an excess of extremity keloids and two families showing an excess of axilla-groin keloids. Conclusion Familial keloids appear to most commonly manifest autosomal dominant or semidominant inheritance, and there may be familial patterns of keloid distribution. PMID:19638218

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

2009-01-01

74

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

75

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

PubMed Central

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

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

2012-01-01

76

Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys  

Microsoft Academic Search

Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys.BackgroundThe proliferation of mural epithelial cells is a major cause of progressive cyst enlargement in autosomal-dominant polycystic kidney disease (ADPKD). Adenosine 3?, 5? cyclic monophosphate (cAMP) stimulates the proliferation of cells from ADPKD cysts, but not cells from normal human kidney cortex (HKC), through the activation of

Tamio Yamaguchi; Shizuko Nagao; Darren P. Wallace; Franck A. Belibi; Benjamin D. Cowley; Jill C. Pelling; Jared J. Grantham

2003-01-01

77

The anterior segment disorder autosomal dominant keratitis is linked to the Aniridia/PAX-6 gene  

SciTech Connect

Autosomal dominant keratitis (ADK) is an eye disease characterized by anterior stromal corneal opacification and vascularization in the peripheral cornea. Progression into the central cornea may compromise visual acuity. Other anterior segment features include minimal radial defects of the iris stroma. Posterior segment involvement is characterized by foveal hypoplasia with minimal effect on visual acuity. Aniridia is a second autosomal dominantly inherited ocular disorder defined by structural defects of the iris, frequently severe enough to cause an almost complete absence of iris. This may be accompanied by other anterior segment manifestations, including cataract and keratitis. Posterior segment involvement in aniridia is characterized by foveal hypoplasia resulting in a highly variable impairment of visual acuity, often with nystagmus. Aniridia is usually inherited as an autosomal dominant disease and occurs in 1 in 50,000 to 100,000 people. Aniridia has been shown to result from mutations in PAX-6, a gene thought to regulate fetal eye development. The similar clinical findings in ADK and aniridia, with the similar patterns of inheritance, compelled us to investigate if these two ocular disorders are variants of the same genetic disorder. We have tested for linkage between PAX-6 and ADK within an ADK family with 33 members over four generations, including 11 affected individuals. Linkage studies reveal that D11S914 (located within 3 cM of PAX-6) does not recombine with ADK (LOD score 3.61; {theta} = 0.00), consistent with PAX-6 mutations being responsible for ADK. Direct sequencing of PAX-6 RT-PCR products from ADK patients is underway to identify the mutation within the PAX-6 gene that results in ADK. The linkage of PAX-6 with ADK, along with a recent report that mutations in PAX-6 also underlie Peter`s anomaly, implicates PAX-6 widely in anterior segment malformations.

Mirzayans, F.; Pearce, W.G.; Mah, T.S. [Univ. of Alberta, Edmonton (Canada)] [and others

1994-09-01

78

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL): a rare cause of dementia  

PubMed Central

The clinical course of a 60-year-old gentleman with a history of atypical migraine, recurrent encephalopathic episodes and progressive cognitive impairment is presented. He was diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, a rare genetic disorder of the cerebral blood vessels caused by mutations in the Notch 3 gene on chromosome 19. The diagnosis was confirmed by MRI, skin biopsy and genetic testing. His cognitive function has progressively deteriorated and he continues to receive supportive care provision. The course and review of the condition are highlighted. PMID:23355563

Toni-Uebari, Thelma K

2013-01-01

79

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

80

Clinical and laboratory markers of autosomal dominant polycystic kidney disease (ADPKD) progression: an overview.  

PubMed

Autosomal dominant polycystic kidney (ADPKD) is the most common inherited renal cystic disease and it occurs in all races, the reported prevalence is between 1:400 and 1:1000. It is characterized by development of cysts in both kidneys and progressive renal function loss. Among most Autosomal Dominant Polycystic Kidney patients, renal function remains intact until the fourth decade of life. It is very important to identify early markers of disease progression to recognize patients with a worse prognosis. The aim of this study is to review the clinical and laboratory markers of ADPKD progression. The early clinical parameters evaluated seem to be directly correlated with the volume of the cysts that determine the kidney volume. From a clinical point of view, total kidney volume (TKV) appears to be the best marker of early ADPKD progression. This review evaluated several ADPKD progression markers comparing the early consolidated clinical and the new promising laboratory indicators. From a laboratory point of view, copeptin has a potential role between the serum biomarkers of ADPKD progression. However, further studies are necessary to validate the potential predictive value of its serum level and to adopt it for routine use. The combination of biomarkers could probably predict ADPKD progression with more accuracy than the use of a single biomarker. PMID:25300895

Corradi, V; Gastaldon, F; Virzì, G M; Caprara, C; Martino, F; Ronco, C

2015-02-01

81

Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy  

PubMed Central

Background Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500) is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients. Methods Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA). When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible. Results Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease. Conclusion Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis. PMID:21457585

2011-01-01

82

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

SciTech Connect

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-D7S553-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. The authors propose the name SHSF2 for this second locus. 34 refs., 4 figs., 1 tab.

Palmer, S.E.; Wijsman, E.M.; Stephens, K.; Evans, J.P. (Univ. of Washington School of Medicine, Seattle, WA (United States)); Scherer, S.W.; Tsui, L.C. (Univ. of Toronto (Canada)); Kukolich, M. (Genetic Screening and Counseling Service, Denton, TX (United States))

1994-07-01

83

Autosomal dominant mouse cataract (Lop-10). Consistent differences of expression in heterozygotes.  

PubMed

The clinical and histologic features are reported of an autosomal dominant mouse cataract that was first observed as a new mutation in a cross between BALB/cJ and AKR/J. In the homozygous state, the eyes were microphthalmic, and a dense white cataract was present when the eyes opened at day 12. Histologic changes were apparent from birth and as early as 18 days' gestation. Liquefaction started by day 4, and herniation of lens contents posteriorly was seen at day 11. Heterozygous mice had variable expression depending both on their genetic background and age. When the single gene was expressed fully, the cataract appeared as a fetal nuclear white opacity; partial expression gave a nuclear haze to snowflake nuclear opacities. Lop-10 appeared to be an excellent model for studying variable expression of a dominant gene. PMID:1399425

Runge, P E; Hawes, N L; Heckenlively, J R; Langley, S H; Roderick, T H

1992-10-01

84

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

SciTech Connect

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

Rodriguez, J.A.; Gannon, A.M.; Daiger, S.P. [Univ. of Texas HSC, Houston, TX (United States)] [and others

1994-09-01

85

Functional heterogeneity of mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa.  

PubMed Central

Thirteen mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa (ADRP) have been produced by transfection of cloned cDNA into tissue culture cells. Three mutants [class I: Phe-45----Leu, Gln-344----termination (deletion of C-terminal positions 344-348), and Pro-347----Leu] resemble wild-type rhodopsin in yield, regenerability with 11-cis-retinal, and plasma membrane localization. Ten mutants [class II: Thr-17----Met, Pro-23----His, Thr-58----Arg, Val-87----Asp, Gly-89----Asp, Gly-106----Trp, Arg-135----Leu, Arg-135----Trp, Tyr-178----Cys, and Asp-190----Gly] accumulate to significantly lower levels, regenerate with 11-cis-retinal variably or not at all, and are transported inefficiently to the plasma membrane, remaining primarily in the endoplasmic reticulum. These data suggest that there are at least two distinct biochemical defects associated with different rhodopsin mutants in ADRP. Images PMID:1924344

Sung, C H; Schneider, B G; Agarwal, N; Papermaster, D S; Nathans, J

1991-01-01

86

Generation of the first Autosomal Dominant Osteopetrosis Type II (ADO2) disease models  

PubMed Central

Autosomal Dominant Osteopetrosis Type II (ADO2) is a heritable osteosclerotic disorder dependent on osteoclast impairment. In most patients it results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene, encoding for a 2Cl?/1H+ antiporter. By a knock-in strategy inserting a missense mutation in the Clcn7 gene, our two research groups independently generated mouse models of ADO2 on different genetic backgrounds carrying the homolog of the most frequent heterozygous mutation (p.G213R) in the Clcn7 gene found in humans. Our results demonstrate that the heterozygous model holds true presenting with higher bone mass, increased numbers of poorly resorbing osteoclasts and a lethal phenotype in the homozygous state. Considerable variability is observed in the heterozygous mice according with the mouse background, suggesting that modifier genes could influence the penetrance of the disease gene. PMID:24185277

Alam, Imranul; Gray, Amie K.; Chu, Kang; Ichikawa, Shoji; Mohammad, Khalid S.; Capannolo, Marta; Capulli, Mattia; Maurizi, Antonio; Muraca, Maurizio; Teti, Anna; Econs, Michael J.; Fattore, Andrea Del

2013-01-01

87

[Cardiac tamponade as first manifestation in mediterranean fever with autosomal dominant form].  

PubMed

Familial Mediterranean fever (FMF) is a hereditary disease characterized by brief, recurring and self-limited episodes of fever and pain with inflammation, of one or several serous (peritoneum, pleura, pericardium, synovial or vaginal tunic of the testicle). Amyloidosis is its more important complication and the principal reason of death in the cases in which it appears. Diagnosis is based on the clinic and is confirmed by genetic tests. The treatment with Colchicine (0,02-0,03mg/kg/day) prevents the recurrence of FMF attacks and the development of secondary (AA) amyloidosis. We report a case of a 13-year-old child in which FMF was diagnosed after several coincidental episodes with fever, pericarditis and cardiac tamponade. The genetic confirmation showed an autosomal dominant inheritance that is less frecuent than the recesive form, in this disease. PMID:24365392

Sánchez Ferrer, F; Martinez Villar, M; Fernández Bernal, A; Martín de Lara, I; Paya Elorza, I

2015-01-01

88

A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment.  

PubMed

Several different mutations in the KCNQ4 K+ channel gene are responsible for autosomal dominant nonsyndromic hearing impairment (DFNA2). Here we describe two additional families originating from Europe and Japan with a KCNQ4 missense mutation (W276S) that was previously found in one European family. We compared the disease-associated haplotype of the three W276S-bearing families using closely linked microsatellite markers and intragenic single nucleotide polymorphisms. Differences between the haplotypes were found, excluding a single founder mutation for the families. Therefore, the W276S mutation has occurred three times independently, and most likely represents a hot spot for mutation in the KCNQ4 gene. PMID:12112653

Van Camp, Guy; Coucke, Paul J; Akita, Jiro; Fransen, Erik; Abe, Satoko; De Leenheer, Els M R; Huygen, Patrick L M; Cremers, Cor W R J; Usami, Shin-Ichi

2002-07-01

89

Non-syndromal autosomal dominant hearing impairment: ongoing phenotypical characterization of genotypes.  

PubMed

This review is concerned with the present state of phenotypical characterization of known genotypes of non-syndromal autosomal dominant hearing impairment. A brief outline of history and context of phenotyping and genotyping of hearing impairment is given with particular reference to the most recent developments in this field, followed by descriptions of DFNA1, DFNA2, DFNA5, DFNA6/14, DFNA8/12, DFNA9, DFNA 13, DFNA17 and DFNA21. Phenotyping those known genotypes may support the ongoing search for mutations in the corresponding gene and enhance genetic counselling. It is recommended that sufficient attention is given to a detailed description of the phenotype in each (newly) described hereditary hearing impairment disorder. PMID:10890148

Bom, S J; Kunst, H P; Huygen, P L; Cremers, F P; Cremers, C W

1999-10-01

90

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease  

PubMed Central

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

Harris, Peter C.; Torres, Vicente E.

2014-01-01

91

Extrapyramidal symptoms and advanced calcification of the basal ganglia in a patient with autosomal dominant hypocalcemia.  

PubMed

Most cases of hypoparathyroidism with decreased parathyroid hormone (PTH) secretion, excluding secondary hypoparathyroidism, are considered to be idiopathic. We herein report a relatively rare case of hypoparathyroidism with extrapyramidal symptoms, including brachybasia and a frozen gait, caused by advanced basal ganglia calcification in a 64-year-old man with hypoparathyroidism. A DNA (deoxyribonucleic acid) analysis of blood samples obtained from the patient and his eldest daughter revealed autosomal dominant hypocalcemia (ADH) with mutations in the calcium-sensing receptor (CaSR) gene. In cases of chronic hypoparathyroidism, calcification of the basal ganglia is observed if the patient is not treated for a long period. However, extrapyramidal symptoms as a complication of hypoparathyroidism are relatively rare. PMID:24042516

Kurozumi, Akira; Okada, Yosuke; Arao, Tadashi; Endou, Itsuro; Matsumoto, Toshio; Tanaka, Yoshiya

2013-01-01

92

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

93

SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy.  

PubMed

Autosomal dominant proximal spinal muscular atrophy (ADSMA) is a rare disorder with unknown gene defects in the majority of families. Here we describe a family where the diagnosis of juvenile and adult onset ADSMA was made in three individuals. Because of retained tendon reflexes an atypical course of juvenile amyotrophic lateral sclerosis (ALS4) was considered. SETX gene sequencing revealed the previously reported heterozygous missense mutation c.1166T

Rudnik-Schöneborn, Sabine; Arning, Larissa; Epplen, Jörg T; Zerres, Klaus

2012-03-01

94

Disseminated kidney tuberculosis complicating autosomal dominant polycystic kidney disease: a case report.  

PubMed

Mycobacterium tuberculosis infection in patients with autosomal dominant polycystic kidney disease (ADPKD) is rare, and its diagnosis and treatment are difficult because numerous cysts are exposed to infection and antibiotics do not easily penetrate infected cysts. Here, we report the case of a 43-year-old Japanese man with disseminated urogenital tuberculosis (TB) and ADPKD without human immunodeficiency virus (HIV) infection. Delayed diagnosis and ineffective anti-TB chemotherapy worsened his condition. Finally, he underwent bilateral nephrectomy but experienced postoperative complications. In conclusion, kidney TB should be recognized as a cause of renal infection in ADPKD, and surgical treatment should be instituted without delay. The importance of early diagnosis and treatment cannot be overemphasized to prevent kidney TB deterioration. PMID:22377257

Takeshita, Hideki; Amemiya, Morimasa; Chiba, Koji; Urushibara, Masayasu; Satoh, Jun-Ichi; Noro, Akira

2012-03-01

95

Mitochondrial Ca(2+) uptake correlates with the severity of the symptoms in autosomal dominant optic atrophy.  

PubMed

The most frequent form of hereditary blindness, autosomal dominant optic atrophy (ADOA), is caused by the mutation of the mitochondrial protein Opa1 and the ensuing degeneration of retinal ganglion cells. Previously we found that knockdown of OPA1 enhanced mitochondrial Ca(2+) uptake (Fülöp et al., 2011). Therefore we studied mitochondrial Ca(2+) metabolism in fibroblasts obtained from members of an ADOA family. Gene sequencing revealed heterozygosity for a splice site mutation (c. 984+1G>A) in intron 9 of the OPA1 gene. ADOA cells showed a higher rate of apoptosis than control cells and their mitochondria displayed increased fragmentation when forced to oxidative metabolism. The ophthalmological parameters critical fusion frequency and ganglion cell-inner plexiform layer thickness were inversely correlated to the evoked mitochondrial Ca(2+) signals. The present data indicate that enhanced mitochondrial Ca(2+) uptake is a pathogenetic factor in the progress of ADOA. PMID:25533789

Fülöp, László; Rajki, Anikó; Maka, Erika; Molnár, Mária Judit; Spät, András

2015-01-01

96

Autosomal Dominant Type I Osteopetrosis Is Related with Iatrogenic Fractures in Arthroplasty  

PubMed Central

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

van Hove, Ruud P.; de Jong, Tjitte

2014-01-01

97

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

PubMed

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

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

2014-12-01

98

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

PubMed

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

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

2014-03-01

99

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease  

PubMed Central

Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease. PMID:24194552

Benzinger, Tammie L. S.; Blazey, Tyler; Jack, Clifford R.; Koeppe, Robert A.; Su, Yi; Xiong, Chengjie; Raichle, Marcus E.; Snyder, Abraham Z.; Ances, Beau M.; Bateman, Randall J.; Cairns, Nigel J.; Fagan, Anne M.; Goate, Alison; Marcus, Daniel S.; Aisen, Paul S.; Christensen, Jon J.; Ercole, Lindsay; Hornbeck, Russ C.; Farrar, Angela M.; Aldea, Patricia; Jasielec, Mateusz S.; Owen, Christopher J.; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A.; Ringman, John; Thompson, Paul M.; Ghetti, Bernardino; Saykin, Andrew J.; Sperling, Reisa A.; Johnson, Keith A.; Salloway, Stephen; Correia, Stephen; Schofield, Peter R.; Masters, Colin L.; Rowe, Christopher; Villemagne, Victor L.; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N.; Fox, Nick C.; Cash, David M.; Weiner, Michael W.; Holtzman, David M.; Buckles, Virginia D.; Moulder, Krista; Morris, John C.

2013-01-01

100

Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q  

SciTech Connect

Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North American kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.

Fink, J.K.; Wu, C.T.B.; Jones, S.M.

1994-09-01

101

Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese.  

PubMed

Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied, most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for autosomal dominant sensorineural hearing loss. The present study reports that a mutation in KCNQ4, a member of a large family of potassium channel genes, was responsible for ADSNHL in one Japanese family. PMID:11450843

Akita, J; Abe, S; Shinkawa, H; Kimberling, W J; Usami, S

2001-01-01

102

A Three-Generation Family with Idiopathic Facial Palsy Suggesting an Autosomal Dominant Inheritance with High Penetrance  

PubMed Central

Idiopathic facial palsy (IFP), also known as Bell's palsy, is a common neurologic disorder, but recurrent and familial forms are rare. This case series presents a three-generation family with idiopathic facial palsy. The mode of inheritance of IFP has previously been suggested as autosomal dominant with low or variable penetrance, but the present family indicates an autosomal dominant trait with high or complete penetrance. Chromosome microarray studies did not reveal a pathogenic copy number variation, which could enable identification of a candidate gene. PMID:25685580

Grønhøj Larsen, Christian; Gyldenløve, Mette; Jønch, Aia Elise; Charabi, Birgitte; Tümer, Zeynep

2015-01-01

103

Autosomal dominant polycystic kidney disease with diffuse proliferative glomerulonephritis - an unusual association: a case report and review of the literature  

PubMed Central

Introduction Autosomal dominant polycystic kidney disease is an inherited disorder that is characterized by the development and growth of cysts in the kidneys and other organs. Urinary protein excretion is usually less than 1 g/24 hours in autosomal dominant polycystic kidney disease, and an association of nephrotic syndrome with this condition is considered rare. There are only anecdotal case reports of autosomal dominant polycystic kidney disease associated with nephrotic syndrome, with focal segmental glomerulosclerosis being the most commonly reported histopathological diagnosis. Nephrotic-range proteinuria in the presence of autosomal dominant polycystic kidney disease, with or without an accompanying decline in renal function, should be investigated by open renal biopsy to exclude coexisting glomerular disease. To the best of our knowledge, this is the first case of autosomal dominant polycystic kidney disease with histologically proven diffuse proliferative glomerulonephritis presenting with nephrotic-range proteinuria. No other reports of this could be found in a global electronic search of the literature. Case presentation We report the case of a 35-year-old Indo-Aryan man with autosomal dominant polycystic kidney disease associated with nephrotic syndrome and a concomitant decline in his glomerular filtration rate. Open renal biopsy revealed diffuse proliferative glomerulonephritis. An accurate diagnosis enabled us to manage him conservatively with a successful outcome, without the use of corticosteroid which is the standard treatment and the drug most commonly used to treat nephrotic syndrome empirically. Conclusion Despite the reluctance of physicians to carry out a renal biopsy on patients with autosomal dominant polycystic kidney disease, our case supports the idea that renal biopsy is needed in patients with polycystic kidney disease with nephrotic-range proteinuria to make an accurate diagnosis. It also illustrates the importance of open renal biopsy in planning appropriate treatment for patients with autosomal dominant polycystic kidney disease with nephrotic-range proteinuria. The treatment for various histological subtypes leading to nephrotic syndrome is different, and in this modern era we should practice evidence-based medicine and should avoid empirical therapy with its associated adverse effects. PMID:20429898

2010-01-01

104

Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: a clinical masquerader.  

PubMed

Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature. PMID:24813031

Jain, Rajendra S; Prakash, Swayam; Raghavendra, B S; Nagpal, Kadam; Handa, Rahul

2014-06-01

105

Transcatheter arterial embolization therapy for a massive polycystic liver in autosomal dominant polycystic kidney disease patients.  

PubMed

Polycystic liver is the most common extra-renal manifestation associated with autosomal dominant polycystic kidney disease (ADPKD), comprising up to 80% of all features. Patients with polycystic liver often suffer from abdominal discomfort, dyspepsia, or dyspnea; however, there have been few ways to relieve their symptoms effectively and safely. Therefore, we tried transcatheter arterial embolization (TAE), which has been used in treating hepatocellular carcinoma. We enrolled four patients with ADPKD in Seoul National University Hospital, suffering from enlarged polycystic liver. We embolized the hepatic arteries supplying the dominant hepatic segments replaced by cysts using polyvinyl alcohol particles and micro-coils. The patients were evaluated 12 months after embolization for the change in both liver and cyst volumes. Among four patients, one patient was lost in follow up and 3 patients were included in the analysis. Both liver (33%; 10%) and cyst volume (47.7%; 11.4%) substantially decreased in two patients. Common adverse events were fever, epigastric pain, nausea, and vomiting. We suggest that TAE is effective and safe in treating symptomatic polycystic liver in selected ADPKD patients. PMID:19270814

Park, Hayne Cho; Kim, Chi Weon; Ro, Han; Moon, Ju-Young; Oh, Kook-Hwan; Kim, Yonsu; Lee, Jung Sang; Yin, Yong Hu; Jae, Hwan Jun; Chung, Jin Wook; Ahn, Curie; Hwang, Young-Hwan

2009-02-01

106

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

107

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

Microsoft Academic Search

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

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

2009-01-01

108

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

ERIC Educational Resources Information Center

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

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

2008-01-01

109

Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.  

PubMed

We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss. PMID:10369879

Coucke, P J; Van Hauwe, P; Kelley, P M; Kunst, H; Schatteman, I; Van Velzen, D; Meyers, J; Ensink, R J; Verstreken, M; Declau, F; Marres, H; Kastury, K; Bhasin, S; McGuirt, W T; Smith, R J; Cremers, C W; Van de Heyning, P; Willems, P J; Smith, S D; Van Camp, G

1999-07-01

110

Evidence of angiogenesis and microvascular regression in autosomal-dominant polycystic kidney disease kidneys: A corrosion cast study  

Microsoft Academic Search

Autosomal-dominant polycystic kidney disease (ADPKD) accounts for about 10% of all cases of chronic renal failure requiring dialysis. The disease is characterized by proliferation of renal epithelial cells and formation of cysts that expand over years and replace the normal parenchyma of the kidney. As the cysts grow, the volume of the kidney can increase by more than 10-fold, implying

W Wei; V Popov; J A Walocha; J Wen; E Bello-Reuss

2006-01-01

111

Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same  

Microsoft Academic Search

Summary Autosomal dominant juvenile amyotrophic lateral scler- osis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagno- sis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal

P. De Jonghe; M. Auer-Grumbach; J. Irobi; K. Wagner; B. Plecko; M. Kennerson; D. Zhu; E. De Vriendt; V. Van Gerwen; G. Nicholson; H.-P. Hartung; V. Timmerman

112

Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.  

PubMed

Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by hypoplasia or absence of the terminal portions of the index to little fingers, usually with absence of the nails. The thumbs may be of normal length but are often flattened and occasionally are bifid. The feet are similarly but less severely affected. We have performed a genomewide linkage analysis of three families with BDB, two English and one Portugese. The two English families show linkage to the same region on chromosome 9 (combined multipoint maximum LOD score 8.69 with marker D9S257). The 16-cM disease interval is defined by recombinations with markers D9S1680 and D9S1786. These two families share an identical disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provides strong evidence that the English families have the same ancestral mutation, which reduces the disease interval to <12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, we excluded linkage to this region, a result indicating that BDB is genetically heterogeneous. Reflecting this, there were atypical clinical features in this family, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enable a refined classification of BDB and identify a novel locus for digit morphogenesis in 9q22. PMID:9973296

Oldridge, M; Temple, I K; Santos, H G; Gibbons, R J; Mustafa, Z; Chapman, K E; Loughlin, J; Wilkie, A O

1999-02-01

113

A Novel GJA8 Mutation (p.V44A) Causing Autosomal Dominant Congenital Cataract  

PubMed Central

Purpose To examine the mechanism by which a novel connexin 50 (Cx50) mutation, Cx50 V44A, in a Chinese family causes suture-sparing autosomal dominant congenital nuclear cataracts. Methods Family history and clinical data were recorded and direct gene sequencing was used to identify the disease-causing mutation. The Cx50 gene was cloned from a human lens cDNA library. Connexin protein distributions were assessed by fluorescence microscopy. Hemichannel functions were analyzed by dye uptake assay. Formation of functional channels was assessed by dye transfer experiments. Results Direct sequencing of the candidate GJA8 gene revealed a novel c.131T>C transition in exon 2, which cosegregated with the disease in the family and resulted in the substitution of a valine residue with alanine at codon 44 (p. V44A) in the extracellular loop 1 of the Cx50 protein. Both Cx50 and Cx50V44A formed functional gap junctions, as shown by the neurobiotin transfer assay. However, unlike wild-type Cx50, Cx50V44A was unable to form open hemichannels in dye uptake experiments. Conclusion This work identified a unique congenital cataract in the Chinese population, caused by the novel mutation Cx50V44A, and it showed that the V44A mutation specifically impairs the gating of the hemichannels but not the gap junction channels. The dysfunctional hemichannels resulted in the development of human congenital cataracts. PMID:25517998

Zhu, Yanan; Yu, Hao; Wang, Wei; Gong, Xiaohua; Yao, Ke

2014-01-01

114

Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy.  

PubMed

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene. PMID:22328086

Winkelmann, Juliane; Lin, Ling; Schormair, Barbara; Kornum, Birgitte R; Faraco, Juliette; Plazzi, Giuseppe; Melberg, Atle; Cornelio, Ferdinando; Urban, Alexander E; Pizza, Fabio; Poli, Francesca; Grubert, Fabian; Wieland, Thomas; Graf, Elisabeth; Hallmayer, Joachim; Strom, Tim M; Mignot, Emmanuel

2012-05-15

115

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

2013-01-01

116

Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy  

PubMed Central

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30–40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy–cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene. PMID:22328086

Winkelmann, Juliane; Lin, Ling; Schormair, Barbara; Kornum, Birgitte R.; Faraco, Juliette; Plazzi, Giuseppe; Melberg, Atle; Cornelio, Ferdinando; Urban, Alexander E.; Pizza, Fabio; Poli, Francesca; Grubert, Fabian; Wieland, Thomas; Graf, Elisabeth; Hallmayer, Joachim; Strom, Tim M.; Mignot, Emmanuel

2012-01-01

117

Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease.  

PubMed

The goal of this study was to determine whether use of postmenopausal estrogen (Premarin, Wyeth-Ayerst, Philadelphia, PA) in women with autosomal dominant polycystic kidney disease (ADPKD) increases liver, hepatic cyst, or kidney volume. We also determined whether clinical symptoms correlated with the volume of either the liver or kidneys. Eight women off estrogen (control, C) and 11 others on estrogen (Premarin, E) were studied basally and after 1 year. The two groups were similar in age, weight, age at menarche, and gravida. Volumes of total liver, hepatic cysts, hepatic parenchyma, and total kidney were measured by a validated computed tomography (CT) technique. Estrogen treatment was associated with a selective increase in total liver volume (E vs. C: delta = 7% +/- 12% vs. -2% +/- 8%, P < .03) and no change in kidney volume (E vs. C: delta = 0% +/- 6% vs. -2% +/- 6%, P = NS). Symptoms were common, regardless of estrogen treatment (abdominal pain 60%, shortness of breath 40%, or both 35%). Patients with symptoms of abdominal pain and shortness of breath had significantly increased hepatic volumes (P < .03) but similar kidney volume compared with patients without symptoms. We conclude that estrogen treatment of postmenopausal ADPKD women is associated with selective liver enlargement and that abdominal symptoms in ADPKD patients may be because of extensive hepatic cystic disease. PMID:9362373

Sherstha, R; McKinley, C; Russ, P; Scherzinger, A; Bronner, T; Showalter, R; Everson, G T

1997-11-01

118

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

PubMed Central

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

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

2003-01-01

119

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

120

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

121

More adverse renal prognosis of autosomal dominant polycystic kidney disease in families with primary hypertension.  

PubMed

Marked variability of age at renal death is noted in autosomal dominant polycystic kidney disease (ADPKD). The hypothesis that the coexistence of primary hypertension and ADPKD within families is associated with earlier renal death was tested. Of a total of 162 ADPKD patients treated in one Austrian and three German centers, 57 propositi were identified whose families provided (1) information concerning blood pressure; (2) documented presence of ADPKD (by sonography or autopsy) in one parent; and (3) age at renal death in the propositus. Hypertension of the unaffected parent was defined as blood pressure above 140/90 mm Hg or antihypertensive treatment before age 60 yr. Age at renal death in the propositus was defined as the start of renal replacement therapy. Median age at renal death of 23 offspring (11 male, 12 female) from families with a history of primary hypertension of the nonaffected parent was lower than that of 34 offspring (16 male, 18 female) from families without a known history of primary hypertension of the nonaffected parent, i.e., 49 yr (26 to 64) versus 54 yr (28 to 82) (P < 0.03). The data are consistent with the notion that genetic predisposition to primary hypertension is associated with an earlier onset of terminal renal failure in families with ADPKD. PMID:8749692

Geberth, S; Stier, E; Zeier, M; Mayer, G; Rambausek, M; Ritz, E

1995-12-01

122

Nonsyndromic autosomal dominant progressive sensorineural hearing loss: audiologic analysis of a pedigree linked to DFNA2.  

PubMed

An analysis was performed of the regression of the individual hearing threshold on age in the affected persons in a six-generation Dutch family with nonsyndromic autosomal dominant sensorineural hearing loss, which showed linkage to the DFNA2(1p34) region, similar to at least four previously reported nonrelated families. The offset threshold was significantly higher at the high frequencies (around 30 dB at 2 to 8 kHz) than at the lower ones (approximately 0 dB at 0.25 to 1 kHz). Hearing impairment at the higher frequencies may therefore have been present already at birth or in early childhood. The regression coefficient, or the 'annual threshold increase,' expressed in dB/y, was about 1 dB/y on average, but the higher frequencies (1 to 8 kHz) showed significantly more rapid progression than the lower frequencies (0.25 to 0.5 kHz). PMID:9432071

Kunst, H; Marres, H; Huygen, P; Ensink, R; Van Camp, G; Van Hauwe, P; Coucke, P; Willems, P; Cremers, C

1998-01-01

123

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

124

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

PubMed

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

2013-07-01

125

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

126

Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.  

PubMed

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome. PMID:25329329

Schubert, Desirée; Bode, Claudia; Kenefeck, Rupert; Hou, Tie Zheng; Wing, James B; Kennedy, Alan; Bulashevska, Alla; Petersen, Britt-Sabina; Schäffer, Alejandro A; Grüning, Björn A; Unger, Susanne; Frede, Natalie; Baumann, Ulrich; Witte, Torsten; Schmidt, Reinhold E; Dueckers, Gregor; Niehues, Tim; Seneviratne, Suranjith; Kanariou, Maria; Speckmann, Carsten; Ehl, Stephan; Rensing-Ehl, Anne; Warnatz, Klaus; Rakhmanov, Mirzokhid; Thimme, Robert; Hasselblatt, Peter; Emmerich, Florian; Cathomen, Toni; Backofen, Rolf; Fisch, Paul; Seidl, Maximilian; May, Annette; Schmitt-Graeff, Annette; Ikemizu, Shinji; Salzer, Ulrich; Franke, Andre; Sakaguchi, Shimon; Walker, Lucy S K; Sansom, David M; Grimbacher, Bodo

2014-12-01

127

Determinants of renal volume in autosomal-dominant polycystic kidney disease  

PubMed Central

The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) recently showed that renal enlargement in autosomal-dominant polycystic kidney disease mimicked exponential growth. We determined the effects of cyst initiation rate, total number, and growth rate on the time-dependent change of total cyst volume (TCV). Mathematical models with equations integrating cyst surface area, volume, and an invariant growth rate constant were used to compute the time-dependent change in volume of solitary and multiple cysts. Multiple expanding cysts increased TCV in an exponential-like pattern even when individual cysts formed at different rates or exhibited different but constant growth rates. TCV depended on the rate of cyst initiation and on the total number of cysts; however, the compounding effect of exponential-like growth was the most powerful determinant of long-term cyst expansion. Extrapolation of TCV data plots for individual subjects back to an age of 18 predicted TCV values within an established range. We conclude that cysts started early in life were the main contributor to eventual TCV while their growth rate primarily determined renal size; although the rate of formation and the ultimate number of cysts also contributed. The good fit between the exponential models and the extrapolated CRISP data indicates that the TCV growth rate is a defining trait for individual patients and may be used as a prognostic marker. PMID:17960141

Grantham, JJ; Cook, LT; Torres, VE; Bost, JE; Chapman, AB; Harris, PC; Guay-Woodford, LM; Bae, KT

2009-01-01

128

Periostin induces proliferation of human autosomal dominant polycystic kidney cells through alphaV-integrin receptor.  

PubMed

Progressive renal enlargement due to the growth of innumerable fluid-filled cysts is a central pathophysiological feature of autosomal dominant polycystic kidney disease (ADPKD). These epithelial neoplasms enlarge slowly and damage noncystic parenchyma by mechanisms that have not been clearly defined. In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was overexpressed 15-fold compared with normal human kidney (NHK) cells. Periostin, initially identified in osteoblasts, is not expressed in normal adult kidneys but is expressed transiently during renal development. We found periostin in cyst-lining cells in situ in the extracellular matrix adjacent to the cysts and within cyst fluid. ADPKD cells secreted periostin across luminal and basolateral plasma membranes. Periostin increased proliferation of cyst epithelial cells 27.9 +/- 3.1% (P < 0.001) above baseline and augmented in vitro cyst growth but did not affect proliferation of normal renal cells. Expression of alphaV-integrin, a periostin receptor, was ninefold higher in ADPKD cells compared with NHK cells, and antibodies that block alphaV-integrin inhibited periostin-induced cell proliferation. We conclude that periostin is a novel autocrine mitogen secreted by mural epithelial cells with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD. PMID:18753297

Wallace, Darren P; Quante, Megan T; Reif, Gail A; Nivens, Emily; Ahmed, Farhana; Hempson, Scott J; Blanco, Gustavo; Yamaguchi, Tamio

2008-11-01

129

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

130

Two Novel CRX Mutant Proteins Causing Autosomal Dominant Leber Congenital Amaurosis Interact Differently With NRL  

PubMed Central

Leber congenital amaurosis (LCA) is a congenital retinal dystrophy characterized by severe visual loss in infancy and nystagmus. Although most often inherited in an autosomal recessive fashion, rare individuals with mutations in the cone-rod homeobox gene, CRX, have dominant disease. CRX is critical for photoreceptor development and acts synergistically with the leucine-zipper transcription factor, NRL. We report on the phenotype of two individuals with LCA due to novel, de novo CRX mutations, c.G264T(p.K74N) and c.413delT(p.I138fs48), that reduce transactivation in vitro to 10% and 30% of control values, respectively. Whereas the c.413delT(p.I138fs48) mutant allows co-expressed NRL to transactivate independently at its normal, baseline level, the c.G264T(p.K74N) mutant reduces co-expressed NRL transactivation and reduces steady state levels of both proteins. Although both mutant proteins predominantly localize normally to the nucleus, they also both show variable cytoplasmic localization. These observations suggest that some CRX-mediated LCA may result from effects beyond haploinsufficiency, such as the mutant protein interefering with other transcription factors’ function. Such patients would therefore not likely benefit from a simple, gene-replacement strategy for their disease. PMID:20513135

Nichols, Lorenzo L.; Alur, Ramakrishna P.; Boobalan, Elangovan; Sergeev, Yuri V.; Caruso, Rafael C.; Stone, Edwin M.; Swaroop, Anand; Johnson, Mary A.; Brooks, Brian P.

2010-01-01

131

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

132

Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.  

PubMed

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-hNIPA1) 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 NIPA1 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-hNIPA1 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; Kisanuki, Yaz Y

2013-11-01

133

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

PubMed Central

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

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

2014-01-01

134

Cortical and Hippocampal Atrophy in Patients with Autosomal Dominant Familial Alzheimer's Disease  

PubMed Central

Background Both familial and sporadic Alzheimer's disease (AD) result in progressive cortical and subcortical atrophy. Familial autosomal dominant AD (FAD) allows us to study AD brain changes presymptomatically. Methods 33 subjects at risk for FAD (25 for PSEN1 and 8 for APP mutations; 22 mutation carriers and 11 controls) and 3 demented PSEN1 mutation carriers underwent T1-weighted MPRAGE 1.5T MRI. Using the hippocampal radial distance and cortical pattern matching techniques, we investigated the effects of carrier status and dementia diagnosis on cortical and hippocampal atrophy. All analyses were corrected for age and relative age (years to median age of disease onset in the family). Results The dementia cases had pronounced cortical atrophy in the lateral and medial parietal, posterior cingulate and frontal cortices and hippocampal atrophy bilaterally relative to both nondemented carriers and controls. Nondemented carriers did not show significant cortical thinning or hippocampal atrophy relative to controls. Conclusions FAD is associated with thinning of the posterior association and frontal cortices and hippocampal atrophy. Larger sample sizes may be necessary to reliably identify cortical atrophy in presymptomatic carriers. PMID:21952501

Apostolova, Liana G.; Hwang, Kristy S.; Medina, Luis D.; Green, Amity E.; Braskie, Meredith N.; Dutton, Rebecca A.; Lai, Jeffrey; Geschwind, Daniel H.; Cummings, Jeffrey L.; Thompson, Paul M.; Ringman, John M.

2011-01-01

135

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

136

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

137

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

PubMed Central

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

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

2012-01-01

138

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

SciTech Connect

Manic-depressive illness (MDI), also known as [open quotes]bipolar affective disorder[close quotes], is a common and devastating neuropsychiatric illness. Although pivotal biochemical alterations underlying the disease are unknown, results of family, twin, and adoption studies consistently implicate genetic transmission in the pathogenesis of MDI. In order to carry out linkage analysis, the authors ascertained eight moderately sized pedigrees containing multiple cases of the disease. For a four-allele marker mapping at 5 cM from the disease gene, the pedigree sample has >97% power to detect a dominant allele under genetic homogeneity and has >73% power under 20% heterogeneity. To date, the eight pedigrees have been genotyped with 328 polymorphic DNA loci throughout the genome. When autosomal dominant inheritance was assumed, 273 DNA markers gave lod scores <[minus]2.0 at [theta] = .05, and 4 DNA marker loci yielded lod scores >1 (chromosome 5 -- D5S39, D5S43, and D5S62; chromosome 11 -- D11S85). Of the markers giving lod scores >1, only D5S62 continued to show evidence for linkage when the affected-pedigree-member method was used. The D5S62 locus maps to distal 5q, a region containing neurotransmitter-receptor genes for dopamine, norepinephrine, glutamate, and gamma-aminobutyric acid. Although additional work in this region may be warranted, the linkage results should be interpreted as preliminary data, as 68 unaffected individuals are not past the age of risk. 72 refs., 2 tabs.

Coon, H.; Jensen, S.; Hoff, M.; Holik, J.; Plaetke, R.; Reimherr, F.; Wender, P.; Leppert, M.; Byerley, W. (Univ. of Utah, Salt Lake City (United States))

1993-06-01

139

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

140

A Novel Missense Mutation of Wilms' Tumor 1 Causes Autosomal Dominant FSGS.  

PubMed

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

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

2014-08-21

141

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

PubMed Central

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

2013-01-01

142

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

PubMed Central

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 ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course. PMID:16430766

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

2006-01-01

143

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

PubMed Central

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

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

2014-01-01

144

Novel mutations of PKD genes in the Czech population with autosomal dominant polycystic kidney disease  

PubMed Central

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder caused by mutation in either one of two genes, PKD1 and PKD2. High structural and sequence complexity of PKD genes makes the mutational diagnostics of ADPKD challenging. The present study is the first detailed analysis of both PKD genes in a cohort of Czech patients with ADPKD using High Resolution Melting analysis (HRM) and Multiplex Ligation-dependent Probe Amplification (MLPA). Methods The mutational analysis of PKD genes was performed in a set of 56 unrelated patients. For mutational screening of the PKD1 gene, the long-range PCR (LR-PCR) strategy followed by nested PCR was used. Resulting PCR fragments were analyzed by HRM; the positive cases were reanalyzed and confirmed by direct sequencing. Negative samples were further examined for sequence changes in the PKD2 gene by the method of HRM and for large rearrangements of both PKD1 and PKD2 genes by MLPA. Results Screening of the PKD1 gene revealed 36 different likely pathogenic germline sequence changes in 37 unrelated families/individuals. Twenty-five of these sequence changes were described for the first time. Moreover, a novel large deletion was found within the PKD1 gene in one patient. Via the mutational analysis of the PKD2 gene, two additional likely pathogenic mutations were detected. Conclusions Probable pathogenic mutation was detected in 71% of screened patients. Determination of PKD mutations and their type and localization within corresponding genes could help to assess clinical prognosis of ADPKD patients and has major benefit for prenatal and/or presymptomatic or preimplantational diagnostics in affected families as well. PMID:24694054

2014-01-01

145

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

146

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; Böhm, Johann; Wu, Bin; Xu, Fengping; Boucebci, Samy; Mathis, Stéphane; Neau, Jean-Philippe; Monnier, Nicole; Fardeau, Michel; Laporte, Jocelyn

2014-01-01

147

Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1  

PubMed Central

Distal arthrogryposis type I (DA1) is a disorder characterized by congenital contractures of the hands and feet for which few genes have been identified. Here we describe a five-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genome-wide linkage analysis using Affymetrix GeneChip Mapping 10K data from 12 affected members of this family revealed a multipoint LODmax of 3.27 on chromosome 12q. Sequencing of the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1), located within the linkage interval, revealed a missense mutation (c.706T>C) that segregated with disease in this family and causes a W236R amino acid substitution. A second MYBPC1 missense mutation was identified (c.2566T>C)(Y856H) in another family with DA1, accounting for an MYBPC1 mutation frequency of 13% (two of 15). Skeletal muscle biopsies from affected patients showed type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing WT and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when non-fused GFP and MYBPC1 proteins containing corresponding MYBPC3 amino acid substitutions (R326Q, E334K) that cause hypertrophic cardiomyopathy were expressed. These findings reveal that the MYBPC1 is a novel gene responsible for DA1, though the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy. PMID:20045868

Gurnett, Christina A.; Desruisseau, David M.; McCall, Kevin; Choi, Ryan; Meyer, Zachary I.; Talerico, Michael; Miller, Sara E.; Ju, Jeong-Sun; Pestronk, Alan; Connolly, Anne M.; Druley, Todd E.; Weihl, Conrad C.; Dobbs, Mathew B.

2010-01-01

148

Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1.  

PubMed

Distal arthrogryposis type I (DA1) is a disorder characterized by congenital contractures of the hands and feet for which few genes have been identified. Here we describe a five-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genome-wide linkage analysis using Affymetrix GeneChip Mapping 10K data from 12 affected members of this family revealed a multipoint LOD(max) of 3.27 on chromosome 12q. Sequencing of the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1), located within the linkage interval, revealed a missense mutation (c.706T>C) that segregated with disease in this family and causes a W236R amino acid substitution. A second MYBPC1 missense mutation was identified (c.2566T>C)(Y856H) in another family with DA1, accounting for an MYBPC1 mutation frequency of 13% (two of 15). Skeletal muscle biopsies from affected patients showed type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing WT and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when non-fused GFP and MYBPC1 proteins containing corresponding MYBPC3 amino acid substitutions (R326Q, E334K) that cause hypertrophic cardiomyopathy were expressed. These findings reveal that the MYBPC1 is a novel gene responsible for DA1, though the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy. PMID:20045868

Gurnett, Christina A; Desruisseau, David M; McCall, Kevin; Choi, Ryan; Meyer, Zachary I; Talerico, Michael; Miller, Sara E; Ju, Jeong-Sun; Pestronk, Alan; Connolly, Anne M; Druley, Todd E; Weihl, Conrad C; Dobbs, Mathew B

2010-04-01

149

Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa  

PubMed Central

Purpose Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. Methods We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. Results We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5? untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. Conclusions The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin. PMID:24959063

Benaglio, Paola; San Jose, Patricia Fernandez; Avila-Fernandez, Almudena; Ascari, Giulia; Harper, Shyana; Manes, Gaël; Ayuso, Carmen; Hamel, Christian; Berson, Eliot L.

2014-01-01

150

Exclusion of the candidate locus FSP1 in six families with late-onset autosomal dominant spastic paraplegia.  

PubMed

Hereditary spastic paraplegias are neurological hereditary conditions of unknown aetiology. In pure spastic paraplegia, most of the pedigrees display an autosomal dominant mode of inheritance. A gene for pure autosomal dominant spastic paraplegia (ADSP), termed FSP1, was mapped to chromosome 14q in a large pedigree with early-onset disease. This locus was tested by linkage analysis in six large French kindreds of ADSP with late-onset disease, using four microsatellites spanning a 9 cM interval including FSP1. FSP1 could be excluded in five of the six families, while no evidence for linkage was found in the remaining family. These results suggest that FSP1 is not involved in late onset ADSP, at least in the six families studied. PMID:7719135

Fontaine, B; Rime, C S; Hazan, J; Dürr, A; Stevanin, G; Penet, C; Reboul, J; Agid, Y; Lyon-Caen, O; Baumann, N

1995-01-01

151

Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese  

Microsoft Academic Search

Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically\\u000a as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied,\\u000a most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for\\u000a the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for

Jiro Akita; Satoko Abe; Hideichi Shinkawa; William J. Kimberling; Shin-ichi Usami

2001-01-01

152

De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype.  

PubMed

Robinow Syndrome (RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome (ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway. PMID:24716670

Roifman, M; Marcelis, C L M; Paton, T; Marshall, C; Silver, R; Lohr, J L; Yntema, H G; Venselaar, H; Kayserili, H; van Bon, B; Seaward, G; Brunner, H G; Chitayat, D

2015-01-01

153

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

Microsoft Academic Search

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

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

2007-01-01

154

A novel locus for autosomal dominant nonsyndromic hearing loss identified at 5q31.1-32 in a Chinese pedigree  

Microsoft Academic Search

.  ?Hearing impairment is an extremely heterogeneous disorder. A total of 35 loci and 17 related genes for autosomal dominant\\u000a nonsyndromic hearing loss have been identified. In a Chinese pedigree characterized by autosomal dominant inheritance with\\u000a bilateral, postlingual, progressive, and sensorineural nonsyndromic hearing impairment, the putative disease gene locus was\\u000a localized to chromosome 5q31.1-32 by a genome-wide scan. Fine mapping indicated

Jiahui Xia; Hao Deng; Yong Feng; Huali Zhang; Qian Pan; Heping Dai; Zhigao Long; Beisha Tang; Hanxiang Deng; Yong Chen; Ruifang Zhang; Duo Zheng; Yungui He; Kun Xia

2002-01-01

155

Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.  

PubMed

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 pattern of inheritance, with high penetrance, have been described; the estimated prevalence of the disease is 1 in 70,000-100,000. Previous failure to link the disease to any of several candidate genes prompted us to conduct a genome-wide screen on a collection of 38 families with two or more affected siblings, using allele sharing algorithms. Excess allele sharing was found on the short arm of chromosome 16 and confirmed by conventional linkage analysis, localizing the disease gene under a recessive model with a maximum two point lod score of 21.27 on chromosome 16p13.1, an area so far devoid of any obvious candidate genes. Under a dominant transmission pattern linkage with a maximum two point lod score of 14.53 was observed to the same region. Linkage heterogeneity analysis predicted the presence of allelic heterogeneity with different variants of a single gene that resides in this chromosomal region accounting for recessive and dominant forms of PXE. PMID:9302259

Struk, B; Neldner, K H; Rao, V S; St Jean, P; Lindpaintner, K

1997-10-01

156

Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?  

PubMed

Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder. PMID:12023320

De Jonghe, P; Auer-Grumbach, M; Irobi, J; Wagner, K; Plecko, B; Kennerson, M; Zhu, D; De Vriendt, E; Van Gerwen, V; Nicholson, G; Hartung, H-P; Timmerman, V

2002-06-01

157

[Autosomal dominant nocturnal frontal lobe epilepsy. An electroclinical and genetic description of a Norwegian family with ten affected members].  

PubMed

We describe a Norwegian family with clusters of brief nocturnal motor seizures with hyperkinetic or tonic manifestations. Seizures started in childhood. Neurological examination and neuroimaging were normal. Interictal EEG registrations were mostly normal, ictal EEG registrations disclosed left frontal epileptiform discharges in two of three patients examined and just shallow arousal preceding the attack in one of the three patients. Segregation analysis indicated an autosomal dominant inheritance pattern, and the patients were subsequently diagnosed as having autosomal dominant nocturnal frontal lobe epilepsy, a disorder first described in 1995. A missense mutation in the gene for the alpha-4 subunit of the neuronal nicotinergic acetylcholine receptor was recently described in an Australian family with this disorder. Our Norwegian family proved to have a novel insertion mutation (776ins3) in the same gene. This mutation affects the second transmembrane domain (M2) which forms the critical section of the ion channel. This is the first case of idiopathic partial epilepsy where the underlying molecular defect has been found. The fact that a dysfunction of the nicotinergic acetylcholine receptor may give rise to frontal epileptic seizures was surprising and may shed new light on the basic mechanisms of epileptogenesis. Manipulations of the cholinergic system may open up a new therapeutic approach. PMID:9528368

Nakken, K O; Magnusson, A; Steinlein, O K

1998-02-20

158

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

PubMed

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

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

2013-02-01

159

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, Andrés; 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

160

Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy  

PubMed Central

Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA. PMID:23664116

Neveling, Kornelia; Martinez-Carrera, Lilian A.; Hölker, Irmgard; Heister, Angelien; Verrips, Aad; Hosseini-Barkooie, Seyyed Mohsen; Gilissen, Christian; Vermeer, Sascha; Pennings, Maartje; Meijer, Rowdy; te Riele, Margot; Frijns, Catharina J.M.; Suchowersky, Oksana; MacLaren, Linda; Rudnik-Schöneborn, Sabine; Sinke, Richard J.; Zerres, Klaus; Lowry, R. Brian; Lemmink, Henny H.; Garbes, Lutz; Veltman, Joris A.; Schelhaas, Helenius J.; Scheffer, Hans; Wirth, Brunhilde

2013-01-01

161

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

PubMed

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

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

2014-01-01

162

A Novel Mutation in the TECTA Gene in a Chinese Family with Autosomal Dominant Nonsyndromic Hearing Loss  

PubMed Central

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

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

2014-01-01

163

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

164

Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia.  

PubMed

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a genetically heterogeneous neurodegenerative disorder characterized by progressive spasticity of the lower limbs. Among the four loci causing AD-HSP identified so far, the SPG4 locus at chromosome 2p2-1p22 has been shown to account for 40-50% of all AD-HSP families. Using a positional cloning strategy based on obtaining sequence of the entire SPG4 interval, we identified a candidate gene encoding a new member of the AAA protein family, which we named spastin. Sequence analysis of this gene in seven SPG4-linked pedigrees revealed several DNA modifications, including missense, nonsense and splice-site mutations. Both SPG4 and its mouse orthologue were shown to be expressed early and ubiquitously in fetal and adult tissues. The sequence homologies and putative subcellular localization of spastin suggest that this ATPase is involved in the assembly or function of nuclear protein complexes. PMID:10610178

Hazan, J; Fonknechten, N; Mavel, D; Paternotte, C; Samson, D; Artiguenave, F; Davoine, C S; Cruaud, C; Dürr, A; Wincker, P; Brottier, P; Cattolico, L; Barbe, V; Burgunder, J M; Prud'homme, J F; Brice, A; Fontaine, B; Heilig, B; Weissenbach, J

1999-11-01

165

Cerebro-costo-mandibular syndrome in a father and a female fetus: early prenatal ultrasonographic diagnosis and autosomal dominant transmission.  

PubMed

Ultrasonography in a female fetus revealed cystic cervical hygroma, severe micrognathia, and vertebral and upper limb anomalies suggestive of cerebro-costo-mandibular syndrome (CCMS) which was diagnosed ultrasonographically at 16 weeks' gestation. The father is affected and presents with a Pierre Robin sequence, short stature and typical costovertebral anomalies. CCMS is a rare and severe disorder. The high frequency of sporadic cases, vertical transmission, and the excess of sibs affected via horizontal transmission suggest dominant autosomal mutation with possible germinal mosaicism. The vertical familial case detailed in the present report is a reminder of the high risk when one parent or one sibling is affected and the extreme variability of phenotype and costal ossification. Early prenatal ultrasound diagnosis is possible in a severely affected fetus. PMID:11746136

Morin, G; Gekas, J; Naepels, P; Gondry, J; Devauchelle, B; Testelin, S; Sevestre, H; Thépôt, F; Mathieu, M

2001-10-01

166

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.; Lundström, Anita; Kelsell, David P.

2013-01-01

167

Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma.  

PubMed

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; Lundström, Anita; Kelsell, David P

2013-08-01

168

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

PubMed

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

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

2013-01-01

169

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

PubMed

The authors report the use of adaptive-optics scanning laser ophthalmoscopy (AO-SLO) to investigate RHO, D190N autosomal-dominant retinitis pigmentosa in two siblings (11 and 16 years old, respectively). Each patient exhibited distinct hyperautofluorescence patterns in which the outer borders corresponded to inner segment ellipsoid band disruption. Areas within the hyperautofluorescence patterns exhibited normal photoreceptor outer segments and retinal pigment epithelium. However, AO-SLO imaging revealed noticeable spacing irregularities in the cone mosaic. AO-SLO allows researchers to characterize retinal structural abnormalities with precision so that early structural changes in retinitis pigmentosa can be identified and reconciled with genetic findings. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:xxx-xxx.]. PMID:25215869

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

2014-09-18

170

Dystrophic Epidermolysis Bullosa in Pregnancy: A Case Report of the Autosomal Dominant Subtype and Review of the Literature  

PubMed Central

Epidermolysis bullosa (EB) is a group of inherited blistering skin diseases that vary widely in their pathogenesis and severity. There are three main categories of EB: simplex, junctional, and dystrophic. This classification is based on the level of tissue separation within the basement membrane zone and this is attributed to abnormalities of individual or several anchoring proteins that form the interlocking network spanning from the epidermis to the dermis underneath. Dystrophic EB results from mutations in COL7A1 gene coding for type VII collagen leading to blister formation within the dermis. Diagnosis ultimately depends on the patient's specific genetic mutation, but initial diagnosis can be made from careful examination and history taking. We present a pregnant patient known to have autosomal dominant dystrophic EB and discuss the obstetrical and neonatal outcome. The paper also reviews the current English literature on this rare skin disorder. PMID:24864146

Herrell, Howard

2014-01-01

171

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

172

A New Locus on Chromosome 12p13.3 for Pseudohypoaldosteronism Type II, an Autosomal Dominant Form of Hypertension  

PubMed Central

Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2–6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63–129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [?] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, ?=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date. PMID:10869238

Disse-Nicodème, Sandra; Achard, Jean-Michel; Desitter, Isabelle; Houot, Anne-Marie; Fournier, Albert; Corvol, Pierre; Jeunemaitre, Xavier

2000-01-01

173

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

174

Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.  

PubMed

Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5 % of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria. PMID:25193783

Ajroud-Driss, Senda; Fecto, Faisal; Ajroud, Kaouther; Lalani, Irfan; Calvo, Sarah E; Mootha, Vamsi K; Deng, Han-Xiang; Siddique, Nailah; Tahmoush, Albert J; Heiman-Patterson, Terry D; Siddique, Teepu

2015-01-01

175

Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy.  

PubMed

Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies. PMID:25192047

Herrmann, David N; Horvath, Rita; Sowden, Janet E; Gonzalez, Michael; Gonzales, Michael; Sanchez-Mejias, Avencia; Guan, Zhuo; Whittaker, Roger G; Almodovar, Jorge L; Lane, Maria; Bansagi, Boglarka; Pyle, Angela; Boczonadi, Veronika; Lochmüller, Hanns; Griffin, Helen; Chinnery, Patrick F; Lloyd, Thomas E; Littleton, J Troy; Zuchner, Stephan

2014-09-01

176

In cis autosomal dominant mutation of Senataxin associated with tremor/ataxia syndrome.  

PubMed

Senataxin mutations are the molecular basis of two distinct syndromes: (1) ataxia oculomotor apraxia type 2 (AOA2) and (2) juvenile amyotrophic lateral sclerosis 4 (ALS4). The authors describe clinical and molecular genetic studies of mother and daughter who display symptoms of cerebellar ataxia/atrophy, oculomotor defects, and tremor. Both patients share Senataxin mutations N603D and Q653K in cis (N603D-Q653K), adjacent to an N-terminal domain thought to function in protein-protein interaction. The N-terminal and helicase domains appear to harbor missense mutation clusters associated with AOA2 and ALS4. Working synergistically, the N603D-Q653K mutations may confer a partial dominant negative effect, acting on the senataxin N-terminal, further expanding the phenotypic spectrum associated with Senataxin mutations. PMID:17096168

Bassuk, A G; Chen, Y Z; Batish, S D; Nagan, N; Opal, P; Chance, P F; Bennett, C L

2007-01-01

177

Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2.  

PubMed

Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K(+) channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded non-functional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2. PMID:20966080

Kim, Hyo Jeong; Lv, Ping; Sihn, Choong-Ryoul; Yamoah, Ebenezer N

2011-01-14

178

Cellular and Molecular Mechanisms of Autosomal Dominant Form of Progressive Hearing Loss, DFNA2*  

PubMed Central

Despite advances in identifying deafness genes, determination of the underlying cellular and functional mechanisms for auditory diseases remains a challenge. Mutations of the human K+ channel hKv7.4 lead to post-lingual progressive hearing loss (DFNA2), which affects world-wide population with diverse racial backgrounds. Here, we have generated the spectrum of point mutations in the hKv7.4 that have been identified as diseased mutants. We report that expression of five point mutations in the pore region, namely L274H, W276S, L281S, G285C, and G296S, as well as the C-terminal mutant G321S in the heterologous expression system, yielded non-functional channels because of endoplasmic reticulum retention of the mutant channels. We mimicked the dominant diseased conditions by co-expressing the wild-type and mutant channels. As compared with expression of wild-type channel alone, the blend of wild-type and mutant channel subunits resulted in reduced currents. Moreover, the combinatorial ratios of wild type:mutant and the ensuing current magnitude could not be explained by the predictions of a tetrameric channel and a dominant negative effect of the mutant subunits. The results can be explained by the dependence of cell surface expression of the mutant on the wild-type subunit. Surprisingly, a transmembrane mutation F182L, which has been identified in a pre-lingual progressive hearing loss patient in Taiwan, yielded cell surface expression and functional features that were similar to that of the wild type, suggesting that this mutation may represent redundant polymorphism. Collectively, these findings provide traces of the cellular mechanisms for DFNA2. PMID:20966080

Kim, Hyo Jeong; Lv, Ping; Sihn, Choong-Ryoul; Yamoah, Ebenezer N.

2011-01-01

179

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

180

Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture  

PubMed Central

Autosomal-dominant woolly hair (ADWH) is a rare disorder characterized by tightly curled hair. The molecular basis of ADWH has not previously been reported. In this study, we identified a Pakistani family with ADWH. The family showed linkage to chromosome 12q12-q14.1, containing the type II keratin gene cluster. We discovered a heterozygous mutation, p.Asn148Lys, within the helix initiation motif of the keratin 74 (KRT74) gene in all affected family members. KRT74 encodes the inner root sheath (IRS)-specific epithelial (soft) keratin 74. We demonstrate that the mutant K74 protein results in disruption of keratin intermediate filament formation in cultured cells, most likely in a dominant-negative manner. Furthermore, we sequenced the mouse Krt71-74 genes in the dominant Caracul-like 4 (Cal4) allele, which is characterized by a wavy-coat phenotype and maps to the same region of mouse chromosome 15 as the Caracul (Ca) and Reduced coat (Rco) alleles. We identified a heterozygous mutation, p.Glu440Lys, not in Krt74 but in the neighboring gene, Krt71. Krt71 was previously reported to harbor Ca and Rco mutations, as well as a coding SNP that is associated with curly-coated dogs. In this study, we define the ADWH phenotype resulting from a mutation in a hair-follicle-specific epithelial keratin in humans. Our findings not only further underscore the crucial roles of the IRS-specific epithelial keratin genes Krt71-74 in hair disorders but also open the possibility that these genes might function as genetic determinants of normal variation in hair texture across mammalian species. PMID:20346438

Shimomura, Yutaka; Wajid, Muhammad; Petukhova, Lynn; Kurban, Mazen; Christiano, Angela M.

2010-01-01

181

Diastolic Function in Several Stages of Chronic Kidney Disease in Patients with Autosomal Dominant Polycystic Kidney Disease: A Tissue Doppler Imaging Study  

Microsoft Academic Search

Background: This study evaluates the prevalence of diastolic dysfunction (DD) in several stages of chronic kidney disease (CKD) in patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: 107 ADPKD patients performed echocardiographic and Doppler studies and a tissue Doppler imaging (TDI) study. Patients were divided in three groups: group 1, 57 patients with CKD stage I, group 2, 37

Edgar A. F. de Almeida; Eduardo I. de Oliveira; José António Lopes; Ana G. Almeida; Mário G. Lopes; M. Martins Prata

2007-01-01

182

A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus  

Microsoft Academic Search

Non-syndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 reported gene localisations. We have identified a large Dutch family with autosomal dominant non-syndromic sensorineural hearing impairment. In most patients, the onset of hearing impairment is in the first or second decade of life, with a slow decline in the following decades, which stops short

Guy Van Camp; Henricus Kunst; Kris Flothmann; Wyman McGuirt; Jan Wauters; Henri Marres; Margriet Verstreken; Irina N Bespalova; Margit Burmeister; Paul H Van de Heyning; Richard J H Smith; Patrick J Willems; Cor W R J Cremers; Marci M Lesperance

1999-01-01

183

A gene for autosomal dominant juvenile amyotrophic lateral sclerosis ( ALS4? ) localizes to a 500-kb interval on chromosome 9q34  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord. The ALS4 locus was recently mapped by

Ian P. Blair; Craig L. Bennett; Annette Abel; Bruce A. Rabin; John W. Griffin; Kenneth H. Fischbeck; David R. Cornblath; Phillip F. Chance

2000-01-01

184

Buschke-ollendorff syndrome: report of a case and interpretation of the clinical phenotype as a type 2 segmental manifestation of an autosomal dominant skin disease  

Microsoft Academic Search

Buschke-Ollendorff syndrome is a rare, autosomal dominant disease consisting of osteopoikilosis and skin manifestations. A case is reported, and the literature is reviewed with special reference to the clinical distribution patterns of skin lesions. The 2 main types of skin manifestations in this entity are widely disseminated, symmetrically distributed papules and localized, asymmetrically distributed plaques. Both types of lesions have

Torsten Ehrig; Clay J. Cockerell

2003-01-01

185

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

PubMed

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

186

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

187

Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region.  

PubMed

The DFNA2 locus for autosomal dominant nonsyndromic hearing impairment on chromosome 1p34 contains at least 2 genes responsible for hearing loss, GJB3 and KCNQ4. GJB3 is a member of the connexin gene family and KCNQ4 is a voltage-gated potassium channel. KCNQ4 mutations were first found in a French family, and later also in a Belgian, an American and two Dutch families. Here we present the analysis of the GJB3 and KCNQ4 genes in a third Dutch family linked to DFNA2. No mutation was found in GJB3, but a missense mutation changing a conserved Leu residue into His (L274H) was found in the coding region of the KCNQ4 gene in all patients of this DFNA2 family. Examination of the position of all known KCNQ4 mutations showed a clustering of mutations in the pore region of the KCNQ4 gene, responsible for the ion selectivity of the channel. The clustering of mutations in this domain confirms its importance. PMID:10925378

Van Hauwe, P; Coucke, P J; Ensink, R J; Huygen, P; Cremers, C W; Van Camp, G

2000-07-31

188

Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.  

PubMed

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

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

2013-08-01

189

SDOCT Thickness Measurements of Various Retinal Layers in Patients with Autosomal Dominant Optic Atrophy due to OPA1 Mutations  

PubMed Central

Purpose. To specify thickness values of various retinal layers on macular spectral domain Optical Coherence Tomography (SDOCT) scans in patients with autosomal dominant optic atrophy (ADOA) compared to healthy controls. Methods. SDOCT volume scans of 7 patients with ADOA (OPA-1 mutation) and 14 healthy controls were quantitatively analyzed using manual grading software. Mean thickness values for the ETDRS grid subfields 5–8 were calculated for the spaces neurosensory retina, retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), a combined space of inner plexiform layer/outer plexiform layer/inner nuclear layer (IPL+INL+OPL), and a combined space of outer nuclear layer/photoreceptor layers (ONL+PL). Results. ADOA patients showed statistically significant lower retinal thickness values than controls (P < 0.01). RNFL (P < 0.001) and GCL thicknesses (P < 0.001) were significantly lower in ADOA patients. There was no difference in IPL+INL+OPL and in ONL+PL thickness. Conclusion. Manual subanalysis of macular SDOCT volume scans allowed detailed subanalysis of various retinal layers. Not only RNFL but also GCL thicknesses are reduced in the macular area of ADOA patients whereas subjacent layers are not involved. Together with clinical findings, macular SDOCT helps to identify patients with suspicion for hereditary optic neuropathy before genetic analysis confirms the diagnosis. PMID:24024178

Schild, Andrea M.; Fricke, Julia; Neugebauer, Antje; Kirchhof, Bernd; Sadda, Srinivas R.

2013-01-01

190

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

PubMed Central

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

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

2013-01-01

191

Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34.  

PubMed

We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease. The disorder is characterized by slow progression, distal limb amyotrophy, and pyramidal tract signs associated with severe loss of motor neurons in the brain stem and spinal cord. The gene for this disorder, classified as a form of juvenile amyotrophic lateral sclerosis (ALS), is designated "ALS4." We performed a genomewide search and detected strong evidence for linkage of the ALS4 locus to markers from chromosome 9q34. The highest LOD score (Z) was obtained with D9S1847 (Z=18.8, recombination fraction of .00). An analysis of recombinant events identified D9S1831 and D9S164 as flanking markers, on chromosome 9q34, that define an approximately 5-cM interval that harbors the ALS4 gene. These results extend the degree of heterogeneity within familial ALS syndromes, and they implicate a gene on chromosome 9q34 as critical for motor-neuron function. PMID:9497266

Chance, P F; Rabin, B A; Ryan, S G; Ding, Y; Scavina, M; Crain, B; Griffin, J W; Cornblath, D R

1998-03-01

192

A Novel PRPF31 Mutation in a Large Chinese Family with Autosomal Dominant Retinitis Pigmentosa and Macular Degeneration  

PubMed Central

Purpose This study was intended to identify the disease causing genes in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. Methods A genome scan analysis was conducted in this family for disease gene preliminary mapping. Snapshot analysis of selected SNPs for two-point LOD score analysis for candidate gene filter. Candidate gene PRPF31 whole exons' sequencing was executed to identify mutations. Results A novel nonsense mutation caused by an insertion was found in PRPF31 gene. All the 19 RP patients in 1085 family are carrying this heterozygous nonsense mutation. The nonsense mutation is in PRPF31 gene exon9 at chr19:54629961-54629961, inserting nucleotide “A” that generates the coding protein frame shift from p.307 and early termination at p.322 in the snoRNA binding domain (NOP domain). Conclusion This report is the first to associate PRPF31 gene's nonsense mutation and adRP and JMD. Our findings revealed that PRPF31 can lead to different clinical phenotypes in the same family, resulting either in adRP or syndrome of adRP and JMD. We believe our identification of the novel “A” insertion mutation in exon9 at chr19:54629961-54629961 in PRPF31 can provide further genetic evidence for clinical test for adRP and JMD. PMID:24244300

Zheng, Hong; Liu, Xiaoqi; Yang, Jiyun; Shi, Yi; Lin, Ying; Gong, Bo; Zhu, Xianjun; Ma, Shi; Qiao, Lifeng; Lin, He; Cheng, Jing; Yang, Zhenglin

2013-01-01

193

Apelin and copeptin: two opposite biomarkers associated with kidney function decline and cyst growth in autosomal dominant polycystic kidney disease.  

PubMed

Vasopressin (AVP) plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). Copeptin represents a measurable substitute for circulating AVP whereas apelin counteracts AVP signaling. The aim of this study was to investigate the predictive value of apelin and copeptin for the progression of ADPKD disease. 52 ADPKD patients were enrolled and followed until the end of the observation period or the primary study endpoint was reached, defined by the combined outcome of decrease of glomerular filtration rate associated with a total renal volume increase. Receiver operating characteristics (ROC) analysis was employed for identifying the progression of renal disease and Kaplan-Meier curves assessed the renal survival. Adjusted risk estimates for progression endpoint and incident renal replacement therapy (RRT) were calculated using Cox proportional hazard regression analysis. ADPKD patients were characterized by lower apelin levels and higher copeptin levels when compared with healthy subjects. These biomarkers were strictly correlated with osmolality and markers of renal function. At ROC analysis, apelin and copeptin showed a very good diagnostic profile in identifying ADPKD progression. After the follow up of 24 months, 33 patients reached the endpoint. Cox proportional hazard regression analysis showed that apelin predicted renal disease progression and incident RRT independently of other potential confounders. Apelin is associated with kidney function decline in ADPKD, suggesting that it may be a new marker to predict kidney outcome. PMID:23973863

Lacquaniti, Antonio; Chirico, Valeria; Lupica, Rosaria; Buemi, Antoine; Loddo, Saverio; Caccamo, Chiara; Salis, Paola; Bertani, Tullio; Buemi, Michele

2013-11-01

194

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; Ballarín, José; Torra, Roser; Estivill, Xavier; Ars, Elisabet

2014-01-01

195

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

196

Autosomal dominant spastic paraplegia linked to chromosome 2p: clinical and genetic studies of a large Japanese pedigree.  

PubMed

Autosomal dominant spastic paraplegia (ADSP) is a genetically heterogenous disorder. To date, 3 loci of ADSP have been identified on chromosome 2p, 14q, and 15q, but specific gene mutations remain unknown. To determine the genetic background of ADSP in the Japanese, we studied a large 3-generation pedigree, clinically and genetically. Of the 36 individuals clinically examined, 15 were affected. The main feature in the affected individuals was a slowly progressive spastic paraplegia, associated with upper limb hyperreflexia (58%), reduction of vibration sense (27%) and bladder disturbance (13%). Age at onset ranged from 13 to 50 years with a mean of 30.3 +/- 14.2 (SD). There were 6 parent-child pairs with anticipation and at least 3 others with 'anti-anticipation'. Linkage with 14q and 15q ADSP loci was excluded, and a highly significant lod score was obtained only in the case of the 2p locus (Zmax = 3.53 for D2S400/D2S352, at theta = 0.00). Our study is the first to confirm the existence of 2p-linked ADSP in the Japanese. There is a significant variety in age at onset and disease severity in these 2p-linked families, but the implication for underlying ADSP mutation is not clear. PMID:9335012

Matsuura, T; Sasaki, H; Wakisaka, A; Hamada, T; Moriwaka, F; Tashiro, K

1997-10-01

197

The structure and composition of deciduous enamel affected by local hypoplastic autosomal dominant amelogenesis imperfecta resulting from an ENAM mutation.  

PubMed

In a group of families in northern Sweden, a mutation in the ENAM gene (predicted to produce a highly truncated protein) results in the local hypoplastic form of autosomal dominant amelogenesis imperfecta. In this study, sections of deciduous teeth from members of 3 of these families were examined by scanning electron microscopy (SEM) and the enamel mineral was analysed by energy dispersive X-ray spectroscopy (EDX). The sections were also probed with antibodies raised to a conserved sequence of the enamelin protein. Selected intact teeth were first analysed by digital imaging and ascribed with an 'Enamel Defects Index' (EDI) score. SEM of tooth sections revealed disrupted prism morphology and the prisms had a glass-like appearance in some areas. These areas of dysplasia were sometimes irregular but formed regular arrays in others. Comparison of EDI scores with SEM indicated that in one tooth the surface had no measurable defects but significant defects were present in the underlying enamel microstructure. SEM immunohistochemistry with the antibody raised to a fragment of the enamelin protein produced positive, but light, labelling throughout normal enamel. In dysplastic areas, however, the labelling intensity appeared to be reduced. The results indicate that the presence of functional enamelin in the correct amounts is necessary for correct prism morphogenesis. In addition, a combination of EDI and structural analysis indicate that defects in enamel microstructure are not necessarily visible as defects on the surface of the tooth, suggesting the possibility, at least, that some instances of under-diagnosis may occur. PMID:19923784

Shore, R C; Bäckman, B; Elcock, C; Brook, A H; Brookes, S J; Kirkham, J

2010-01-01

198

Primary hyperoxaluria type 1 and brachydactyly mental retardation syndrome caused by a novel mutation in AGXT and a terminal deletion of chromosome 2.  

PubMed

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by mutations in the alanine:glyoxylate aminotransferase (AGXT) gene, located on chromosome 2q37. Mutant AGXT leads to excess production and excretion of oxalate, resulting in accumulation of calcium oxalate in the kidney, and progressive loss of renal function. Brachydactyly mental retardation syndrome (BDMR) is an autosomal dominant disorder, caused by haploinsufficiency of histone deacetylase 4 (HDAC4), also on chromosome 2q37. It is characterized by skeletal abnormalities and developmental delay. Here, we report on a girl who had phenotypes of both PH1 and BDMR. PCR-sequencing of the coding regions of AGXT showed a novel missense mutation, c.32C>G (p.Pro11Arg) inherited from her mother. Functional analyses demonstrated that it reduced the enzymatic activity to 31% of the wild-type and redirected some percentage of the enzyme away from the peroxisome. Microsatellite and array-CGH analyses indicated that the proband had a paternal de novo telomeric deletion of chromosome 2q, which included HDAC4. To our knowledge, this is the first report of PH1 and BDMR, with a novel AGXT mutation and a de novo telomeric deletion of chromosome 2q. PMID:22821680

Tammachote, Rachaneekorn; Kingsuwannapong, Nelawat; Tongkobpetch, Siraprapa; Srichomthong, Chalurmpon; Yeetong, Patra; Kingwatanakul, Pornchai; Monico, Carla G; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk

2012-09-01

199

A novel autosomal dominant condition consisting of congenital heart defects and low atrial rhythm maps to chromosome 9q  

PubMed Central

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21–33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-c critical interval corresponds to 39?Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis. PMID:21386876

van de Meerakker, Judith B A; van Engelen, Klaartje; Mathijssen, Inge B; Lekanne dit Deprez, Ronald H; Lam, Jan; Wilde, Arthur A M; Baars, Marieke J H; Mannens, Marcel M A M; Mulder, Barbara J M; Moorman, Antoon F M; Postma, Alex V

2011-01-01

200

Nicotine Normalizes Intracellular Subunit Stoichiometry of Nicotinic Receptors Carrying Mutations Linked to Autosomal Dominant Nocturnal Frontal Lobe EpilepsyS?  

PubMed Central

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is linked with high penetrance to several distinct nicotinic receptor (nAChR) mutations. We studied (?4)3(?2)2 versus (?4)2(?2)3 subunit stoichiometry for five channel-lining M2 domain mutations: S247F, S252L, 776ins3 in ?4, V287L, and V287M in ?2. ?4 and ?2 subunits were constructed with all possible combinations of mutant and wild-type (WT) M2 regions, of cyan and yellow fluorescent protein, and of fluorescent and nonfluorescent M3-M4 loops. Sixteen fluorescent subunit combinations were expressed in N2a cells. Förster resonance energy transfer (FRET) was analyzed by donor recovery after acceptor photobleaching and by pixel-by-pixel sensitized emission, with confirmation by fluorescence intensity ratios. Because FRET efficiency is much greater for adjacent than for nonadjacent subunits and the ?4 and ?2 subunits occupy specific positions in nAChR pentamers, observed FRET efficiencies from (?4)3(?2)2 carrying fluorescent ?4 subunits were significantly higher than for (?4)2(?2)3; the converse was found for fluorescent ?2 subunits. All tested ADNFLE mutants produced 10 to 20% increments in the percentage of intracellular (?4)3(?2)2 receptors compared with WT subunits. In contrast, 24- to 48-h nicotine (1 ?M) exposure increased the proportion of (?4)2(?2)3 in WT receptors and also returned subunit stoichiometry to WT levels for ?4S248F and ?2V287L nAChRs. These observations may be relevant to the decreased seizure frequency in patients with ADNFLE who use tobacco products or nicotine patches. Fluorescence-based investigations of nAChR subunit stoichiometry may provide efficient drug discovery methods for nicotine addiction or for other disorders that result from dysregulated nAChRs. PMID:19237585

Son, Cagdas D.; Moss, Fraser J.; Cohen, Bruce N.; Lester, Henry A.

2009-01-01

201

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

PubMed Central

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

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

2014-01-01

202

Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation.  

PubMed

A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C>A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma. PMID:21744088

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

2012-09-01

203

Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease.  

PubMed

Meniere's disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD. PMID:25305078

Requena, Teresa; Cabrera, Sonia; Martín-Sierra, Carmen; Price, Steven D; Lysakowski, Anna; Lopez-Escamez, José A

2015-02-15

204

Exon Sequencing of PKD1 Gene in an Iranian Patient with Autosomal-Dominant Polycystic Kidney Disease  

PubMed Central

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with the incidence of 1 in 1,000 births. ADPKD is genetically heterogeneous with two genes identified: PKD1 (16p13.3, 46 exons) and PKD2 (4q21, 15 exons). Eighty five percent of the patients with ADPKD have at least one mutation in the PKD1 gene. Genetic studies have demonstrated an important allelic variability among patients, but very few data are known about the genetic variation among Iranian populations. Methods: In this study, exon direct sequencing of PKD1 was performed in a seven-year old boy with ADPKD and in his parents. The patient’s father was ADPKD who was affected without any kidney dysfunction, and the patient’s mother was congenitally missing one kidney. Results: Molecular genetic testing found a mutation in all three members of this family. It was a missense mutation GTG>ATG at position 3057 in exon 25 of PKD1. On the other hand, two novel missense mutations were reported just in the 7-year-old boy: ACA>GCA found in exon 15 at codon 2241 and CAC>AAC found in exon 38 at codon 3710. For checking the pathogenicity of these mutations, exons 15, 25, and 38 of 50 unrelated normal cases were sequenced. Conclusion: our findings suggested that GTG>ATG is a polymorphism with high frequency (60%) as well as ACA>GCA and CAC>AAC are polymorphisms with frequencies of 14% and 22%, respectively in the population of Southwest Iran. PMID:24842140

Hafizi, Atousa; Khatami, Saeid Reza; Galehdari, Hamid; Shariati, Gholamreza; Saberi, Ali Hossein; Hamid, Mohammad

2014-01-01

205

The Severe Autosomal Dominant Retinitis Pigmentosa Rhodopsin Mutant Ter349Glu Mislocalizes and Induces Rapid Rod Cell Death*  

PubMed Central

Mutations in the rhodopsin gene cause approximately one-tenth of retinitis pigmentosa cases worldwide, and most result in endoplasmic reticulum retention and apoptosis. Other rhodopsin mutations cause receptor mislocalization, diminished/constitutive activity, or faulty protein-protein interactions. The purpose of this study was to test for mechanisms by which the autosomal dominant rhodopsin mutation Ter349Glu causes an early, rapid retinal degeneration in patients. The mutation adds an additional 51 amino acids to the C terminus of the protein. Folding and ligand interaction of Ter349Glu rhodopsin were tested by ultraviolet-visible (UV-visible) spectrophotometry. The ability of the mutant to initiate phototransduction was tested using a radioactive filter binding assay. Photoreceptor localization was assessed both in vitro and in vivo utilizing fluorescent immunochemistry on transfected cells, transgenic Xenopus laevis, and knock-in mice. Photoreceptor ultrastructure was observed by transmission electron microscopy. Spectrally, Ter349Glu rhodopsin behaves similarly to wild-type rhodopsin, absorbing maximally at 500 nm. The mutant protein also displays in vitro G protein activation similar to that of WT. In cultured cells, mislocalization was observed at high expression levels whereas ciliary localization occurred at low expression levels. Similarly, transgenic X. laevis expressing Ter349Glu rhodopsin exhibited partial mislocalization. Analysis of the Ter349Glu rhodopsin knock-in mouse showed a rapid, early onset degeneration in homozygotes with a loss of proper rod outer segment development and improper disc formation. Together, the data show that both mislocalization and rod outer segment morphogenesis are likely associated with the human phenotype. PMID:23940033

Hollingsworth, T. J.; Gross, Alecia K.

2013-01-01

206

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

PubMed Central

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

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

2014-01-01

207

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

PubMed Central

PURPOSE To examine the molecular genetic basis and phenotypic characteristics of an unusual late-onset autosomal dominant 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 members, 17 clinically unaffected members, and 5 unrelated spouses. Clinical analyses included a review of medical history and standard ophthalmic examination with fundus photography, fluorescein angiography, and electroretinography. Linkage and haplotype analyses were performed with microsatellite markers. Mutation analysis was performed by amplification of exons followed by sequencing. RESULTS A wide spectrum of clinical phenotypes including exudative and nonexudative maculopathy was observed, with onset in the late fifth decade. Linkage analysis excluded most of the previously known maculopathy loci. Markers D6S1604 (Zmax of 3.18 at ? = 0), and D6S282 (Zmax of 3.18 at ? = 0) gave significant positive LOD scores and haplotype analysis localized the disease gene to a 9-centimorgan (cM) interval between markers D6S1616 and D6S459. Mutation analysis excluded the GUCA1A and GUCA1B genes and revealed a missense mutation in the RDS/peripherin gene leading to a Tyr141Cys substitution. A phenotype and haplotype comparison between this and a separate family with the Tyr141Cys mutation suggested the presence of a common ancestral haplotype. CONCLUSIONS The RDS mutation in codon 141 is associated with an unusual AMD-like late-onset maculopathy. An apparent selective bias was noted favoring the transmission of the mutant allele. These observations broaden the spectrum of phenotypes associated with RDS gene mutations. PMID:12882809

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

2008-01-01

208

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, Günter; Wenzel, Jörg; Größer, Leopold; Wehner, Maria; Wolf, Sabrina; Fagerberg, Christina; Bygum, Anette; Altmüller, Janine; Rütten, Arno; Parmentier, Laurent; El Shabrawi-Caelen, Laila; Hafner, Christian; Nürnberg, Peter; Kruse, Roland; Schoch, Susanne; Hanneken, Sandra; Betz, Regina C.

2014-01-01

209

Autosomal Dominant Hearing Loss resulting from p.R75Q Mutation in the GJB2 Gene: Nonsyndromic presentation in a South Indian Family.  

PubMed

Mutations in the GJB2 gene encoding the gap junction protein Connexin 26 have been associated with autosomal recessive as well as dominant nonsyndromic hearing loss. Owing to the involvement of connexins in skin homeostasis, GJB2 mutations have also been associated with syndromic forms of hearing loss showing various skin manifestations. We report an assortatively mating hearing impaired family of south Indian origin with three affected members spread over two generations, having p.R75Q mutation in the GJB2 gene in the heterozygous condition. The inheritance pattern was autosomal dominant with mother and son being affected. Dermatological and histopathologic examinations showed absence of palmoplantar keratoderma. To the best of our knowledge, this is the first report from India on p.R75Q mutation in the GJB2 gene with nonsyndromic hearing loss. PMID:25393658

Pavithra, Amritkumar; Selvakumari, Mathiyalagan; Nityaa, Venkatesan; Sharanya, Narasimhan; Ramakrishnan, Rajagopalan; Narasimhan, Murali; Srisailapathy, C R Srikumari

2015-01-01

210

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

211

A gene for autosomal dominant juvenile amyotrophic lateral sclerosis ( ALS4? ) localizes to a 500-kb interval on chromosome 9q34  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower\\u000a motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal\\u000a limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord.\\u000a The \\u000a ALS4\\u000a locus was recently mapped by

I. P. Blair; C. L. Bennett; A. Abel; B. A. Rabin; J. W. Griffin; K. H. Fischbeck; D. R. Cornblath; P. F. Chance

2000-01-01

212

Regional brain metabolism with cytochrome c oxidase histochemistry in a PS1\\/A246E mouse model of autosomal dominant Alzheimer's disease: Correlations with behavior and oxidative stress  

Microsoft Academic Search

Mitochondrial dysfunction and brain metabolic alteration are early neurofunctional aspects in Alzheimer's disease (AD). Regional brain metabolism was analyzed by cytochrome c oxidase (COX) histochemistry in PS1-A246E mouse mutants, a model of autosomal dominant AD overexpressing beta-amyloid (A?) peptide without amyloidosis or cell degeneration. Immunohistochemical samples were analyzed on adjacent sections for regional A?1-42 levels, as well as DNA oxidative

Catherine Strazielle; Rozat Jazi; Yann Verdier; Sue Qian; Robert Lalonde

2009-01-01

213

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

Microsoft Academic Search

Congenital microphthalmia is a developmental disorder characterized by shortened axial length of the eye. We have previously mapped the gene responsible for autosomal dominant colobomatous microphthalmia in a 5-generation family to chromosome 15q12–q15. Here, we set up a physical and transcript map of the 13.8 cM critical region, flanked by loci D15S1002 and D15S1040. Physical mapping and genetic linkage analysis

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

2004-01-01

214

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

215

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

PubMed

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

Sainaresh, Vv; Jain, Sh; Patel, Hv; Shah, Pr; Vanikar, Av; Trivedi, Hl

2011-04-01

216

Chronic kidney pain in autosomal dominant polycystic kidney disease: a case report of successful treatment by catheter-based renal denervation.  

PubMed

Chronic pain is a common concern in patients with autosomal dominant polycystic kidney disease (ADPKD). We report what to our knowledge is the first catheter-based renal denervation procedure in a patient with ADPKD resulting in successful management of chronic pain. The patient was a 43-year-old woman whose chronic pain could not be controlled by pain medication or splanchnic nerve blockade. Transluminal radiofrequency renal denervation was performed as an experimental therapeutic option with an excellent result, indicating that this procedure should be considered for chronic pain management in ADPKD. PMID:24518126

Casteleijn, Niek F; de Jager, Rosa L; Neeleman, M Peer; Blankestijn, Peter J; Gansevoort, Ron T

2014-06-01

217

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

PubMed Central

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

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

2014-01-01

218

A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E  

PubMed Central

Parathyroid hormone-like hormone (PTHLH) is an important chondrogenic regulator; however, the gene has not been directly linked to human disease. We studied a family with autosomal-dominant Brachydactyly Type E (BDE) and identified a t(8;12)(q13;p11.2) translocation with breakpoints (BPs) upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 on 8q13. We sequenced the BPs and identified a highly conserved Activator protein 1 (AP-1) motif on 12p11.2, together with a C-ets-1 motif translocated from 8q13. AP-1 and C-ets-1 bound in vitro and in vivo at the derivative chromosome 8 breakpoint [der(8) BP], but were differently enriched between the wild-type and BP allele. We differentiated fibroblasts from BDE patients into chondrogenic cells and found that PTHLH and its targets, ADAMTS-7 and ADAMTS-12 were downregulated along with impaired chondrogenic differentiation. We next used human and murine chondrocytes and observed that the AP-1 motif stimulated, whereas der(8) BP or C-ets-1 decreased, PTHLH promoter activity. These results are the first to identify a cis-directed PTHLH downregulation as primary cause of human chondrodysplasia. PMID:20015959

Maass, Philipp G.; Wirth, Jutta; Aydin, Atakan; Rump, Andreas; Stricker, Sigmar; Tinschert, Sigrid; Otero, Miguel; Tsuchimochi, Kaneyuki; Goldring, Mary B.; Luft, Friedrich C.; Bähring, Sylvia

2010-01-01

219

Targeted high-throughput sequencing identifies pathogenic mutations in KCNQ4 in two large Chinese families with autosomal dominant hearing loss.  

PubMed

Autosomal dominant non-syndromic hearing loss (ADNSHL) is highly heterogeneous, among them, KCNQ4 is one of the most frequent disease-causing genes. More than twenty KCNQ4 mutations have been reported, but none of them were detected in Chinese mainland families. In this study, we identified a novel KCNQ4 mutation in a five generation Chinese family with 84 members and a known KCNQ4 mutation in a six generation Chinese family with 66 members. Mutation screening of 30 genes for ADNSHL was performed in the probands from thirty large Chinese families with ADNSHL by targeted region capture and high-throughput sequencing. The candidate variants and the co-segregation of the phenotype were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing in all ascertained family members. Then we identified a novel KCNQ4 mutation p.W275R in exon 5 and a known KCNQ4 mutation p.G285S in exon 6 in two large Chinese ADNSHL families segregating with post-lingual high frequency-involved and progressive sensorineural hearing loss. This is the first report of KCNQ4 mutation in Chinese mainland families. KCNQ4, a member of voltage-gated potassium channel family, is likely to be a common gene in Chinese patients with ADNSHL. The results also support that the combination of targeted enrichment and high-throughput sequencing is a valuable molecular diagnostic tool for autosomal dominant hereditary deafness. PMID:25116015

Wang, Hongyang; Zhao, Yali; Yi, Yuting; Gao, Yun; Liu, Qiong; Wang, Dayong; Li, Qian; Lan, Lan; Li, Na; Guan, Jing; Yin, Zifang; Han, Bing; Zhao, Feifan; Zong, Liang; Xiong, Wenping; Yu, Lan; Song, Lijie; Yi, Xin; Yang, Ling; Petit, Christine; Wang, Qiuju

2014-01-01

220

A novel locus for autosomal dominant non?syndromic deafness, DFNA53, maps to chromosome 14q11.2?q12  

PubMed Central

Background Non?syndromic hearing loss is among the most genetically heterogeneous traits known in humans. To date, at least 50 loci for autosomal dominant non?syndromic sensorineural hearing loss (ADNSSHL) have been identified by linkage analysis. Objective To report the mapping of a novel autosomal dominant deafness locus on the long arm of chromosome 14 at 14q11.2?q12, DFNA53, in a large multigenerational Chinese family with post?lingual, high frequency hearing loss that progresses to involve all frequencies. Results A maximum multipoint LOD score of 5.4 was obtained for marker D14S1280. The analysis of recombinant haplotypes mapped DFNA53 to a 9.6?cM region interval between markers D14S581 and D14S1021. Four deafness loci (DFNA9, DFNA23, DFNB5, and DFNB35) have previously been mapped to the long arm of chromosome 14. The critical region for DFNA53 contains the gene for DFNA9 but does not overlap with the regions for DFNB5, DFNA23, or DFNB35. Screening of the COCH gene (DFNA9), BOCT, EFS, and HSPC156 within the DFNA53 interval did not identify the cause for deafness in this family. Conclusions Identifying the DFNA53 locus is the first step in isolating the gene responsible for hearing loss in this large multigeneration Chinese family. PMID:15958501

Yan, D; Ke, X; Blanton, S H; Ouyang, X M; Pandya, A; Du, L L; Nance, W E; Liu, X Z

2006-01-01

221

Targeted High-Throughput Sequencing Identifies Pathogenic Mutations in KCNQ4 in Two Large Chinese Families with Autosomal Dominant Hearing Loss  

PubMed Central

Autosomal dominant non-syndromic hearing loss (ADNSHL) is highly heterogeneous, among them, KCNQ4 is one of the most frequent disease-causing genes. More than twenty KCNQ4 mutations have been reported, but none of them were detected in Chinese mainland families. In this study, we identified a novel KCNQ4 mutation in a five generation Chinese family with 84 members and a known KCNQ4 mutation in a six generation Chinese family with 66 members. Mutation screening of 30 genes for ADNSHL was performed in the probands from thirty large Chinese families with ADNSHL by targeted region capture and high-throughput sequencing. The candidate variants and the co-segregation of the phenotype were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing in all ascertained family members. Then we identified a novel KCNQ4 mutation p.W275R in exon 5 and a known KCNQ4 mutation p.G285S in exon 6 in two large Chinese ADNSHL families segregating with post-lingual high frequency-involved and progressive sensorineural hearing loss. This is the first report of KCNQ4 mutation in Chinese mainland families. KCNQ4, a member of voltage-gated potassium channel family, is likely to be a common gene in Chinese patients with ADNSHL. The results also support that the combination of targeted enrichment and high-throughput sequencing is a valuable molecular diagnostic tool for autosomal dominant hereditary deafness. PMID:25116015

Gao, Yun; Liu, Qiong; Wang, Dayong; Li, Qian; Lan, Lan; Li, Na; Guan, Jing; Yin, Zifang; Han, Bing; Zhao, Feifan; Zong, Liang; Xiong, Wenping; Yu, Lan; Song, Lijie; Yi, Xin; Yang, Ling; Petit, Christine; Wang, Qiuju

2014-01-01

222

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

PubMed Central

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

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

2014-01-01

223

Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with ?-tectorin and is mutated in autosomal dominant hearing loss (DFNA4)  

PubMed Central

We report on a secreted protein found in mammalian cochlear outer hair cells (OHC) that is a member of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family of adhesion proteins. Ceacam16 mRNA is expressed in OHC, and its protein product localizes to the tips of the tallest stereocilia and the tectorial membrane (TM). This specific localization suggests a role in maintaining the integrity of the TM as well as in the connection between the OHC stereocilia and TM, a linkage essential for mechanical amplification. In agreement with this role, CEACAM16 colocalizes and coimmunoprecipitates with the TM protein ?-tectorin. In addition, we show that mutation of CEACAM16 leads to autosomal dominant nonsyndromic deafness (ADNSHL) at the autosomal dominant hearing loss (DFNA4) locus. In aggregate, these data identify CEACAM16 as an ?-tectorin–interacting protein that concentrates at the point of attachment of the TM to the stereocilia and, when mutated, results in ADNSHL at the DFNA4 locus. PMID:21368133

Zheng, Jing; Miller, Katharine K.; Yang, Tao; Hildebrand, Michael S.; Shearer, A. Eliot; DeLuca, Adam P.; Scheetz, Todd E.; Drummond, Jennifer; Scherer, Steve E.; Legan, P. Kevin; Richardson, Guy P.; Cheatham, Mary Ann; Smith, Richard J.; Dallos, Peter

2011-01-01

224

Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum.  

PubMed Central

Mutations in the arginine vasopressin (AVP) gene cause autosomal dominant familial neurohypophyseal diabetes insipidus (FNDI). The dominant inheritance pattern has been postulated to reflect neuronal toxicity of the mutant proteins, but the mechanism for such cytotoxicity is unknown. In this study, wild-type or several different mutant AVP genes were stably expressed in neuro2A neuroblastoma cells. When cells were treated with valproic acid to induce neuronal differentiation, each of the mutants caused reduced viability. Metabolic labeling revealed diminished intracellular trafficking of mutant AVP precursors and confirmed inefficient secretion of immunoreactive AVP. Immunofluorescence studies demonstrated marked accumulation of mutant AVP precursors within the endoplasmic reticulum. These studies suggest that the cellular toxicity in FNDI may be caused by the intracellular accumulation of mutant precursor proteins. PMID:9109434

Ito, M; Jameson, J L; Ito, M

1997-01-01

225

Mutations in the Gene DNAJC5 Cause Autosomal Dominant Kufs Disease in a Proportion of Cases: Study of the Parry Family and 8 Other Families  

PubMed Central

Background The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD). Methodology and Principal Findings We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment. Conclusions Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change. PMID:22235333

Velinov, Milen; Dolzhanskaya, Natalia; Gonzalez, Michael; Powell, Eric; Konidari, Ioanna; Hulme, William; Staropoli, John F.; Xin, Winnie; Wen, Guang Y.; Barone, Rosemary; Coppel, Scott H.; Sims, Katherine; Brown, W. Ted; Züchner, Stephan

2012-01-01

226

Genetic Linkage of Autosomal-Dominant Alport Syndrome with Leukocyte Inclusions and Macrothrombocytopenia (Fechtner Syndrome) to Chromosome 22q11-13  

PubMed Central

Summary Fechtner syndrome is an autosomal-dominant variant of Alport syndrome, manifested by nephritis, sensorineural hearing loss, cataract formation, macrothrombocytopenia, and polymorphonuclear inclusion bodies. As opposed to autosomal-recessive and X-linked Alport syndromes, which have been genetically well studied, the genetic basis of Fechtner syndrome remains elusive. We have mapped the disease-causing gene to the long arm of chromosome 22 in an extended Israeli family with Fechtner syndrome plus impaired liver functions and hypercholesterolemia in some individuals. Six markers from chromosome 22q yielded a LOD score >3.00. A maximum two-point LOD score of 7.02 was obtained with the marker D22S283 at a recombination fraction of 0. Recombination analysis placed the disease-causing gene in a 5.5-Mb interval between the markers D22S284 and D22S1167. No collagen genes or genes comprising the basement membrane have been mapped to this region. PMID:10577925

Toren, Amos; Amariglio, Ninette; Rozenfeld-Granot, Galit; Simon, Amos J.; Brok-Simoni, Frida; Pras, Elon; Rechavi, Gideon

1999-01-01

227

Localization of the autosomal dominant HLA-linked spinocerebellar ataxia (SCA1) locus, in two kindreds, within an 8-cM subregion of chromosome 6p.  

PubMed Central

Two large kindreds with HLA-linked, autosomal dominant spinocerebellar ataxia (SCA1) were examined with markers from chromosome 6p to determine the location of the SCA1 locus. Results of the three-point analysis between the markers HLA-A, SCA1, and F13A overwhelmingly favor the conclusion that SCA1 is located distal of HLA and proximal of F13A. In addition, our data strongly support the conclusion that SCA1 lies centromeric and genetically very close to the highly informative D6S89 marker within the 8-cM chromosomal segment flanked by the D6S88 and D6S89 markers. In the two kindreds, one recombinant was observed between D6S89 and SCA1, resulting in a recombination fraction of .014 between the two loci. PMID:1676561

Ranum, L P; Duvick, L A; Rich, S S; Schut, L J; Litt, M; Orr, H T

1991-01-01

228

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

229

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

230

A novel GCAP1(N104K) mutation in EF hand 3 (EF3) linked to autosomal dominant cone dystrophy  

PubMed Central

The GUCA1A gene encodes a guanylate cyclase-activating protein (GCAP1) that is involved in regulation of phototransduction in the vertebrate retina. We discovered a novel C312A transversion in exon 2 of the human GUCA1A gene, replacing Asn-104 (N104) in GCAP1 with Lys (K), in two affected members of a family with dominant cone dystrophy. The mutation N104K is located in the third EF hand motif (EF3) shown previously to be instrumental in converting Ca2+-free GCAP1 to a GC inhibitor in the Ca2+-bound form. In one patient, rod ERGs were fairly stable over a 12-year-period whereas 30 Hz flicker ERG and single-flash cone ERGs declined. In both patients, double flash ERGs showed that rod recovery from an intense test flash was significantly delayed. The EC50 for GC stimulation shifted from ~250 nM in wild-type GCAP1 to ~800 nM in the GCAP1(N104K) mutant suggesting inability of the mutant to assume an inactive form under physiological conditions. The replacement of N104 by K in GCAP1 is the first naturally occurring mutation identified in the EF3 loop. The rod recovery delays observed in double-flash ERG of affected patients suggest a novel dominant-negative effect that slows GC stimulation. PMID:18706439

Jiang, Li; Wheaton, Dianna; Bereta, Greg; Zhang, Kang; Palczewski, Krzysztof; Birch, David G.; Baehr, Wolfgang

2008-01-01

231

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

PubMed Central

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

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

2014-01-01

232

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

233

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

PubMed

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

234

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

235

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

236

A missense mutation in the Kv1.1 voltage-gated potassium channel–encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia  

PubMed Central

Primary hypomagnesemia is a heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting, resulting in tetany, cardiac arrhythmias, and seizures. The kidney plays an essential role in maintaining blood Mg2+ levels, with a prominent function for the Mg2+-transporting channel transient receptor potential cation channel, subfamily M, member 6 (TRPM6) in the distal convoluted tubule (DCT). In the DCT, Mg2+ reabsorption is an active transport process primarily driven by the negative potential across the luminal membrane. Here, we studied a family with isolated autosomal dominant hypomagnesemia and used a positional cloning approach to identify an N255D mutation in KCNA1, a gene encoding the voltage-gated potassium (K+) channel Kv1.1. Kv1.1 was found to be expressed in the kidney, where it colocalized with TRPM6 along the luminal membrane of the DCT. Upon overexpression in a human kidney cell line, patch clamp analysis revealed that the KCNA1 N255D mutation resulted in a nonfunctional channel, with a dominant negative effect on wild-type Kv1.1 channel function. These data suggest that Kv1.1 is a renal K+ channel that establishes a favorable luminal membrane potential in DCT cells to control TRPM6-mediated Mg2+ reabsorption. PMID:19307729

Glaudemans, Bob; van der Wijst, Jenny; Scola, Rosana H.; Lorenzoni, Paulo J.; Heister, Angelien; van der Kemp, AnneMiete W.; Knoers, Nine V.; Hoenderop, Joost G.; Bindels, René J.

2009-01-01

237

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

PubMed Central

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

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

1994-01-01

238

Urinary N-acetyl-?-D glucosaminidase as a surrogate marker for renal function in autosomal dominant polycystic kidney disease: 1 year prospective cohort study  

PubMed Central

Background Renal failure is one of the most serious complications associated with autosomal dominant polycystic kidney disease (ADPKD). To date, early markers have failed to predict renal function deterioration at the early stages. This 1-year prospective study evaluated N-acetyl-?-D-glucosaminidase (NAG) as a new surrogate marker for renal function in ADPKD. Methods A total of 270 patients were enrolled in the study, and we measured urinary NAG, ?2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) prospectively for 1?year to compare their predictive values for renal function. Results Baseline urinary NAG/Cr was negatively correlated with estimated glomerular filtration rate (GFR) (r2?=?0.153, P?

2012-01-01

239

Inhibition of MiR-199a-5p Reduced Cell Proliferation in Autosomal Dominant Polycystic Kidney Disease through Targeting CDKN1C  

PubMed Central

Background With a prevalence of about 1:500 to 1:1,000, autosomal dominant polycystic kidney disease (ADPKD) often causes renal failure, with many serious complications. However, there is no Food and Drug Administration (FDA) approved therapy available. Material/Methods MiR-199a-5p level in ADPKD patient samples, rat model, and cell lines were determined with Realtime PCR assay. After miR-199a-5p inhibitor was transfected, we detected the cell proliferation and apoptosis using an MTT assay and an Annexin V-FITC staining kit, respectively. Finally, TargetScan version 5.1 was used to predict the miRNA target and the target gene of miR-199a-5p was proved by a Luciferase assay. Results We identified a dramatically up-regulated microRNA, miR-199a-5p, in ADPKD tissues and cell lines. Our data show that inhibition of miR-199a-5p suppressed cyst cells proliferation and induced cell apoptosis. We found that miR-199a-5p might exert this effect through targeting CDKN1C/p57. Conclusions Up-regulation of miR-199a-5p in ADPKD tissues might promote cell proliferation through suppressing CDKN1C, suggesting miR-199a-5p as a novel target for ADPKD treatment. PMID:25588980

Sun, Lijun; Zhu, Jiaqi; Wu, Ming; Sun, Haipeng; Zhou, Chenchen; Fu, Lili; Xu, Chenggang; Mei, Changlin

2015-01-01

240

Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes  

PubMed Central

We describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly), respectively. To test whether one of these genes was also implicated in this French family, we performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fibl5) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of –11.39 (for Fibl5) and –13.34 (for Fib5), at ? = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome. PMID:8317497

Boileau, Catherine; Jondeau, Guillaume; Babron, Marie-Claude; Coulon, Monique; Alexandre, Jeanne-Armelle; Sakai, Lynn; Melki, Judith; Delorme, Gabriel; Dubourg, Olivier; Bonaïti-Pellié, Catherine; Bourdarias, Jean-Pierre; Junien, Claudine

1993-01-01

241

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease.  

PubMed

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies. PMID:23304619

Friedrich, L; Barbey, F; Pascual, M; Venetz, J-P

2012-01-01

242

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies. PMID:23304619

Friedrich, L.; Barbey, F.; Pascual, M.; Venetz, J.-P.

2012-01-01

243

A new locus for autosomal dominant "pure" hereditary spastic paraplegia mapping to chromosome 12q13, and evidence for further genetic heterogeneity.  

PubMed Central

Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is clinically characterized by slowly progressive lower-limb spasticity. The condition is genetically heterogeneous, and loci have been mapped at chromosomes 2p, 8q, 14q, and 15q. We have performed a genomewide linkage screen on a large family with ADPHSP, in which linkage to all four previously known loci was excluded. Analysis of markers on chromosome 12q gave a peak pairwise LOD score of 3.61 at D12S1691, allowing us to assign a new locus for ADPHSP (a locus that we have designated "SPG10") to this region. Haplotype construction and analysis of recombination events narrowed the SPG10 locus to a 9.2-cM region between markers D12S368 and D12S83. In addition, our data strongly suggest that there are at least six ADPHSP loci, since we describe a further family in which linkage to all five known ADPHSP loci has been excluded. PMID:10441583

Reid, E; Dearlove, A M; Rhodes, M; Rubinsztein, D C

1999-01-01

244

A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34.  

PubMed

Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower motor neurons. ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord. The ALS4 locus was recently mapped by linkage analysis to a large genetic interval on chromosome 9q34. By undertaking extensive genetic linkage analysis, we have significantly refined the ALS4 locus to a critical interval of less than 3 cM, flanked by D9S149 and D9S1198. Previous physical mapping in this region has indicated that this critical interval spans approximately 500 kb. Seventeen putative transcripts have been localized within this interval including 7 characterized genes, 2 partially characterized genes, and 8 "anonymous" expressed sequence tags . These are therefore positional candidate genes for the ALS4 locus. We have also undertaken mutation analysis and genetic mapping to investigate and exclude candidate genes, including RING3L/ORFX and RALGDS, from a pathogenic role in ALS4. PMID:11085590

Blair, I P; Bennett, C L; Abel, A; Rabin, B A; Griffin, J W; Fischbeck, K H; Cornblath, D R; Chance, P F

2000-09-01

245

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

PubMed Central

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

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

2014-01-01

246

Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the ?2 nicotinic receptor.  

PubMed

High-affinity nicotinic receptors containing ?2 subunits (?2*) are widely expressed in the brain, modulating many neuronal processes and contributing to neuropathologies such as Alzheimer's disease, Parkinson's disease and epilepsy. Mutations in both the ?4 and ?2 subunits are associated with a rare partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In this study, we introduced one such human missense mutation into the mouse genome to generate a knock-in strain carrying a valine-to-leucine mutation ?2V287L. ?2(V287L) mice were viable and born at an expected Mendelian ratio. Surprisingly, mice did not show an overt seizure phenotype; however, homozygous mice did show significant alterations in their activity-rest patterns. This was manifest as an increase in activity during the light cycle suggestive of disturbances in the normal sleep patterns of mice; a parallel phenotype to that found in human ADNFLE patients. Consistent with the role of nicotinic receptors in reward pathways, we found that ?2(V287L) mice did not develop a normal proclivity to voluntary wheel running, a model for natural reward. Anxiety-related behaviors were also affected by the V287L mutation. Mutant mice spent more time in the open arms on the elevated plus maze suggesting that they had reduced levels of anxiety. Together, these findings emphasize several important roles of ?2* nicotinic receptors in complex biological processes including the activity-rest cycle, natural reward and anxiety. PMID:20603624

Xu, J; Cohen, B N; Zhu, Y; Dziewczapolski, G; Panda, S; Lester, H A; Heinemann, S F; Contractor, A

2011-10-01

247

The Impact of the Availability of Prevention Studies on the Desire to Undergo Predictive Testing in Persons at-risk for Autosomal Dominant Alzheimer’s Disease  

PubMed Central

Persons at-risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n = 26) and non-Latinos at-risk for familial Alzheimer’s disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug "felt to be very safe.” If there were a 50% chance of receiving placebo, this number dropped to 62% (p = 0.02). For those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the U.S. (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggests that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered. PMID:23876673

Hooper, Megan; Grill, Joshua D.; Rodriguez-Agudelo, Yaneth; Medina, Luis D.; Fox, Michelle; Alvarez-Retuerto, Ana Isabel; Wharton, David; Brook, Jenny; Ringman, John M.

2013-01-01

248

A missense mutation in the alpha-actinin 1 gene (ACTN1) is the cause of autosomal dominant macrothrombocytopenia in a large French family.  

PubMed

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

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

2013-01-01

249

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

PubMed Central

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

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

2013-01-01

250

Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus.  

PubMed Central

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder characterized by progressive postnatal deficiency of arginine vasopressin as a result of mutation in the gene that encodes the hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindreds with the disorder. We sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindreds each mutation was unique. There were two missense mutations that altered the cleavage region of the signal peptide, seven missense mutations in exon 2, which codes for the conserved portion of the protein, one nonsense mutation in exon 2, and three nonsense mutations in exon 3. These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the production of a pre-prohormone that cannot be folded, processed, or degraded properly and eventually destroys vasopressinergic neurons. Images Figure 3 PMID:8554046

Rittig, S.; Robertson, G. L.; Siggaard, C.; Kovács, L.; Gregersen, N.; Nyborg, J.; Pedersen, E. B.

1996-01-01

251

Brachydactyly E: isolated or as a feature of a syndrome  

PubMed Central

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

2013-01-01

252

Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk. German Working Group on Paediatric Nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie.  

PubMed Central

In a systematic study on the clinical picture and genetics of cystic kidneys in children, in association with the German working group on paediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie), we have investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease (ADPKD). They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined in this study as clinical symptoms (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. In order to estimate the recurrence risk to sibs of a previously diagnosed patient with early manifesting ADPKD, we found that 15 out of a total of 65 sibs of the 64 index patients (45% of the theoretically expected 32.5 gene carriers) showed comparable early manifestation. Another 10 symptom free children were diagnosed sonographically as having ADPKD before the age of 18 years, so that the total number of affected sibs was 25/65 in the study group, representing 76% of the gene carriers. Although the gene in childhood manifesting ADPKD can be transmitted through both sexes, a statistically significant (p < 0.05) maternal predominance was observed (M:F = 23:41). In affected sibs ages of onset, initial presentation, and the development of complications appeared to be similar in the majority of families. Our data indicate a high recurrence risk to sibs for early manifestation of ADPKD which has important implications for genetic counselling and clinical care of affected families and gives clues to the underlying genetic mechanism of childhood onset ADPKD. PMID:8411032

Zerres, K; Rudnik-Schöneborn, S; Deget, F

1993-01-01

253

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.  

PubMed

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

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

2013-01-01

254

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

PubMed Central

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

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

1999-01-01

255

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

PubMed Central

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

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

2013-01-01

256

DFNA8/12 Caused by TECTA Mutations is the Most Identified Subtype of Non-syndromic Autosomal Dominant Hearing Loss  

PubMed Central

The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant non-syndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the ?-tectorin protein, including those for the first time identified in the entactin domain, the vWFD1, vWFD2 and vWFD3 repeats, and the D1-D2 and TIL2 connectors. While the majority are private mutations, four of them – p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met and p.Arg1890Cys – were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype-phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of ?-tectorin (entactin domain, vWFD1 and vWFD2) lead to mid frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL. PMID:21520338

Hildebrand, Michael S.; Morín, Matías; Meyer, Nicole C.; Mayo, Fernando; Modamio-Hoybjor, Silvia; Mencía, Angeles; Olavarrieta, Leticia; Morales-Angulo, Carmelo; Nishimura, Carla J.; Workman, Heather; DeLuca, Adam P.; del Castillo, Ignacio; Taylor, Kyle R.; Tompkins, Bruce; Goodman, Corey W.; Schrauwen, Isabelle; Van Wesemael, Maarten; Lachlan, K.; Shearer, A. Eliot; Braun, Terry A.; Huygen, Patrick L.M.; Kremer, Hannie; Van Camp, Guy; Moreno, Felipe; Casavant, Thomas L.; Smith, Richard J.H.; Moreno-Pelayo, Miguel A.

2012-01-01

257

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

PubMed Central

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

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

2015-01-01

258

Identification and characterization of C106R, a novel mutation in the DNA-binding domain of GCMB, in a family with autosomal-dominant hypoparathyroidism  

PubMed Central

Summary Overview Glial cells missing B (GCMB) is a transcription factor that is expressed in the parathyroid hormone (PTH)-secreting cells of the parathyroid glands. Several mutations in GCMB have been reported to cause hypoparathyroidism (HP). We identified a family with two individuals in two generations (mother and son), who are affected by autosomal-dominant hypoparathyroidism (AD-HP). A novel heterozygous mutation in exon 2 of GCMB was identified in both affected individuals that changes cysteine at position 106 of the putative DNA-binding domain of GCMB to arginine (C106R). Methods We performed mutational analysis of the genes encoding GCMB, pre-pro PTH, GATA3 and CaSR using polymerase chain reaction (PCR)-amplified genomic DNA. The identified GCMB mutant was characterized by functional studies including nuclear localization, electrophoretic mobility shift assays (EMSA) and luciferase reporter assays, and homology modelling was performed to generate a three-dimensional structural model for the DNA-binding domain of GCMB to predict the structural consequences of the identified mutation. Results The C106R mutant of GCMB failed to interact with the DNA consensus recognition motif, as determined by EMSA. Furthermore, in comparison with wild-type GCMB, the C106R mutant demonstrated reduced transactivation in luciferase reporter assays; however, the mutant GCMB failed to reduce the activity of the wild-type protein. Consistent with the EMSA findings, homology modelling analysis suggested that replacement of cysteine 106 with arginine would interfere with DNA binding. Conclusions We have identified a novel GCMB mutation that may explain AD-HP in our family. However, the exact mechanism by which this heterozygous mutation leads to the disease in the described family remains to be elucidated. PMID:22066718

Yi, Hyon-Seung; Eom, Young Sil; Park, Ie Byung; Lee, Sangho; Hong, Suntaek; Jüppner, Harald; Mannstadt, Michael; Lee, Sihoon

2013-01-01

259

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

PubMed Central

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

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

2013-01-01

260

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

261

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

PubMed Central

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

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

2014-01-01

262

Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.  

PubMed

Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome. PMID:20691407

Williams, Stephen R; Aldred, Micheala A; Der Kaloustian, Vazken M; Halal, Fahed; Gowans, Gordon; McLeod, D Ross; Zondag, Sara; Toriello, Helga V; Magenis, R Ellen; Elsea, Sarah H

2010-08-13

263

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

264

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

265

Brachydactyly mental retardation syndrome in differential diagnosis of pseudopseudohypoparathyroidism.  

PubMed

Patients with Albright hereditary osteodystrophy (AHO) phenotype are usually seen in pediatric endocrinology policlinics when they are evaluated for short stature and/or obesity. Brachydactyly mental retardation syndrome (BDMR, OMIM #600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and characterized with AHO-like phenotype without any hormone resistance. Diagnosis of BDMR is based on the detection of the deletion on the long arm of chromosome 2. Diagnosis can usually be made with karyotype analysis but sometimes chromosomal deletion can only be detected by fluorescent in situ hybridization (FISH) screening. We report a patient with the AHO phenotype whose karyotype was normal but who was diagnosed with BDMR with FISH analysis showing 2q deletion. In pediatric endocrinology practice, in patients with AHO phenotype but without parathormone (PTH) resistance, BDMR should be considered. For the diagnosis of BDMR, the subtelomeric region of chromosome 2 should be screened for deletion by FISH analysis even in patients with normal karyotypes. PMID:23645122

Hac?hamdio?lu, Bülent; Arslan, Mutluay; Sar?, Erkan; Kurtçu, Kemal; Yesilkaya, Ediz

2013-01-01

266

Molecular cytogenetic analysis of five 2q37 deletions: refining the brachydactyly candidate region.  

PubMed

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 set of 15 BACs, PACs and YACs. In four patients, terminal deletions of variable size ranged between 6.2 and 10 Mb. The fifth patient had an interstitial deletion with an AHO-like phenotype including brachydactyly. These findings when compared to previous observations allowed us to narrow down the brachydactyly critical region between BACs RP11-585E12 and RP11-351E10. It contains HDAC4 and STK25 candidate genes loci. PMID:16762827

Chaabouni, M; Le Merrer, M; Raoul, O; Prieur, M; de Blois, M C; Philippe, A; Vekemans, M; Romana, S P

2006-01-01

267

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.  

PubMed Central

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

1997-01-01

268

A novel locus for autosomal dominant non-syndromic hearing loss, DFNA31, maps to chromosome 6p21.3  

PubMed Central

Objective:To investigate the genes involved in a Dutch family with NSSHL. Methods:Linkage analysis in a large Dutch pedigree with progressive bilateral loss of the mid and high frequencies, in which a novel dominant locus for postlingual NSSHL (DFNA31) has been identified. Results:DFNA31 was found to be located in a 7.5 cM region of chromosome 6p21.3 between D6S276 (telomeric) and D6S273 (centromeric), with a maximum two point LOD score of 5.99 for D6S1624. DNA sequencing of coding regions and exon/intron boundaries of two candidate genes (POU5F1, GABBR1) in this interval did not reveal disease causing mutations. Conclusions:Haplotype analysis indicated that the genetic defect in this family does not overlap the DFNA13 and DFNA21 regions that are also located on 6p. Identification of the disease gene will be of major importance in understanding the pathophysiology of hearing impairment. PMID:14729819

Snoeckx, R; Kremer, H; Ensink, R; Flothmann, K; de Brouwer, A; Smith, R; Cremers, C; Van Camp, G

2004-01-01

269

Dissociation of Pupillary Post-Illumination Responses from Visual Function in Confirmed OPA1 c.983A?>?G and c.2708_2711delTTAG Autosomal Dominant Optic Atrophy  

PubMed Central

Purpose: To test whether the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs), as evaluated by examination of the pupillary light reflex (PLR), are preserved in genetically confirmed autosomal dominant optic atrophy (ADOA). Method: Twenty-nine patients with either the c.983A?>?G (n?=?14) or the c.2708_ 2711delTTAG mutation (n?=?15) were examined with monochromatic pupillometry, using isoluminant (300?cd/m2), red (660?nm) or blue (470?nm) light, optical coherence tomography, automated visual field analysis, and with determination of best corrected visual acuity (BCVA). Since we examined two different mutations, initially we compared all outcome variables between the two, and finding no statistically significant difference, pooled them. Results: Despite a poor BCVA (56 letters, ETDRS) in the ADOA patients, their post-illuminatory pupil responses did not differ significantly from those of healthy controls (blue, p?=?0.45, red, p?=?0.49, t-test), and no statistically significant effect was noted of peripapillary retinal nerve fiber layer thickness, ganglion cell-inner plexiform layer thickness, or age. Conclusion: The PLR to blue light of high luminance (300?cd/m2) was preserved in both c.983A?>?G and c.2708_2711delTTAG ADOA despite severe visual loss and optic nerve atrophy. The study confirms, in a large sample of two genetically homogenous groups, that the ipRGCs are spared in ADOA.

Nissen, Claus; Rönnbäck, Cecilia; Sander, Birgit; Herbst, Kristina; Milea, Dan; Larsen, Michael; Lund-Andersen, Henrik

2015-01-01

270

Genetics Home Reference: Autosomal dominant vitreoretinochoroidopathy  

MedlinePLUS

... a channel that transports charged chlorine atoms (chloride ions) across the cell membrane. Mutations in the BEST1 ... clear how these versions of bestrophin affect chloride ion transport or lead to the eye abnormalities characteristic ...

271

Amino Alcohol- (NPS-2143) and Quinazolinone-Derived Calcilytics (ATF936 and AXT914) Differentially Mitigate Excessive Signalling of Calcium-Sensing Receptor Mutants Causing Bartter Syndrome Type 5 and Autosomal Dominant Hypocalcemia  

PubMed Central

Introduction Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants. Methods All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914. Results All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants. Conclusion The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations. PMID:25506941

Letz, Saskia; Haag, Christine; Schulze, Egbert; Frank-Raue, Karin; Raue, Friedhelm; Hofner, Benjamin; Mayr, Bernhard; Schöfl, Christof

2014-01-01

272

Multi-electrode array study of neuronal cultures expressing nicotinic ?2-V287L subunits, linked to autosomal dominant nocturnal frontal lobe epilepsy. An in vitro model of spontaneous epilepsy  

PubMed Central

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial sleep-related epilepsy which can be caused by mutant neuronal nicotinic acetylcholine receptors (nAChR). We applied multi-electrode array (MEA) recording methods to study the spontaneous firing activity of neocortical cultures obtained from mice expressing or not (WT) an ADNFLE-linked nAChR subunit (?2-V287L). More than 100,000 up-states were recorded during experiments sampling from several thousand neurons. Data were analyzed by using a fast sliding-window procedure which computes histograms of the up-state durations. Differently from the WT, cultures expressing ?2-V287L displayed long (10–32 s) synaptic-induced up-state firing events. The occurrence of such long up-states was prevented by both negative (gabazine, penicillin G) and positive (benzodiazepines) modulators of GABAA receptors. Carbamazepine (CBZ), a drug of choice in ADNFLE patients, also inhibited the long up-states at micromolar concentrations. In cultures expressing ?2-V287L, no significant effect was observed on the action potential waveform either in the absence or in the presence of pharmacological treatment. Our results show that some aspects of the spontaneous hyperexcitability displayed by a murine model of a human channelopathy can be reproduced in neuronal cultures. In particular, our cultures represent an in vitro chronic model of spontaneous epileptiform activity, i.e., not requiring pre-treatment with convulsants. This opens the way to the study in vitro of the role of ?2-V287L on synaptic formation. Moreover, our neocortical cultures on MEA platforms allow to determine the effects of prolonged pharmacological treatment on spontaneous network hyperexcitability (which is impossible in the short-living brain slices). Methods such as the one we illustrate in the present paper should also considerably facilitate the preliminary screening of antiepileptic drugs (AEDs), thereby reducing the number of in vivo experiments. PMID:25104926

Gullo, Francesca; Manfredi, Irene; Lecchi, Marzia; Casari, Giorgio; Wanke, Enzo; Becchetti, Andrea

2014-01-01

273

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

274

Restriction fragment length polymorphism associated with the pro alpha 2(I) gene of human type I procollagen. Application to a family with an autosomal dominant form of osteogenesis imperfecta.  

PubMed Central

One cloned complementary DNA and one genomic subclone were used to detect restriction fragment length polymorphism associated with the pro alpha 2(I) gene for human type I procollagen. The restriction fragments obtained from examination of 30-122 chromosomes confirmed previous indications that the pro alpha 2(I) gene is found in a single copy in the human haploid genome. One highly polymorphic site was detected with EcoRI in the 5'-half of the gene. The restriction site polymorphism at the site had an allelic frequency of 0.38, and it generated two fragments of 10.5 and 3.5 kilobase in homozygous individuals. The restriction fragment length polymorphism generated at the EcoRI site was used to study affected and non-affected individuals in four generations of a family with an autosomal dominant form of osteogenesis imperfecta. The data demonstrated a linkage of the phenotype to a pro alpha 2(I) allele with a lod score of 2.41 at a recombination fraction (theta) of 0. The data therefore provided presumptive evidence that osteogenesis imperfecta in this family is caused by a mutation in the pro alpha 2(I) gene or some contiguous region of the genome. The relatively high frequency of polymorphism at the EcoRI site makes it useful for studying a broad range of genetic disorders in which mutations in type I procollagen are suspected. In addition, the polymorphic site should provide useful markers for linkage studies with other loci located on human chromosome 7. Images PMID:6313757

Tsipouras, P; Myers, J C; Ramirez, F; Prockop, D J

1983-01-01

275

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

276

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

277

Structurally abnormal human autosomes  

SciTech Connect

Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

NONE

1993-12-31

278

Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome.  

PubMed

Histone deacetylase 4 (HDAC4) serves important roles in multiple human systems, including neurological, cardiac, and skeletal functions. Mutation or deletion of HDAC4 causes brachydactyly mental retardation syndrome (BDMR), a disorder that includes intellectual disability, behavioral abnormalities, autism spectrum disorder, and craniofacial and skeletal anomalies, including brachydactyly type E. We present a case of familial BDMR, including a parent with mild symptoms of the disorder and a child exhibiting a more severe phenotype. Cytogenetic testing showed a cryptic balanced translocation in the mother that resulted in a 2q37.1 monosomy and a 10q26.1 trisomy in the son. Gene expression analyses demonstrated 67% HDAC4 expression in the mother and 23% HDAC4 expression in the son relative to normal controls, lending evidence to the hypothesis that HDAC4 modulates severity of this disorder in a dosage-dependent manner. PMID:22753018

Morris, Benjamin; Etoubleau, Cécile; Bourthoumieu, Sylvie; Reynaud-Perrine, Sandrine; Laroche, Cécile; Lebbar, Aziza; Yardin, Catherine; Elsea, Sarah H

2012-08-01

279

Brachydactyly and mental retardation: An Albright hereditary osteodystrophy-like syndrome localized to 2q37  

SciTech Connect

We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the {alpha} subunit of Gs (Gs{alpha}), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly. 28 refs., 6 figs., 1 tab.

Wilson, L.C. [Univ. of Leicester (United Kingdom)]|[Institute of Child Health, London (United Kingdom); Oude Luttikhuis, M.E.M. [Univ. of Leicester (United Kingdom); Duckett, D.P.; Barrow, M.A. [Leicestershire Genetics Centre, Leicester (United Kingdom); Leverton, K.; Read, A.P. [St. Mary`s Hospital, Manchester (United Kingdom); Oley, C.A.; Wolstenholme, J. [Univ. of Newcastle upon Tyne (United Kingdom); Flint, J. [Institute of Molecular Medicine, Oxford (United Kingdom); Leonard, J.V. [Institute of Child Health, London (United Kingdom)] [and others

1995-02-01

280

Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37.  

PubMed

We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the alpha subunit of Gs (Gs alpha), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly. PMID:7847374

Wilson, L C; Leverton, K; Oude Luttikhuis, M E; Oley, C A; Flint, J; Wolstenholme, J; Duckett, D P; Barrow, M A; Leonard, J V; Read, A P

1995-02-01

281

Dominant carpotarsal osteochondromatosis.  

PubMed Central

Dominant carpotarsal osteochondromatosis is a particular disorder of the wrist and tibiotalar joints with abnormal bone proliferation and osteochondromas. Two patients, a mother and son, are described here; a similar condition has previously been described in seven affected members of a family. The upper and the lower limbs are affected in the same patient and the lesion can be bilateral. Autosomal dominant inheritance is a further criterion allowing the diagnosis of dysplasia epiphysealis hemimelica. Images PMID:8411062

Maroteaux, P; Le Merrer, M; Bensahel, H; Freisinger, P

1993-01-01

282

The first familial case of inherited 2q37.3 interstitial deletion with isolated skeletal abnormalities including brachydactyly type E and short stature.  

PubMed

Albright hereditary osteodystrophy (AHO)-like syndrome is also known as brachydactyly-mental retardation syndrome (BDMR; OMIM 60040). This disorder includes intellectual disability in all patients, skeletal abnormalities, including brachydactyly E (BDE) in approximately half, obesity, and facial dysmorphism. Patients with 2q37 microdeletion or HDAC4 mutation are defined as having an AHO-like phenotype with normal stimulatory G (Gs) function. HDAC4 is involved in neurological, cardiac, and skeletal function. This paper reports the first familial case of 2q37.3 interstitial deletion affecting two genes, HDAC4 and TWIST2. Patients presented with BDE and short stature without intellectual disability, showing that haploinsufficiency of the HDAC4 critical region may lead to a spectrum of phenotypes, ranging from isolated brachydactyly type E to BDMR. © 2014 Wiley Periodicals, Inc. PMID:25402011

Jean-Marçais, Nolwenn; Decamp, Matthieu; Gérard, Marion; Ribault, Virginie; Andrieux, Joris; Kottler, Marie-Laure; Plessis, Ghislaine

2015-01-01

283

Congenital vocal cord paralysis with possible autosomal recessive inheritance: Case report and review of the literature  

SciTech Connect

We describe an infant with congenital vocal cord paralysis born to consanguineous parents. While autosomal dominant and X-linked inheritance have been previously reported in this condition, we conclude that the degree of parental consanguinity in this case strongly suggests autosomal recessive inheritance. Although we cannot exclude X-linked inheritance, evidence from animal studies demonstrates autosomal recessive inheritance and provides a possible molecular basis for congenital vocal cord paralysis. 14 refs., 1 fig.

Koppel, R.; Friedman, S.; Fallet, S. [Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY (United States)] [Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY (United States)

1996-08-23

284

The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations.  

PubMed Central

Functional characterization of a gene often requires the discovery of the full spectrum of its associated phenotypes. Mutations in the human GLI3 gene have been identified in Greig cepalopolysyndactyly, Pallister-Hall syndrome (PHS), and postaxial polydactyly type-A (PAP-A). We studied the involvement of GLI3 in additional phenotypes of digital abnormalities in one family (UR003) with preaxial polydactyly type-IV (PPD-IV), three families (UR014, UR015, and UR016) with dominant PAP-A/B (with PPD-A and -B in the same family), and one family with PHS. Linkage analysis showed no recombination with GLI3-linked polymorphisms. Family UR003 had a 1-nt frameshift insertion, resulting in a truncated protein of 1,245 amino acids. A frameshift mutation due to a 1-nt deletion was found in family UR014, resulting in a truncated protein of 1,280 amino acids. Family UR015 had a nonsense mutation, R643X, and family UR016 had a missense mutation, G727R, in a highly conserved amino acid of domain 3. The patient with PHS had a nonsense mutation, E1147X. These results add two phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-IV. These mutations do not support the suggested association between the mutations in GLI3 and the resulting phenotypes. We propose that all phenotypes associated with GLI3 mutations be called "GLI3 morphopathies," since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation. PMID:10441570

Radhakrishna, U; Bornholdt, D; Scott, H S; Patel, U C; Rossier, C; Engel, H; Bottani, A; Chandal, D; Blouin, J L; Solanki, J V; Grzeschik, K H; Antonarakis, S E

1999-01-01

285

Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology  

Microsoft Academic Search

Background—Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. Methods and Results—We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance

Timothy M. Olson; Margaret L. Karst; Frank G. Whitby; David J. Driscoll

2010-01-01

286

Genetics Home Reference: Autosomal dominant partial epilepsy with auditory features  

MedlinePLUS

... suddenly become unable to understand language before losing consciousness during a seizure. This inability to understand speech ... seizures, which do not cause a loss of consciousness. These seizures are thought to begin in a ...

287

[Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy].  

PubMed

CADASIL is an inherited small vessel disease of the brain caused by mutations of the NOTCH3 gene encoding a receptor of smooth muscle cells and pericytes within the wall of arterioles and capillaries. The mutated gene is responsible for accumulation of NOTCH3 protein and aggregation of various proteins in the vascular wall. The disease occurs during mid-adulthood and is responsible for attacks of migraine with aura, ischemic stroke, mood disorders and cognitive impairment ranging from mild alterations of attentional performances and executive functions to severe dementia. The disease develops in adults with aging and is responsible at the latest stage of gait and balance troubles associated with cognitive impairment that may lead to severe disability and dependence. MRI shows widespread white matter lesions that may involve the anterior part of temporal lobes often associated with small cerebral infarcts and with microbleeds. The clinical severity is related to accumulation of small infarcts and the development of cerebral atrophy over time. The diagnosis of the disease is confirmed by genetic testing or skin biopsy. PMID:24939405

Chabriat, Hugues

2014-06-01

288

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts and Leukoencephalopathy (CADASIL)  

MedlinePLUS

... such as diabetes and heart disease as a prophylactic (preventative) medication. In the event of an acute ... improved concentration and attention. Other forms of supportive therapies such as physicial therapy and speech therapy are ...

289

Genetics Home Reference: Autosomal dominant nocturnal frontal lobe epilepsy  

MedlinePLUS

... psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear whether these additional features are directly related to epilepsy in these individuals. How common is ADNFLE? ADNFLE ...

290

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

291

Dominant inheritance of Scheuermann's juvenile kyphosis.  

PubMed Central

We report a family in which Scheuermann's juvenile kyphosis is present in three successive generations with male to male transmission. This provides further evidence for autosomal dominant inheritance in at least some families with this condition. Images PMID:2738903

Findlay, A; Conner, A N; Connor, J M

1989-01-01

292

Autosomal Recessive Osteopetrosis in Chuvashiya  

Microsoft Academic Search

A genetic epidemiological study of osteopetrosis was carried out in Chuvashiya. The major signs of this disorder are severe anemia developed in the prenatal or early postnatal life, hepatosplenomegaly, and a progressive loss of sight and hearing. Osteopetrosis showed the autosomal recessive inheritance with a somewhat increased proportion of affected patients in families. The lowest estimate of osteopetrosis frequency in

E. K. Ginter; A. G. Kirillov; E. I. Rogaev

2001-01-01

293

Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B  

PubMed Central

Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a. Wnt5a/Ror2 can activate multiple branches of non-canonical Wnt signaling, but it is unclear which branch(es) mediates Wnt5a/Ror2 function in limb skeletal development. Here, we provide evidence implicating the planar cell polarity (PCP) pathway as the downstream component of Wnt5a in the limb. We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges. Halving the dosage of Wnt5a in Vangl2 mutants enhances the severity and penetrance of the digit defects and causes long bone defects reminiscent of RRS, suggesting that Wnt5a and Vangl2 function in the same pathway and disruption of PCP signaling may underlie both BDB1 and RRS. Consistent with a role for PCP signaling in tissue morphogenesis, mutation of Vangl2 alters the shape and dimensions of early limb buds: the width and thickness are increased, whereas the length is decreased. The digit pre-chondrogenic condensates also become wider, thicker and shorter. Interestingly, altered limb bud dimensions in Vangl2 mutants also affect limb growth by perturbing the signaling network that regulates the balance between Fgf and Bmp signaling. Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect. These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS. PMID:20962035

Wang, Bing; Sinha, Tanvi; Jiao, Kai; Serra, Rosa; Wang, Jianbo

2011-01-01

294

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

295

A family with spondyloepimetaphyseal dwarfism: a 'new' dysplasia or Kniest disease with autosomal recessive inheritance?  

PubMed Central

We present an Arab family with some features of Kniest disease. The proband was a six year old boy with rhizomelic short limbed dwarfism, 'dish-like' facies, cleft palate, deafness, and camptodactyly. Most radiological changes were compatible with Kniest disease. Two younger sibs, similarly affected, had died at a few months old, and the pedigree shows strong evidence of autosomal recessive inheritance, unlike previously reported cases of Kniest disease which have shown autosomal dominant inheritance. Images PMID:3681904

Farag, T I; Al-Awadi, S A; Hunt, M C; Satyanath, S; Zahran, M; Usha, R; Uma, R

1987-01-01

296

Loss of CHSY1, a Secreted FRINGE Enzyme, Causes Syndromic Brachydactyly in Humans via Increased NOTCH Signaling  

PubMed Central

We delineated a syndromic recessive preaxial brachydactyly with partial duplication of proximal phalanges to 16.8 Mb over 4 chromosomes. High-throughput sequencing of all 177 candidate genes detected a truncating frameshift mutation in the gene CHSY1 encoding a chondroitin synthase with a Fringe domain. CHSY1 was secreted from patients' fibroblasts and was required for synthesis of chondroitin sulfate moieties. Noticeably, its absence triggered massive production of JAG1 and subsequent NOTCH activation, which could only be reversed with a wild-type but not a Fringe catalytically dead CHSY1 construct. In vitro, depletion of CHSY1 by RNAi knockdown resulted in enhanced osteogenesis in fetal osteoblasts and remarkable upregulation of JAG2 in glioblastoma cells. In vivo, chsy1 knockdown in zebrafish embryos partially phenocopied the human disorder; it increased NOTCH output and impaired skeletal, pectoral-fin, and retinal development. We conclude that CHSY1 is a secreted FRINGE enzyme required for adjustment of NOTCH signaling throughout human and fish embryogenesis and particularly during limb patterning. PMID:21129727

Tian, Jing; Ling, Ling; Shboul, Mohammad; Lee, Hane; O'Connor, Brian; Merriman, Barry; Nelson, Stanley F.; Cool, Simon; Ababneh, Osama H.; Al-Hadidy, Azmy; Masri, Amira; Hamamy, Hanan; Reversade, Bruno

2010-01-01

297

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

298

Connexin 26 gene linked to a dominant deafness  

Microsoft Academic Search

A high proportion of all cases of congenital deafness is causedby mutations in a gene coding for a gap-junction protein,connexin 26. The deafness associated with this gene, Cx26, is the autosomal recessive form, DFNB1(refs ref. 1-3) its involvement in autosomal dominant forms of deafness has remained controversial. Here we show that a mutation in Cx26 underlies the dominant form of

Françoise Denoyelle; Genevieve Lina-Granade; Henri Plauchu; Roberto Bruzzone; Hassan Chaïb; Fabienne Lévi-Acobas; Dominique Weil; Christine Petit

1998-01-01

299

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

300

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

301

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

302

Genetics Home Reference: Autosomal recessive hypotrichosis  

MedlinePLUS

... can compensate for the function of the missing protein, so not all areas with hair are affected ... condition is inherited in an autosomal recessive pattern, which means both copies of the gene in ...

303

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

304

Behavioral Retardation in a Macaque with Autosomal Trisomy and Aging Mother.  

ERIC Educational Resources Information Center

The social development of a female rhesus monkey was followed from birth until death, age 32 months. The monkey had an extra autosome and was hydrocephalic. The monkey showed serious motor deficiencies, delayed social development, poorly established dominance relationships, and heavy dependence on mother and kin. The monkey was, however, well…

Waal, Frans B. M. de; And Others

1996-01-01

305

Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX.  

PubMed

Mutations in the Senataxin gene (SETX) are associated with autosomal recessive ataxia-ocular apraxia 2 (AOA2) and autosomal dominant juvenile ALS (ALS4). Here, the authors describe novel homozygous missense mutations in SETX, M274I, and R1294C, found in two siblings with ataxia, peripheral neuropathy, and increased serum alpha-fetoprotein level and three other siblings with heterozygous missense mutations who were neurologically asymptomatic. The results demonstrate that the double missense mutations are responsible for AOA2 but not for ALS4. PMID:16717225

Asaka, T; Yokoji, H; Ito, J; Yamaguchi, K; Matsushima, A

2006-05-23

306

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

307

Sequential Dominance  

E-print Network

We review the mechanism of sequential right-handed neutrino dominance proposed in the framework of the type I see-saw mechanism to account for bi-large neutrino mixing and a neutrino mass hierarchy in a natural way. We discuss how sequential dominance may also be applied to the right-handed charged leptons, which alternatively allows bi-large lepton mixing from the charged lepton sector. We review how such sequential dominance models may be upgraded to include type II see-saw contributions, resulting in a partially degenerate neutrino mass spectrum with bi-large lepton mixing arising from sequential dominance. We also summarise the model building applications and the phenomenological implications of sequential dominance.

Stefan Antusch; S. F. King

2004-05-27

308

Recessive anonychia totalis and dominant aplasia (or hypoplasia) of upper lateral incisors in the same kindred  

Microsoft Academic Search

This paper describes and discusses the occurrence of 2 genetic traits, autosomal recessive anonychia and autosomal dominant hypoplasia of the upper lateral incisors (ULI) in 4 (2 males and 2 females) members of 2 sibships of the same kindred. Three of them also had spaced teeth and agenesis of one or more third molars. Anonychia was also present in another

N. Freire-Maia; Marta Pinheiro

1979-01-01

309

Clinical Impact of Proximal Autosomal Imbalances  

PubMed Central

Centromere-near gain of copy number can be induced by intra- or inter-chromosomal rearrangements or by the presence of a small supernumerary marker chromosome (sSMC). Interestingly, partial trisomy to hexasomy of euchromatic material may be present in clinically healthy or affected individuals, depending on origin and size of chromosomal material involved. Here we report the known minimal sizes of all centromere-near, i.e., proximal auto-somal regions in humans, which are tolerated; over 100 Mb of coding DNA are comprised in these regions. Additionally, we have summarized the typical symptoms for nine proximal autosomal regions including genes obviously sensitive to copy numbers. Overall, studying the carriers of specific chromosomal imbalances using genomics-based medicine, combined with single cell analysis can provide the genotype-phenotype correlations and can also give hints where copy-number-sensitive genes are located in the human genome. PMID:24052727

Hamid, AB; Weise, A; Voigt, M; Bucksch, M; Kosyakova, N; Liehr, T; Klein, E

2012-01-01

310

VSX2 mutations in autosomal recessive microphthalmia  

PubMed Central

Purpose To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia. Methods We screened 95 probands with syndromic or isolated developmental ocular conditions (including 55 with anophthalmia/microphthalmia) for mutations in VSX2. Results Homozygous mutations in VSX2 were identified in two out of five consanguineous families with isolated microphthalmia. A novel missense mutation, c.668G>C (p.G223A), was identified in a large Pakistani family with multiple sibships affected with bilateral microphthalmia. This p.G223A mutation affects the conserved CVC motif that was shown to be important for DNA binding and repression activities of VSX2. The second mutation, c.249delG (p.Leu84SerfsX57), was identified in an Iranian family with microphthalmia; this mutation has been previously reported and is predicted to generate a severely truncated mutant protein completely lacking the VSX2 homeodomain, CVC domain and COOH-terminal regions. Conclusions Mutations in VSX2 represent an important cause of autosomal recessive microphthalmia in consanguineous pedigrees. Identification of a second missense mutation in the CVC motif emphasizes the importance of this region for normal VSX2 function. PMID:21976963

Reis, Linda M.; Khan, Ayesha; Kariminejad, Ariana; Ebadi, Farhad; Tyler, Rebecca C.

2011-01-01

311

Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations  

SciTech Connect

With the evidence that deletions in the region responsible for childhood- and juvenile-onset proximal spinal muscular atrophy (SMA) are on chromosome 5 it is now possible to confirm autosomal recessive inheritance in most patients (denoted {open_quotes}SMA 5q{close_quotes}). Homozygous deletions in the telomeric copy of the survival motor neuron (SMN) gene can be detected in 95%-98% of patients with early-onset SMA (types I and II), whereas as many as 10%-20% of patients with the milder, juvenile-onset form (type III SMA) do not show deletions. In families with affected subjects in two generations, it is difficult to decide whether they are autosomal dominantly inherited or caused by three independent recessive mutations (pseudodominant inheritance). Given an incidence of >1/10,000 of SMA 5q, patients with autosomal recessive SMA have an {approximately}1% recurrence risk to their offspring. Although the dominant forms are not linked to chromosome 5q, pseudodominant families can now be identified by the presence of homozygous deletions in the SMN gene. 5 refs., 1 fig., 1 tab.

Rudnik-Schoeneborn, S.; Zerres, K.; Hahnen, E. [Bonn Univ. (Germany)] [and others

1996-11-01

312

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

313

The spreading of X inactivation into autosomal material of an x;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA.  

PubMed Central

X inactivation involves initiation, propagation, and maintenance of genetic inactivation. Studies of replication timing in X;autosome translocations have suggested that X inactivation may spread into adjacent autosomal DNA. To examine the inactivation of autosomal material at the molecular level, we assessed the transcriptional activity of X-linked and autosomal loci spanning an inactive translocation in a phenotypically normal female with a karyotype of 46,X,der(X)t(X;4)(q22;q24). Since 4q duplications usually manifest dysmorphic features and severe growth and mental retardation, the normal phenotype of this individual suggested the spreading of X inactivation throughout the autosomal material. Consistent with this model, reverse transcription-PCR analysis of 20 transcribed sequences spanning 4q24-qter revealed that three known genes and 11 expressed sequence tags (ESTs) were not expressed in a somatic-cell hybrid that carries the translocation chromosome. However, three ESTs and three known genes were expressed from the t(X;4) chromosome and thus "escaped" X inactivation. This direct assay of expression demonstrated that the spreading of inactivation from the adjoining X chromosome was incomplete and noncontiguous. These findings are broadly consistent with the existence of genes known to escape inactivation on normal inactive X chromosomes. However, the fact that a high proportion (30%) of tested autosomal genes escaped inactivation may indicate that autosomal material lacks X chromosome-specific features that are associated with the spreading and/or maintenance of inactivation. PMID:9634520

White, W M; Willard, H F; Van Dyke, D L; Wolff, D J

1998-01-01

314

[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

315

On identification problems requiring linked autosomal markers.  

PubMed

This paper considers identification problems based on DNA marker data. The topics we discuss are general, but we will exemplify them in a simple context. There is DNA available from two persons. There is uncertainty about the relationship between the two individuals and a number of hypotheses describing the possible relationship is available. The task is to determine the most likely pedigree. This problem is fairly standard. However, there are some problems that cannot be solved using DNA from independently segregating loci. For example, the likelihoods for (i) grandparent-grandchild, (ii) uncle-niece and (iii) half-sibs coincide for such DNA data and so these relations cannot be distinguished on the basis of markers normally used for forensic identification problems: the likelihood ratio comparing any pair of hypotheses will be unity. Sometimes, but not in the examples we consider, other sources of DNA like mtDNA or sex chromosomes can help to distinguish between such equally likely possibilities. Prior information can likewise be of use. For instance, age information can exclude alternative (i) above and also indicate that alternative (iii) is apriori more likely than alternative (ii). More generally, the above problems can be solved using linked autosomal markers. To study the problem in detail and understand how linkage works in this regard, we derive an explicit formula for a pair of linked markers. The formula extends to independent pairs of linked markers. While this approach adds to the understanding of the problem, more markers are required to obtain satisfactory results and then the Lander-Green algorithm is needed. Simulation experiments are presented based on a range of scenarios and we conclude that useful results can be obtained using available freeware (MERLIN and R). The main message of this paper is that linked autosomal markers deserve greater attention in forensic genetics and that the required laboratory and statistical analyses can be performed based on existing technology and freeware. PMID:19083824

Egeland, Thore; Sheehan, Nuala

2008-06-01

316

A balancing act between the X chromosome and the autosomes  

PubMed Central

Dosage compensation equalizes gene dosage between males and females, but its role in balancing expression between the X chromosome and the autosomes may be far more important. Now, DNA microarrays have shown equality between the average expression of X-linked genes and that of autosomal genes, in male and female tissues of flies, worms and mice. PMID:16515717

Cheng, Mimi K; Disteche, Christine M

2006-01-01

317

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

318

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.  

PubMed

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for ?80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP. PMID:24473461

Khan, Tahir Naeem; Klar, Joakim; Tariq, Muhammad; Anjum Baig, Shehla; Malik, Naveed Altaf; Yousaf, Raja; Baig, Shahid Mahmood; Dahl, Niklas

2014-10-01

319

Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.  

PubMed

The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT. PMID:23781959

Tazir, Meriem; Bellatache, Mounia; Nouioua, Sonia; Vallat, Jean-Michel

2013-06-01

320

A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta.  

PubMed

Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene. PMID:24835313

Rubinato, Elisa; Morgan, Anna; D'Eustacchio, Angela; Pecile, Vanna; Gortani, Giulia; Gasparini, Paolo; Faletra, Flavio

2014-07-25

321

Brachmann-de Lange syndrome: Autosomal dominant inheritance and male-to-male transmission  

SciTech Connect

We report on familial occurrence of the Brachmann-de Lange syndrome (BDLS): a mildly affected father and his severely affected son and daughter who have different mothers. Both children are severely affected while the father has a much milder but definite BDLS phenotype. Our report documents the third example of male-to-male transmission and adds to the argument against exclusively maternal transmission in familial cases. In addition, our findings illustrate the occurrence of severe manifestations in cases of familial BDLS. 29 refs., 3 figs.

McKenney, R.R.; Elder, F.F.B.; Northrup, H.; Garcia, J. [Univ. of Texas Health Science Center, Houston, TX (United States)] [Univ. of Texas Health Science Center, Houston, TX (United States)

1996-12-30

322

Audiometric characterization of a family with digenic autosomal, dominant, progressive sensorineural hearing loss.  

PubMed

In this study, a non-syndromic progressive bilateral high frequency hearing loss is described in a family with 141 identified members. Recent genetic analyses indicated a digenic inheritance with linkage to the gene loci DFNA2 and DFNA12. The affected family members who shared haplotypes at both loci (type I) showed an early postlingual onset and a more rapid rate of progress compared with those with one either of the two disease associated haplotypes (type II). The audiometric pattern was cochlear without a vestibular involvement. Auditory brainstem response audiometry and magnetic resonance imaging indicated normal retrocochlear features. The otoacoustic emissions were affected for both type I and type II, whereas the acoustic stapedius reflex thresholds were normal in most cases. It is concluded that both types had an outer hair cell/micro-mechanical abnormality, but that the DFNA 2 type might have an additional dysfunction at the level of the inner hair cells. It is furthermore pointed out that the application of refined audiometric techniques as well as a further development of new techniques is needed in order to characterize the phenotypes of the rapidly expanding number of genetically defined inner ear abnormalities. PMID:10779186

Borg, E; Samuelsson, E; Dahl, N

2000-01-01

323

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

324

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

325

In cis autosomal dominant mutation of Senataxin associated with tremor\\/ataxia syndrome  

Microsoft Academic Search

Senataxin mutations are the molecular basis of two distinct syndromes: (1) ataxia oculomotor apraxia type 2 (AOA2) and (2) juvenile\\u000a amyotrophic lateral sclerosis 4 (ALS4). The authors describe clinical and molecular genetic studies of mother and daughter\\u000a who display symptoms of cerebellar ataxia\\/atrophy, oculomotor defects, and tremor. Both patients share Senataxin mutations N603D and Q653K in cis (N603D–Q653K), adjacent to

A. G. Bassuk; Y. Z. Chen; S. D. Batish; N. Nagan; P. Opal; P. F. Chance; C. L. Bennett

2007-01-01

326

Genetic Heterogeneity in Autosomal Dominant Pseudohypoaldosteronism Type I: Exclusion of Claudin-8 as a Candidate Gene  

Microsoft Academic Search

Background\\/Aims: Pseudohypoaldosteronism type I (PHAI) is an inherited disorder characterized by renal salt wasting, hyperkalemic metabolic acidosis, and hyperaldosteronism. Its known causes are mutations in the mineralocorticoid receptor and the epithelial sodium channel (ENaC), but there are reports of genetic heterogeneity. Claudin-8 is a tight junction protein that acts as a paracellular cation barrier in the distal nephron. The aim

Catherine L. Huey; Felix G. Riepe; Wolfgang G. Sippell; Alan S. L. Yu

2004-01-01

327

Linkage between Rh blood group and autosomal dominant retinitis pigmentosa in ten Chinese families.  

PubMed

Since Fei et al reported a tentative linkage between ADRP and the Rhesus(Rh) blood group in the unrelated Chinese families in 1987, additional individuals of these ADRP families have been typed for Rh. Further linkage analysis with the LIPED Program on the Rh data of the ten ADRP families showed a maximum summed LOD score of 2.01 at theta = 0.12, which is a further suggestion of linkage between ADRP and Rh. However, genetic heterogeneity certainly exists in these families. It is our presumption that ADRP in those families, which do not exhibit linkage to 3q markers, may map to the short arm of chromosome 1. PMID:1451549

Fei, Y J; Blanton, S H; Daiger, S P; Luo, C R

1992-06-01

328

Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal degeneration.  

PubMed

Snowflake vitreoretinal degeneration (SVD, MIM 193230) is a developmental and progressive hereditary eye disorder that affects multiple tissues within the eye. Diagnostic features of SVD include fibrillar degeneration of the vitreous humor, early-onset cataract, minute crystalline deposits in the neurosensory retina, and retinal detachment. A genome-wide scan previously localized the genetic locus for SVD to a 20 Mb region flanked by D2S2158 and D2S2202. This region contains 59 genes, of which 20 were sequenced, disclosing a heterozygous mutation (484C > T, R162W) in KCNJ13, member 13 of subfamily J of the potassium inwardly rectifying channel family in all affected individuals. The mutation in KCNJ13, the gene encoding Kir7.1, was not present in unaffected family members and 210 control individuals. Kir7.1 localized to human retina and retinal pigment epithelium and was especially prevalent in the internal limiting membrane adjacent to the vitreous body. Molecular modeling of this mutation predicted disruption of the structure of the potassium channel in the closed state located immediately adjacent to the cell-membrane inner boundary. Functionally, unlike wild-type Kir7.1 whose overexpression in CHO-K1 cells line produces highly selective potassium current, overexpression of R162W mutant Kir7.1 produces a nonselective cation current that depolarizes transfected cells and increases their fragility. These results indicate that the KCNJ13 R162W mutation can cause SVD and further show that vitreoretinal degeneration can arise through mutations in genes whose products are not structural components of the vitreous. PMID:18179896

Hejtmancik, J Fielding; Jiao, Xiaodong; Li, Anren; Sergeev, Yuri V; Ding, Xiaoyan; Sharma, Anil K; Chan, Chi-Chao; Medina, Igor; Edwards, Albert O

2008-01-01

329

Autosomal dominant tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome: report of a Brazilian family.  

PubMed

We report on 3 persons in a 3-generation Brazilian family affected with complex limb defects. The spectrum of limb anomalies ranged from isolated toe syndactyly to severe bilateral tibial aplasia. Radioulnar synostosis was present in 2 of the 3 patients. Clinical and genetic aspects are discussed. PMID:2333896

Richieri-Costa, A; de Miranda, E; Kamiya, T Y; Freire-Maia, D V

1990-05-01

330

Genetics Home Reference: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy  

MedlinePLUS

... matter that can be seen with magnetic resonance imaging (MRI). The age at which the signs and ... cholesterol ; dementia ; epilepsy ; familial ; gene ; heart attack ; hereditary ; imaging ; infarct ; inherited ; leukoencephalopathy ; magnetic resonance imaging ; muscle cells ; ...

331

LMNA-Associated Cardiocutaneous Progeria: a Novel Autosomal Dominant Premature Aging Syndrome with Late Onset  

PubMed Central

Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. PMID:23666920

Kane, Megan S.; Lindsay, Mark E.; Judge, Daniel P.; Barrowman, Jemima; Rhys, Colette Ap; Simonson, Lisa; Dietz, Harry C.; Michaelis, Susan

2013-01-01

332

Mutations in SCO2 Are Associated with Autosomal-Dominant High-Grade Myopia  

PubMed Central

Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than ?6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of ?22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a ?15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development. PMID:23643385

Tran-Viet, Khanh-Nhat; Powell, Caldwell; Barathi, Veluchamy A.; Klemm, Thomas; Maurer-Stroh, Sebastian; Limviphuvadh, Vachiranee; Soler, Vincent; Ho, Candice; Yanovitch, Tammy; Schneider, Georg; Li, Yi-Ju; Nading, Erica; Metlapally, Ravikanth; Saw, Seang-Mei; Goh, Liang; Rozen, Steve; Young, Terri L.

2013-01-01

333

A Novel HSF4 Gene Mutation Causes Autosomal-Dominant Cataracts in a Chinese Family  

PubMed Central

Congenital cataracts are a significant cause of visual impairment or blindness in children. One-third of cases estimated to have a genetic cause. We carried out gene analysis and bioinformatics analysis to map the locus and to identify the underlying genetic defect in a 12-member, four-generation Chinese family affected with bilateral congenital cataracts. We screened individuals of the family and discovered a distinct missense mutation in HSF4 (a gene at this locus that encodes teat-shock transcription factor 4). Bioinformatics analysis was used to determine possible changes in the protein structure that could affect the phenotype. Sequencing of the candidate genes showed a heterozygous c.69 G?T change in the heat shock transcription factor 4 (HSF4) gene, which resulted in the substitution of a lysine with an asparagine (p. K23N). This mutation cosegregated with all affected individuals and was not observed in unaffected family members. Bioinformatics analysis indicated that the p. K23N mutation was predicted to be disease causing. This is the first report of the novel missense mutation, c.69 G?T (p. K23N), in exon 3 of the HSF4 locus on 16q21-q22 associated with bilateral congenital cataracts in a Chinese family. This novel mutation could enable propergenetic diagnostics and counseling in affected families and could lead to a better understanding of the structure and function of HSF4 in health and disease. PMID:24637349

Lv, Huibin; Huang, Chen; Zhang, Jing; Liu, Ziyuan; Zhang, Zhike; Xu, Haining; You, Yuchen; Hu, Jinping; Li, Xuemin; Wang, Wei

2014-01-01

334

Autosomal and X-chromosome imprinting.  

PubMed

Mouse genetic studies using Robertsonian and reciprocal translocations have shown that certain autosomal regions of loci are subject to a parental germ line imprint, which renders maternal and paternal copies functionally inequivalent in the embryo or later stages of development. Duplication of maternal or paternal copies with corresponding paternal/maternal deficiencies in chromosomally balanced zygotes causes various effects. These range from early embryonic lethalities through to mid-fetal and neonatal lethalities, and in some instances viable young with phenotypic effects are obtained. Eight to nine chromosomal regions that give such imprinting effects have been identified. Six to seven of these regions are located in only three chromosomes (2, 7 and 17). The two other regions are located in chromosomes 6 and 11. Maternal and paternal disomies for each of four other chromosomes (1, 5, 9 and 14) have been recovered with different frequencies, but the possibility that this may be due to imprinting has yet to be supported by follow-up studies on regions of the chromosomes concerned. No clear evidence of genetic-background modifications of the imprinting process have been observed in these mouse genetic experiments. The mammalian X chromosome is also subject to imprinting, as demonstrated by the non-random, paternal X-inactivation in female mouse extra-embryonic tissues and in the somatic cells of marsupial females. There is also the opposite bias towards inactivation of the maternal X in the somatic cells of female mice.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2090432

Cattanach, B M; Beechey, C V

1990-01-01

335

Other autosomal recessive and childhood ataxias.  

PubMed

The label of "early-onset cerebellar ataxia with retained tendon reflexes" (EOCA) has been created to differentiate it from Friedreich ataxia (FRDA) patients with preserved knee jerks and absence of cardiomyopathy, optic atrophy, and diabetes mellitus. However, EOCA is a heterogeneous syndrome and several FRDA patients present with an EOCA-like phenotype. Cerebellar ataxia with hypogonadism is another heterogeneous syndrome for which no locus has been mapped yet. Two peculiar ataxic syndromes have been identified in genetically isolated populations: autosomal recessive ataxia of Charlevoix-Saguenay (ARSACS) in Quebec and infantile-onset spinocerebellar ataxia (IOSCA) in Finland. Both conditions present usually within the second year of life. ARSACS is characterized by marked spasticity and IOSCA by a complex phenotype which includes, besides ataxia, epilepsy, optic atrophy, ophthalmoplegia, hearing loss, and areflexia. The responsible genes are SACS, encoding sacsin, a protein which may act as a chaperone, and C10orf2, encoding Twinkle, a mitochondrial DNA-specific helicase. Marinesco-Sjögren syndrome, clinically characterized by cerebellar ataxia, cataracts, myopathy, and mental retardation, is genetically heterogeneous. One gene, SIL1, encodes a nucleotide exchange factor for the heat-shock protein 70 chaperone HSPA5. Five conditions account for most cases of progressive myoclonic ataxia: Unverricht-Lundborg disease, Lafora disease, myoclonic epilepsy with ragged-red fibers, neuronal ceroid lipofuscinoses, and sialidoses. PMID:21827899

De Michele, Giuseppe; Filla, Alessandro

2012-01-01

336

A Novel Autosomal Recessive GJA1 Missense Mutation Linked to Craniometaphyseal Dysplasia  

PubMed Central

Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder with progressive hyperostosis of craniofacial bones. CMD can be inherited in an autosomal dominant (AD) trait or occur after de novo mutations in the pyrophosphate transporter ANKH. Although the autosomal recessive (AR) form of CMD had been mapped to 6q21-22 the mutation has been elusive. In this study, we performed whole-exome sequencing for one subject with AR CMD and identified a novel missense mutation (c.716G>A, p.Arg239Gln) in the C-terminus of the gap junction protein alpha-1 (GJA1) coding for connexin 43 (Cx43). We confirmed this mutation in 6 individuals from 3 additional families. The homozygous mutation cosegregated only with affected family members. Connexin 43 is a major component of gap junctions in osteoblasts, osteocytes, osteoclasts and chondrocytes. Gap junctions are responsible for the diffusion of low molecular weight molecules between cells. Mutations in Cx43 cause several dominant and recessive disorders involving developmental abnormalities of bone such as dominant and recessive oculodentodigital dysplasia (ODDD; MIM #164200, 257850) and isolated syndactyly type III (MIM #186100), the characteristic digital anomaly in ODDD. However, characteristic ocular and dental features of ODDD as well as syndactyly are absent in patients with the recessive Arg239Gln Cx43 mutation. Bone remodeling mechanisms disrupted by this novel Cx43 mutation remain to be elucidated. PMID:23951358

Hu, Ying; Chen, I-Ping; de Almeida, Salome; Tiziani, Valdenize; Do Amaral, Cassio M. Raposo; Gowrishankar, Kalpana; Passos-Bueno, Maria Rita; Reichenberger, Ernst J.

2013-01-01

337

AIPL1 implicated in the pathogenesis of two cases of autosomal recessive retinal degeneration  

PubMed Central

Purpose To localize and identify the gene and mutations causing autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Methods Consanguineous families from Pakistan were ascertained to be affected with autosomal recessive retinal degeneration. All affected individuals underwent thorough ophthalmologic examinations. Blood samples were collected, and genomic DNA was extracted using a salting out procedure. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point linkage analysis was performed with the lod score method. Direct DNA sequencing of amplified genomic DNA was performed for mutation screening of candidate genes. Results Genome-wide linkage scans yielded a lod score of 3.05 at ?=0 for D17S1832 and 3.82 at ?=0 for D17S938, localizing the disease gene to a 12.22 cM (6.64 Mb) region flanked by D17S1828 and D17S1852 for family 61032 and family 61227, which contains aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), a gene previously implicated in recessive Leber congenital amaurosis and autosomal dominant cone-rod dystrophy. Sequencing of AIPL1 showed a homozygous c.773G>C (p.Arg258Pro) sequence change in all affected individuals of family 61032 and a homozygous c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Conclusions The results strongly suggest that the c.773G>C (p.R258P) and c.465G>T (p.(H93_Q155del)) mutations in AIPL1 cause autosomal recessive retinal degeneration in these consanguineous Pakistani families. PMID:24426771

Li, David; Jin, Chongfei; Jiao, Xiaodong; Li, Lin; Bushra, Tahmina; Naeem, Muhammad Asif; Butt, Nadeem H.; Husnain, Tayyab; Sieving, Paul A.; Riazuddin, Sheikh; Riazuddin, S. Amer

2014-01-01

338

Molecular mechanisms of autosomal recessive hypercholesterolemia.  

PubMed

Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation. LDL uptake by the LDL receptor (LDLR) is markedly reduced in the liver but is normal or only moderately impaired in cultured fibroblasts of ARH patients. To define the molecular mechanism underlying ARH we examined ARH mRNA and protein in fibroblasts and lymphocytes from six probands with different ARH mutations. None of the probands had detectable full-length ARH protein in fibroblasts or lymphoblasts. Five probands were homozygous for mutations that introduced premature termination codons. No relationship was apparent between the site of the mutation in ARH and the amount of mRNA. The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA. (125)I-LDL degradation was normal in ARH fibroblasts, as previously reported. In contrast, LDLR function was markedly reduced in ARH lymphoblasts, despite a 2-fold increase in LDL cell surface binding in these cells. These data indicate that all ARH mutations characterized to date preclude the synthesis of full-length ARH and that ARH is required for normal LDLR function in lymphocytes and hepatocytes, but not in fibroblasts. Residual LDLR function in cells that do not require ARH may explain why ARH patients have lower plasma LDL levels than do patients with homozygous familial hypercholesterolemia who have no functional LDLRs. PMID:12417523

Wilund, Kenneth R; Yi, Ming; Campagna, Filomena; Arca, Marcello; Zuliani, Giovanni; Fellin, Renato; Ho, Yiu-Kee; Garcia, J Victor; Hobbs, Helen H; Cohen, Jonathan C

2002-11-15

339

Genetics Home Reference: Autosomal recessive axonal neuropathy with neuromyotonia  

MedlinePLUS

... Patients and Families Resources for Health Professionals What glossary definitions help with understanding autosomal recessive axonal neuropathy ... many other terms in the Genetics Home Reference Glossary . See also Understanding Medical Terminology . References (4 links) ...

340

The autosomal recessively inherited progressive myoclonus epilepsies and their genes.  

PubMed

Autosomal recessively inherited progressive myoclonus epilepsies (PMEs) include Lafora disease, Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, type I sialidosis (cherry-red spot myoclonus), action myoclonus-renal failure syndrome, and type III Gaucher disease. Almost all the autosomal recessively inherited PMEs are lysosomal diseases, with the exception of Lafora disease in which neither the accumulating material nor the gene products are in lysosomes. Progress in identifying the causative defects of PME is near-complete. Much work lies ahead to resolve the pathobiology and neurophysiology of this group of devastating disorders. PMID:19469843

Ramachandran, Nivetha; Girard, Jean-Marie; Turnbull, Julie; Minassian, Berge A

2009-05-01

341

A Lebanese family with autosomal recessive oculo-auriculo-vertebral (OAV) spectrum and review of the literature: is OAV a genetically heterogeneous disorder?  

PubMed Central

Oculo-auriculo-vertebral (OAV) spectrum summarizes a continuum of ocular, auricular, and vertebral anomalies. Goldenhar syndrome is a variant of this spectrum and is characterized by pre-auricular skin tags, microtia, facial asymmetry, ocular abnormalities, and vertebral anomalies of different sizes and shapes. Most cases are thought to be sporadic. However, a few families were reported to have an autosomal recessive inheritance and other families’ presentation of the syndrome strongly supported an autosomal dominant inheritance. We report OAV in a female infant presenting with tracheomalacia, diaphragmatic hernia, encephalomeningocele, sacral neural tube defect, and cardiac defect and her brother having no more than dysmorphic features. The mode of inheritance in this family supports an autosomal recessive inheritance where the transmission was from normal first-degree consanguineous parents to one of the sons and to the daughter. This report further broadens the clinical presentation and symptoms of OAV and supports the hypothesis advancing OAV as a genetically heterogeneous disorder. PMID:23776370

Farra, Chantal; Yunis, Khaled; Yazbeck, Nadine; Majdalani, Marianne; Charafeddine, Lama; Wakim, Rima; Awwad, Johnny

2011-01-01

342

Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis  

SciTech Connect

Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocortiocoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provides evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families. 34 refs., 3 figs., 2 tabs.

Chung, E.; Hanukoglu, A.; Rees, M.; Thompson, R.; Gardiner, R.M. [Univ. College London Medical School, London (United Kingdom)] [and others] [Univ. College London Medical School, London (United Kingdom); and others

1995-10-01

343

CATSPER2, a human autosomal nonsyndromic male infertility gene  

E-print Network

ARTICLE CATSPER2, a human autosomal nonsyndromic male infertility gene Nili Avidan1 , Hannah Tamary in spermatozoa) may explain the observed deafness and male infertility phenotypes. To the best of our knowledge associated with nonsyndromic male infertility. European Journal of Human Genetics (2003) 11, 497­502. doi:10

Lancet, Doron

344

For many autosomal genes in diploid organisms, expression is almost  

E-print Network

For many autosomal genes in diploid organisms, expression is almost exclusively from one allele for underlying chromatin features of the genes that are known to be randomly mono- allelically expressed in humanme3) and H3K36me3 constitute a reliable signature of randomly monoallelically expressed genes

345

Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies  

Microsoft Academic Search

Stargardt disease (STGD) and late-onset fundus flavimaculatus (FFM) are autosomal recessive conditions leading to macular degenerations in childhood and adulthood, respectively. Recently, mutations of the photoreceptor cell-specific ATP binding transporter gene (ABCR) have been reported in Stargardt disease. Here, we report on the screening of the whole coding sequence of the ABCR gene in 40 unrelated STGD and 15 FFM

Jean-Michel Rozet; Sylvie Gerber; Eric Souied; Isabelle Perrault; Sophie Châtelin; Imad Ghazi; Corinne Leowski; Jean-Louis Dufier; Arnold Munnich; Josseline Kaplan; J-M Rozet

1998-01-01

346

Specific transcriptional changes in human fetuses with autosomal trisomies  

Microsoft Academic Search

Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome) are compatible with postnatal survival. But the mechanisms, how a supernumerary chromosome disrupts the normal development and causes specific phenotypes, are still not fully explained. As an alternative to gene dosage effect due to the trisomic chromosome a genome-wide transcriptional dysregulation has

Ö. Altug-Teber; M. Bonin; M. Walter; U. A. Mau-Holzmann; A. Dufke; H. Stappert; I. Tekesin; H. Heilbronner; K. Nieselt; O. Riess

2007-01-01

347

Autosomally Determined Polymorphism of Glucose6Phosphate Dehydrogenase in Peromyscus  

Microsoft Academic Search

Glucose-6-phosphate dehydrogenase commonly occurs in at least two forms in most tissues of the deer mouse, Peromyscus maniculatus, as demonstrated by starch-gel electrophoresis. An autosomally determined genetic polymorphism in one of the enzymes was discovered. A hybrid molecule occurs in the heterozygote; this suggests a dimeric structure of this enzyme.

Charles R. Shaw; Elizabeth Barto

1965-01-01

348

X-linked dominant retinitis pigmentosa in an American family  

SciTech Connect

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

McGuire, R.E.; Daiger, S.P. [Univ. of Texas HSC, Houston, TX (United States); Blanton, S.H. [Univ. of Virginia, Charlottesville, VA (United States)] [and others

1994-09-01

349

A novel deletion partly removing the AVP gene causes autosomal recessive inheritance of early-onset neurohypophyseal diabetes insipidus.  

PubMed

Familial neurohypophyseal diabetes insipidus (FNDI) typically presents with age-dependent penetrance and autosomal dominant inheritance caused by missense variations in one allele of the AVP gene encoding the arginine vasopressin (AVP) prohormone. We present the molecular genetic characteristics underlying an unusual form of FNDI occurring with very early onset and seemingly autosomal recessive inheritance. By DNA amplification and sequencing, we identified a novel variant allele of the AVP gene carrying a 10,396 base pair deletion involving the majority of the AVP gene as well as its regulatory sequences in the intergenic region between the AVP and the OXT gene, encoding the oxytocin prohormone. We found two chromosomes carrying the deletion in affected family members and one in unaffected family members suspected to transmit the deleted allele. Whole-genome array analysis confirmed the results and excluded the presence of any additional major pathogenic abnormalities. The deletion is predicted to abolish the transcription of the AVP gene, thus the fact that family members heterozygous for the deletion remain healthy argues, in general, against haploinsufficiency as the pathogenic mechanism FNDI. Accordingly, our data is strong support to the prevailing idea that dominant inheritance of FNDI is due to a dominant-negative effect exerted by variant AVP prohormone. PMID:22168581

Christensen, J H; Kvistgaard, H; Knudsen, J; Shaikh, G; Tolmie, J; Cooke, S; Pedersen, S; Corydon, T J; Gregersen, N; Rittig, S

2013-01-01

350

The social dominance paradox.  

PubMed

Dominant individuals report high levels of self-sufficiency, self-esteem, and authoritarianism. The lay stereotype suggests that such individuals ignore information from others, preferring to make their own choices. However, the nonhuman animal literature presents a conflicting view, suggesting that dominant individuals are avid social learners, whereas subordinates focus on learning from private experience. Whether dominant humans are best characterized by the lay stereotype or the animal view is currently unknown. Here, we present a "social dominance paradox": using self-report scales and computerized tasks, we demonstrate that socially dominant people explicitly value independence, but, paradoxically, in a complex decision-making task, they show an enhanced reliance (relative to subordinate individuals) on social learning. More specifically, socially dominant people employed a strategy of copying other agents when the agents' responses had a history of being correct. However, in humans, two subtypes of dominance have been identified [1]: aggressive and social. Aggressively dominant individuals, who are as likely to "get their own way" as socially dominant individuals but who do so through the use of aggressive or Machiavellian tactics, did not use social information, even when it was beneficial to do so. This paper presents the first study of dominance and social learning in humans and challenges the lay stereotype in which all dominant individuals ignore others' views [2]. The more subtle perspective we offer could have important implications for decision making in both the boardroom and the classroom. PMID:25454588

Cook, Jennifer Louise; den Ouden, Hanneke E M; Heyes, Cecilia M; Cools, Roshan

2014-12-01

351

Molecular mechanisms of dominant expression in porphyria.  

PubMed

Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified. PMID:15868463

Badminton, M N; Elder, G H

2005-01-01

352

Two new X-autosome translocations in the mouse  

Microsoft Academic Search

The reciprocal translocations T(X;4)37H and T(X;11)38H were induced by acute X-irradiation of spermatozoa. Male heterozygotes are completely aspermic with a spermatogenic block at pachytene and testis masses about one third of normal, though metaphase I is very occasionally reached in T37H. For both translocations the X chromosome breakpoints are in band XA2, and the autosomal breakpoints are in 4D3 for

A. G. Searle; C. V. Beechey; E. P. Evans; M. Kirk

1983-01-01

353

A probably distinct autosomal recessive thoraco-limb dysplasia.  

PubMed Central

A Mexican mestizo family is reported in which two opposite sexed sibs, born to consanguineous parents, had a skeletal dysplasia. The salient features were a bell shaped thorax owing to short ribs, short limbed dwarfism, pelvic hypoplasia, dislocatable radial heads, elongated distal fibulae, and improvement with age. It is concluded that the present observation probably represents a distinct autosomal recessive thoraco-limb dysplasia identifiable at birth. Images PMID:3184141

Rivera, H; Perez-Salas, J M; Nazara, Z; Ramirez, M L

1988-01-01

354

Autosomal recessive disorders among Arabs: an overview from Kuwait.  

PubMed Central

Kuwait has a cosmopolitan population of 1.7 million, mostly Arabs. This population is a mosaic of large and small minorities representing most Arab communities. In general, Kuwait's population is characterized by a rapid rate of growth, large family size, high rates of consanguineous marriages within the Arab communities with low frequency of intermarriage between them, and the presence of genetic isolates and semi-isolates in some extended families and Bedouin tribes. Genetic services have been available in Kuwait for over a decade. During this time it has become clear that Arabs have a high frequency of genetic disorders, and in particular autosomal recessive traits. Their pattern is unique and some disorders are relatively common. Examples are Bardet-Biedl and Meckel syndromes, phenylketonuria, and familial Mediterranean fever. A relatively large number of new syndromes and variants have been delineated in Kuwait's population, many being the result of homozygosity for autosomal recessive genes that occurred because of inbreeding. Some of these syndromes have subsequently been found in other parts of the world, negating the concept of the private syndrome. This paper provides an overview of autosomal recessive disorders among the Arabs in Kuwait from a personal perspective and published studies, and highlights the need for genetic services in Arab countries with the goal of prevention and treatment of genetic disorders. PMID:8014972

Teebi, A S

1994-01-01

355

Recessive anonychia totalis and dominant aplasia (or hypoplasia) of upper lateral incisors in the same kindred  

PubMed Central

This paper describes and discusses the occurrence of 2 genetic traits, autosomal recessive anonychia and autosomal dominant hypoplasia of the upper lateral incisors (ULI) in 4 (2 males and 2 females) members of 2 sibships of the same kindred. Three of them also had spaced teeth and agenesis of one or more third molars. Anonychia was also present in another dead sib. Many other cases of aplasia and/or hypoplasia of ULI, as well as persistence of deciduous ULI, have been verified in the same kindred. Images PMID:469885

Freire-Maia, N.; Pinheiro, Marta

1979-01-01

356

Genetic Dominance & Cellular Processes  

ERIC Educational Resources Information Center

In learning genetics, many students misunderstand and misinterpret what "dominance" means. Understanding is easier if students realize that dominance is not a mechanism, but rather a consequence of underlying cellular processes. For example, metabolic pathways are often little affected by changes in enzyme concentration. This means that…

Seager, Robert D.

2014-01-01

357

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

SciTech Connect

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

Orth, U.; Oehlmann, R.; Gal, A. [Inst. Humangenetik, Med. Univ., Luebeck (Germany)] [and others

1994-09-01

358

Localization of a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, PARK6, on Human Chromosome 1p35-p36  

PubMed Central

The cause of Parkinson disease (PD) is still unknown, but genetic factors have recently been implicated in the etiology of the disease. So far, four loci responsible for autosomal dominant PD have been identified. Autosomal recessive juvenile parkinsonism (ARJP) is a clinically and genetically distinct entity; typical PD features are associated with early onset, sustained response to levodopa, and early occurrence of levodopa-induced dyskinesias, which are often severe. To date, only one ARJP gene, Parkin, has been identified, and multiple mutations have been detected both in families with autosomal recessive parkinsonism and in sporadic cases. The Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD. In ?50% of families with ARJP that have been analyzed, no mutations could be detected in the Parkin gene. We identified a large Sicilian family with four definitely affected members (the Marsala kindred). The phenotype was characterized by early-onset (range 32–48 years) parkinsonism, with slow progression and sustained response to levodopa. Linkage of the disease to the Parkin gene was excluded. A genomewide homozygosity screen was performed in the family. Linkage analysis and haplotype construction allowed identification of a single region of homozygosity shared by all the affected members, spanning 12.5 cM on the short arm of chromosome 1. This region contains a novel locus for autosomal recessive early-onset parkinsonism, PARK6. A maximum LOD score 4.01 at recombination fraction .00 was obtained for marker D1S199. PMID:11254447

Valente, Enza Maria; Bentivoglio, Anna Rita; Dixon, Peter H.; Ferraris, Alessandro; Ialongo, Tamara; Frontali, Marina; Albanese, Alberto; Wood, and Nicholas W.

2001-01-01

359

Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia.  

PubMed

Metaphyseal anadysplasia (MANDP) is an uncommon chondrodysplasia characterized by early-onset metaphyseal dysplasia and short stature that improves with age. MANDP is caused by mutations in the matrix metalloproteinase (MMP) 9 and 13 genes. Autosomal dominant (AD) MANDP has been described as more severe, and has been associated with dominant-negative MMP13 mutations that suppress activity of both MMP9 and MMP13; autosomal recessive (AR) MANDP has been described as a milder form associated with AR missense mutations in MMP9 or MMP13. Here we describe the molecular characterization of skeletal dysplasia in two brothers who presented with short stature and mixed epiphyseal and metaphyseal dysplasia. Whole-exome sequencing (WES) identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T) on chromosome 11q22.2 resulting in a premature stop codon p.(R109*) that is predicted to abolish MMP13 activity. This report extends the MANDP phenotype by illustrating that AR nonsense mutations in MMP13 can lead to short stature that persists beyond childhood. PMID:24781753

Li, Dong; Weber, David R; Deardorff, Matthew A; Hakonarson, Hakon; Levine, Michael A

2015-02-01

360

Mutations of the tyrosinase gene produce autosomal recessive ocular albinism  

SciTech Connect

Albinism has historically been divided into ocular (OA) and oculocutaneous (OCA) types based on the presence or absence of clinically apparent skin and hair involvement in an individual with the ocular features of albinism. The major genes for OCA include the tyrosinase gene in OCA1 and the P gene in OCA2. X-linked and autosomal recessive OA have been described and the responsible genes have not been identified. We now present six Caucasian individuals who have the phenotype of autosomal recessive OA but who have OCA1 as shown by the presence of mutations of the tyrosinase. They had white or very light hair and white skin at birth, and cutaneous pigment developed in the first decade of life. At ages ranging from 1.5-23 years, hair color was dark blond to light brown. The skin had generalized pigment and well developed tan was present on the exposed arm and face skin of four. Iris pigment was present and iris translucency varied. Molecular analysis of the tyrosinase gene, using PCR amplification and direct di-deoxy sequencing showed the following mutations: E398Z/E398Q, P406S/g346a, R402E/T373K, ?/D383N, and H211N/T373K. The homozygous individual was not from a known consanguineous mating. T373K is the most common tyrosinase gene mutation in our laboratory. Three of these mutations are associated with a total loss of tyrosinase activity (g346a splice-site, T373K, and D383N), while four are associated with residual enzyme activity (H211N, R402E, E398Q, and P406S). These studies show that mutations of the tyrosinase gene can produce the phenotype of autosomal recessive OA in an individual who has normal amounts of cutaneous pigment and the ability to tan after birth. This extends the phenotypic range of OCA1 to normal cutaneous pigment after early childhood, and suggest that mutations of the tyrosinase gene account for a significant number of individuals with autosomal recessive OA.

King, R.A.; Summers, C.G.; Oetting, W.S. [Univ. of Minnesota, Minneapolis, MN (United States)] [and others

1994-09-01

361

STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly.  

PubMed

Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly. PMID:25218063

Kakar, Naseebullah; Ahmad, Jamil; Morris-Rosendahl, Deborah J; Altmüller, Janine; Friedrich, Katrin; Barbi, Gotthold; Nürnberg, Peter; Kubisch, Christian; Dobyns, William B; Borck, Guntram

2015-01-01

362

Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation.  

PubMed

A 4-base pair deletion in the neuronal serine protease neurotrypsin gene was associated with autosomal recessive nonsyndromic mental retardation (MR). In situ hybridization experiments on human fetal brains showed that neurotrypsin was highly expressed in brain structures involved in learning and memory. Immuno-electron microscopy on adult human brain sections revealed that neurotrypsin is located in presynaptic nerve endings, particularly over the presynaptic membrane lining the synaptic cleft. These findings suggest that neurotrypsin-mediated proteolysis is required for normal synaptic function and suggest potential insights into the pathophysiological bases of mental retardation. PMID:12459588

Molinari, Florence; Rio, Marlene; Meskenaite, Virginia; Encha-Razavi, Férechté; Augé, Joelle; Bacq, Delphine; Briault, Sylvain; Vekemans, Michel; Munnich, Arnold; Attié-Bitach, Tania; Sonderegger, Peter; Colleaux, Laurence

2002-11-29

363

A new locus for dominant "zonular pulverulent" cataract, on chromosome 13.  

PubMed Central

Inherited cataract is a clinically and genetically heterogeneous disease that most often presents as a congenital autosomal dominant trait. Here we report the linkage of a new locus for dominant "zonular pulverulent" cataract (CZP) to chromosome 13. To map the CZP locus we performed molecular-genetic linkage analysis using microsatellite markers in a five-generation English pedigree. After exclusion of eight known loci and several candidate genes for autosomal dominant cataract, we obtained significantly positive LOD scores (Z) for markers D13S175 (maximum Z [Zmax] = 4.06; maximum recombination frequency [theta max] = 0) and D13S1236 (Zmax = 5.75, theta max = 0). Multipoint analysis gave Zmax = 6.62 (theta max = 0) at marker D13S175. Haplotype data indicated that CZP probably lies in the centromeric region of chromosome 13, provocatively close to the gene for lens connexin46. PMID:9199569

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

1997-01-01

364

Robin Teigland Dominic Power  

E-print Network

and Dominic Power 2013 Individual chapters© Respective authors 2013 All rights reserved. No reproduction, copy-1-137-28301-6 This book is printed on paper suitable for recycling and made from fully managed and sustained forest

Brody, James P.

365

Some Genes Are Dominant  

NSDL National Science Digital Library

This interactive activity, adapted from the Dolan DNA Learning Center, illustrates how Gregor Mendel used pure-bred yellow and green peas to show that some genes are dominant and others are recessive.

Foundation, Wgbh E.

2007-04-19

366

Autosomal linkage analysis for cannabis use behaviors in Australian adults.  

PubMed

Cannabis is the most commonly used illicit drug in developed and in developing nations. Twin studies have highlighted the role of genetic influences on early stages of cannabis use, such as a lifetime history of use, early-onset use and frequent use, however, we are not aware of any genomic studies that have examined these phenotypes. Using data on 2314 families consisting of 5600 adult Australian offspring and their parents, all of whom were scanned using 1399 unique autosomal markers, we conducted autosomal linkage analyses for lifetime history of cannabis initiation, early-onset cannabis use and frequency of use, using a variance components approach in the linkage package MERLIN. Suggestive evidence for linkage was found on chromosome 18 (LOD 2.14 for frequency of use, LOD 1.97 for initiation, at 90-97 cM) and also on chromosome 19 (LOD 1.92 for early-onset at 17 cM). These LOD scores did not meet genome-wide significance. Further replication of these linkage regions in other samples will be required, although these initial results suggest further targeted efforts on chromosome 18 may yield interesting candidate genes for early stages of cannabis-related behaviors. PMID:18606503

Agrawal, Arpana; Morley, Katherine I; Hansell, Narelle K; Pergadia, Michele L; Montgomery, Grant W; Statham, Dixie J; Todd, Richard D; Madden, Pamela A F; Heath, Andrew C; Whitfield, John; Martin, Nicholas G; Lynskey, Michael T

2008-12-01

367

NDST1 missense mutations in autosomal recessive intellectual disability.  

PubMed

NDST1 was recently proposed as a candidate gene for autosomal recessive intellectual disability in two families. It encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in heparan sulfate biosynthesis. In mice, Ndst1 is crucial for embryonic development and homozygous null mutations are perinatally lethal. We now report on two additional unrelated families with homozygous missense NDST1 mutations. All mutations described to date predict the substitution of conserved amino acids in the sulfotransferase domain, and mutation modeling predicts drastic alterations in the local protein conformation. Comparing the four families, we noticed significant overlap in the clinical features, including both demonstrated and apparent intellectual disability, muscular hypotonia, epilepsy, and postnatal growth deficiency. Furthermore, in Drosophila, knockdown of sulfateless, the NDST ortholog, impairs long-term memory, highlighting its function in cognition. Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development. PMID:25125150

Reuter, Miriam S; Musante, Luciana; Hu, Hao; Diederich, Stefan; Sticht, Heinrich; Ekici, Arif B; Uebe, Steffen; Wienker, Thomas F; Bartsch, Oliver; Zechner, Ulrich; Oppitz, Cornelia; Keleman, Krystyna; Jamra, Rami Abou; Najmabadi, Hossein; Schweiger, Susann; Reis, André; Kahrizi, Kimia

2014-11-01

368

Autosomal Linkage Analysis for Cannabis Use Behaviors in Australian Adults  

PubMed Central

Cannabis is the most commonly used illicit drug in developed and in developing nations. Twin studies have highlighted the role of genetic influences on early stages of cannabis use, such as a lifetime history of use, early-onset use and frequent use, however, we are not aware of any genomic studies that have examined these phenotypes. Using data on 2,314 families consisting of 5,600 adult Australian offspring and their parents, all of whom were scanned using 1,399 unique autosomal markers, we conducted autosomal linkage analyses for lifetime history of cannabis initiation, early-onset cannabis use and frequency of use, using a variance components approach in the linkage package MERLIN. Suggestive evidence for linkage was found on chromosome 18 (LOD 2.14 for frequency of use, LOD 1.97 for initiation, at 90–97 cM) and also on chromosome 19 (LOD 1.92 for early onset at 17 cM). These LOD scores did not meet genomewide significance. Further replication of these linkage regions in other samples will be required, although these initial results suggest further targeted efforts on chromosome 18 may yield interesting candidate genes for early stages of cannabis-related behaviors. PMID:18606503

Agrawal, Arpana; Morley, Katherine I.; Hansell, Narelle K.; Pergadia, Michele L.; Montgomery, Grant W.; Statham, Dixie J.; Todd, Richard D.; Madden, Pamela A. F.; Heath, Andrew C.; Whitfield, John; Martin, Nicholas G.; Lynskey, Michael T.

2008-01-01

369

Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease  

Microsoft Academic Search

Mutations in the ganglioside-induced differentiation-associated protein 1 gene cause either autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4A or autosomal recessive axonal Charcot-Marie-Tooth disease with vocal cord paresis. We sequenced the ganglioside-induced differentiation-associated protein 1 gene in 138 patients from 119 unrelated families diagnosed with either demyelinating or axonal autosomal recessive Charcot-Marie-Tooth disease. We detected six distinct mutant alleles in four

Nadia Ammar; Eva Nelis; Luciano Merlini; Nina Bariši?; Rim Amouri; Chantal Ceuterick; Jean-Jacques Martin; Vincent Timmerman; Fayçal Hentati; Peter De Jonghe

2003-01-01

370

Progress in the search for genetic linkage with Tourette syndrome: An exclusion map covering more than 50% of the autosomal genome  

PubMed Central

Gilles de la Tourette syndrome is a neuropsychiatric disorder with an autosomal dominant mode of inheritance and reduced penetrance at a single genetic locus. Several research groups have genetic linkage studies underway to detect the chromosomal location of the gene that predisposes for this disorder. Strong and clear evidence of linkage has not yet been produced for Tourette syndrome. This paper presents an overview of the methods and progress of the groups centered at Yale University and Erasmus University in excluding linkage from a large portion of the genome. Our labs have screened 228 genetic marker loci for linkage with a gene for this disorder in a series of affected families in the United States, Canada, The Netherlands, and Norway. More than 50% (and perhaps as much as 66%) of the autosomal genome has now been excluded on the assumption that genetic heterogeneity is not an important factor in the Tourette syndrome pedigrees pooled for this summary. PMID:1990837

Pakstis, Andrew J.; Heutink, Peter; Pauls, David L.; Kurlan, Roger; van de Wetering, Ben J. M.; Leckman, James F.; Sandkuyl, Lodewijk A.; Kidd, Judith R.; Breedveld, Guido J.; Castiglione, Carmela M.; Weber, James; Sparkes, Robert S.; Cohen, Donald J.; Kidd, Kenneth K.; Oostra, Ben A.

1991-01-01

371

Novel mutation in FBN1 causes ectopia lentis and varicose great saphenous vein in one Chinese autosomal dominant family  

PubMed Central

Purpose To identify genetic defects in a Chinese family with ectopia lentis (EL) and varicose great saphenous vein (GSV) and to analyze the correlations between phenotype and genotype. Methods Twenty-two (12 affected subjects and ten unaffected subjects) among 53 members of a Chinese family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from the leukocytes in the subjects’ peripheral blood. A minimum interval was achieved with linkage study and haplotype analysis. All 65 exons and the flanking intronic regions of fibrillin-1 (FBN1) were amplified with PCR and screened for mutations with direct Sanger sequencing. Molecular modeling was analyzed in an in silico study. Results The linkage study showed a strong cosegregation signal on chromosome 15. The non-parametric linkage analysis yielded a maximum score of 29.1(p<0.00001), and the parametric logarithm of the odds (LOD) score was 3.6. The minimum interval of the shared haplotype was rs1565863-rs877228. The best candidate gene in this region was FBN1. A novel mutation, c.3928G>A, p.1310G>S in exon 31, was identified in FBN1 and cosegregated well in the family. We applied molecular modeling to show the effect of this mutation on the fibrillin-1 structure. The mutation significantly distorts the calcium coordination, decreases the binding of the calcium ion in that motif, and affects the local calcium-binding epidermal growth factor (cbEGF) interface that depends on Ca binding. Conclusions FBN1-associated fibrillinopathies are a group of diseases with dynamic phenotype changes. Novel mutation p.1310G>S was first reported to cause Marfan syndrome (MFS). Our results expand the mutation spectrum in FBN1 and enhance our knowledge of genotype–phenotype correlations underlying FBN1 mutations. PMID:24940037

Fu, Qing; Liu, Peng; Lu, Qingsheng; Wang, Feng; Wang, Hui; Shen, Wei; Xu, Fei; Liu, Lin; Sergeev, Yuri V.

2014-01-01

372

Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family  

Microsoft Academic Search

Hereditary hearing impairment affects about 1 in 1000 newborns. In most cases hearing loss is non-syndromic with no other clinical features, while in other families deafness is associated with specific clinical abnormalities. Analysis of large families with non-syndromic and syndromic deafness have been used to identify genes or gene locations that cause hearing impairment. The present report describes a large

T. Fagerheim; Ø. Nilssen; P. Raeymaekers; V. Brox; T. Moum; H. H. Elverland; E. Teig; H. H. Omland; G. K. Fostad; L. Tranebjærg

1996-01-01

373

Pulse Wave Reflection Is Amplified in Normotensive Patients with Autosomal-Dominant Polycystic Kidney Disease and Normal Renal Function  

Microsoft Academic Search

Background: In young ADPKD patients, we have previously found an impaired endothelium-dependent relaxation in small resistance vessels but a normal flow-mediated dilatation of the brachial artery. The present study investigated arterial stiffness in early ADPKD by pulse-wave analysis (PWA) and measurement of pulse-wave velocity (PWV). Methods: 18 young normotensive ADPKD patients with normal renal function and 18 controls were studied

Malene L. Borresen; Dan Wang; Svend Strandgaard

2007-01-01

374

Distinctive spinal changes in two patients with unusual forms of autosomal dominant endosteal hyperostosis: a case series  

PubMed Central

Endosteal hyperostosis was encountered in a 26-year-old-man and his 6-month-old daughter. Both the father and his daughter presented with fractures. Odontoid process hyperplasia, and progressive sclerosis of the posterior spinal elements, was the other significant features. To the best of our knowledge, this is the first clinical report describing distinctive spinal changes in association with fractures and endosteal hyperostosis. PMID:18031587

Al Kaissi, Ali; Varga, Franz; Zandieh, Shahin; Klaushofer, Klaus; Grill, Franz

2007-01-01

375

A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13  

SciTech Connect

Inherited retinal dystrophy is a common cause of visual impairment. Cone dystrophy affects the cone function and is manifested as progressive loss of the central vision, defective color vision, and photophobia. Linkage was demonstrated between progressive cone dystrophy (CORD5) and genetic markers on chromosome 17p12-p13 in a five-generation family. Multipoint analysis gave a maximum lod score of 7.72 at the marker D17S938. Recombinant haplotypes in the family suggest that the cone dystrophy locus is located in a 25-cM interval between the markers D17S926/D17S849 and D17S804/D17S945. Furthermore, one recombination was detected between the disease locus and a microsatellite marker in the candidate gene RCV1, encoding the retinal protein recoverin. Two additional candidate genes encoding retinal guanylate cyclase (GUC2D) and pigment epithelium-derived factor (PEDF) are located at 17p13.1. Moreover, loci for retinitis pigmentosa and Leber congenital amaurosis have been mapped to the same region. Identification of the cone dystrophy locus may be of importance not only for identifying functional genes in the cone system, but also for identifying genes for other retinal disorders. 34 refs., 3 figs., 2 tabs.

Balciuniene, J.; Holmgren, G.; Forsman, K. [University Hospital, Umea (Sweden)] [and others] [University Hospital, Umea (Sweden); and others

1995-11-20

376

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

E-print Network

Pancreatic Cancer Maps to Chromosome 4q32-34 Michael A. Eberle,1,* Roland Pfu¨tzer,5,*, Kay L. Pogue-Geile,5 of Pittsburgh, and 6 Veterans Administration Pittsburgh Health Care System, Pittsburgh Pancreatic cancer cancer will die from it, usually in !6 mo. Familial clustering of pancreatic cancers is commonly

Kruglyak, Leonid

377

Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa.  

PubMed

We inserted into the germline of mice either a mutant or wild-type allele from a patient with retinitis pigmentosa and a missense mutation (P23H) in the rhodopsin gene. All three lines of transgenic mice with the mutant allele developed photoreceptor degeneration; the one with the least severe retinal photoreceptor degeneration had the lowest transgene expression, which was one-sixth the level of endogenous murine rod opsin. Of two lines of mice with the wild-type allele, one expressed approximately equal amounts of transgenic and murine opsin and maintained normal retinal function and structure. The other expressed approximately 5 times more transgenic than murine opsin and developed a retinal degeneration similar to that found in mice carrying a mutant allele, presumably due to the overexpression of this protein. Our findings help to establish the pathogenicity of mutant human P23H rod opsin and suggest that overexpression of wild-type human rod opsin leads to a remarkably similar photoreceptor degeneration. PMID:1418997

Olsson, J E; Gordon, J W; Pawlyk, B S; Roof, D; Hayes, A; Molday, R S; Mukai, S; Cowley, G S; Berson, E L; Dryja, T P

1992-11-01

378

Molecular and Cellular Basis of Autosomal Recessive Primary Microcephaly  

PubMed Central

Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development. PMID:25548773

2014-01-01

379

An autosomal genetic linkage map of the sheep genome  

SciTech Connect

We report the first extensive ovine genetic linkage map covering 2070 cM of the sheep genome. The map was generated from the linkage analysis of 246 polymorphic markers, in nine three-generation full-sib pedigrees, which make up the AgResearch International Mapping Flock. We have exploited many markers from cattle so that valuable comparisons between these two ruminant linkage maps can be made. The markers, used in the segregation analyses, comprised 86 anonymous microsatellite markers derived from the sheep genome, 126 anonymous microsatellites from cattle, one from deer, and 33 polymorphic markers of various types associated with known genes. The maximum number of informative meioses within the mapping flock was 22. The average number of informative meioses per marker was 140 (range 18-209). Linkage groups have been assigned to all 26 sheep autosomes. 102 refs., 8 figs., 5 tabs.

Crawford, A.M.; Ede, A.J.; Pierson, C.A. [Univ. of Otago, Dunedin (New Zealand)] [and others

1995-06-01

380

Germinal mosaicism for LMNA mimics autosomal recessive congenital muscular dystrophy.  

PubMed

Life-threatening cardiac and respiratory complications are common in LMNA-related myopathies and early diagnosis is important for optimal patient care. Lamin A/C related congenital muscular dystrophy (L-CMD) is often caused by de novo mutation in LMNA, affecting a single child in a family. Germinal mosaicism is a rarer variant that can lead to two children inheriting the same new heterozygous mutation from a clinically unaffected parent. Both patterns mimic autosomal recessive (AR) inheritance and the possibility of de novo L-CMD may be forgotten since most causes of congenital muscular dystrophy follow AR inheritance. To illustrate the challenge of diagnosing L-CMD, we present a consanguineous family in which two children have early onset LMNA-related myopathy likely due to paternal germinal mosaicism. This emphasises that germinal mosaicism (and de novo mutations) for LMNA can arise in any family and direct gene sequencing is required to confirm or exclude the diagnosis. PMID:19084400

Makri, Samira; Clarke, Nigel F; Richard, Pascale; Maugenre, Svetlana; Demay, Laurence; Bonne, Gisèle; Guicheney, Pascale

2009-01-01

381

Iron dominated magnets  

SciTech Connect

These two lectures on iron dominated magnets are meant for the student of accelerator science and contain general treatments of the subjects design and construction. The material is arranged in the categories: General Concepts and Cost Considerations, Profile Configuration and Harmonics, Magnetic Measurements, a few examples of ''special magnets'' and Materials and Practices. Extensive literature is provided.

Fischer, G.E.

1985-07-01

382

An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p.  

PubMed Central

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more respiratory-chain enzymes carrying mtDNA-encoded subunits. The pattern of inheritance indicates a nuclear gene defect predisposing to secondary mtDNA deletions. Recently, in one Finnish family, we assigned an adPEO locus to chromosome 10q 23.3-24.3 but also excluded linkage to this same locus in two Italian adPEO families with a phenotype closely resembling the Finnish one. We applied a random mapping approach to informative non-10q-linked Italian families to assign the second locus for adPEO and found strong evidence for linkage on chromosome 3p 14.1-21.2 in three Italian families, with a maximum two-point lod score of 4.62 at a recombination fraction of .0. However, in three additional families, linkage to the same chromosomal region was clearly absent, indicating further genetic complexity of the adPEO trait. PMID:8644740

Kaukonen, J. A.; Amati, P.; Suomalainen, A.; Rötig, A.; Piscaglia, M. G.; Salvi, F.; Weissenbach, J.; Fratta, G.; Comi, G.; Peltonen, L.; Zeviani, M.

1996-01-01

383

A mutation in CTSK gene in an autosomal recessive pycnodysostosis family of Pakistani origin  

Microsoft Academic Search

BACKGROUND: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures and skull deformities. Mutations in the gene encoding cathepsin K (CTSK), a lysosomal cysteine protease, have been found to be responsible for this disease. OBJECTIVES: To identify pathogenic mutation in a consanguineous Pakistani family with 3 affected individuals demonstrating autosomal recessive pycnodysostosis. METHODS:

Muhammad Naeem; Sabeen Sheikh; Wasim Ahmad

2009-01-01

384

Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over sexually  

E-print Network

Pathology from evolutionary conflict, with a theory of X chromosome versus autosome conflict over extreme, pathological expression. In this regard, pathology reveals hidden evolutionary design. We first and the autosomes may be associated with various pathologies caused by extreme expression along the male­female axis

Crespi, Bernard J.

385

Comparative analysis of charged particle-induced autosomal mutations in murine cells and tissues  

Microsoft Academic Search

Carcinogenesis requires the accumulation of mutations and most of these mutations of occur on autosomes. This study seeks to determine the effect of the tissue microenvironment on the frequency and types of autosomal mutations in epithelial cells exposed to the types of charged particles in space radiation environments. Epithelial cells are the principal cells at risk for the development of

Amy Kronenberg; Stacey Gauny; Mitchell Turker; Cristian Dan; Ely Kwoh

2008-01-01

386

Autosomal inheritance of alphamethrin, a synthetic pyrethroid, resistance in Anopheles stephensi-Liston, a malaria mosquito.  

PubMed

Anopheles stephensi–Liston (Culicidae: Diptera) is an important urban malarial vector in the Indian sub-continent, accounting for about 15% of the total annual malaria incidence. Chemical control represents a key strategy in the management of this insect vector. However, owing to erratic and continuous application of insecticides, resistance has become a common phenomenon among them and their control has become an uphill task. The genetics of alphamethrin, a synthetic pyrethroid resistance was studied to determine its mode of inheritance. The late third instar larvae were selectively inbred for 27 and ten generations to synthesize homozygous resistant (R) and susceptible (S) stocks, respectively, to the diagnostic dose of 0.12 mg l?1. The log-dosage probit mortality relationships and degree of dominance (D) were calculated. Resistance was observed in both sexes, the dosage-mortality (d-m) line of F 1 was towards the resistant parent and the ‘D’ value was found to be 0.8 indicating alphamethrin resistant (amr) gene to be autosomal and incompletely dominant. The d-m lines of F 2/backcross exhibited a clear plateau of mortality across a range of doses indicating monogenic resistance. The null hypothesis for monogenic resistance was tested from mortality data of backcross progeny compared with theoretical expectations using the ?2 test and was found to be non-significant. Understanding genetics of insecticide resistance is significant in prediction and management of resistant insects. The amr genes can be used as genetic marker in A. stephensi, which can be used in several applications in conducting basic and applied genetic research. PMID:23521773

Prasad, T P N Hari; Shetty, N J

2013-10-01

387

[Dominant, motivation and behavior].  

PubMed

It was shown in experiments on cats with elaborated conditioned running to the left (with fresh food) and right (with salted food) feeding troughs that conditioned signals may change the current behaviour in spite of real unconditioned stimuli. The fresh food signal produces a conditioned "freshening" of the salt meat, which may be regarded as a successful physiological model of gustatory illusions. With a free choice of different salinity of food from different cups of each feeding though, behaviour is corrected by unconditioned factors, i.e. real salinity of food. As a result the thresholds of eating salt food from both feeding troughs are equalized. The facts are discussed in the light of the dominant principle, i.e. that central program which is built on the basis of the dominant motivation, of previous experience and current analysis of surroundings. PMID:7164569

Batuev, A S

1982-01-01

388

Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1.  

PubMed

Autosomal recessive lethal congenital contractural syndrome (LCCS) is a severe form of neuromuscular arthrogryposis. We previously showed that this phenotype is caused in two unrelated inbred Bedouin tribes by different defects in the phosphatidylinositol pathway. However, the molecular basis of the same phenotype in other tribes remained elusive. Whole exome sequencing identified a novel LCCS founder mutation within a minimal shared homozygosity locus of approximately 1 Mb in two affected individuals of different tribes: a homozygous premature stop producing mutation in MYBPC1, encoding myosin-binding protein C, slow type. A dominant missense mutation in MYBPC1 was previously shown to cause mild distal arthrogryposis. We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS. PMID:22610851

Markus, Barak; Narkis, Ginat; Landau, Daniella; Birk, Ruth Z; Cohen, Idan; Birk, Ohad S

2012-10-01

389

Viability of X-autosome translocations in mammals: an epigenomic hypothesis from a rodent case-study  

Microsoft Academic Search

X-autosome translocations are highly deleterious chromosomal rearrangements due to meiotic disruption, the effects of X-inactivation on the autosome, and the necessity of maintaining different replication timing patterns between the two segments. In spite of this, X-autosome translocations are not uncommon. We here focus on the genus Taterillus (Rodentia, Gerbillinae) which provides two sister lineages differing by two autosome–gonosome translocations. Despite

G. Dobigny; C. Ozouf-Costaz; C. Bonillo; V. Volobouev

2004-01-01

390

Thermophoretically Dominated Aerosol Coagulation  

NASA Astrophysics Data System (ADS)

A theory of aerosol coagulation due to size-dependent thermophoresis is presented. This previously overlooked effect is important when local temperature gradients are large, the sol population is composed of particles of much greater thermal conductivity than the carrier gas, with mean diameters much greater than the prevailing gas mean free path, and an adequate “spread” in sizes (as in metallurgical mists or fumes). We illustrate this via a population-balance analysis of the evolution of an initially log-normal distribution when this mechanism dominates ordinary Brownian diffusion.

Rosner, Daniel E.; Arias-Zugasti, Manuel

2011-01-01

391

SLC7A14 linked to autosomal recessive retinitis pigmentosa.  

PubMed

Retinitis pigmentosa (RP) is characterized by degeneration of the retinal photoreceptors and is the leading cause of inherited blindness worldwide. Although few genes are known to cause autosomal recessive RP (arRP), a large proportion of disease-causing genes remain to be revealed. Here we report the identification of SLC7A14, a potential cationic transporter, as a novel gene linked to arRP. Using exome sequencing and direct screening of 248 unrelated patients with arRP, we find that mutations in the SLC7A14 gene account for 2% of cases of arRP. We further demonstrate that SLC7A14 is specifically expressed in the photoreceptor layer of the mammalian retina and its expression increases during postnatal retinal development. In zebrafish, downregulation of slc7a14 expression leads to an abnormal eye phenotype and defective light-induced locomotor response. Furthermore, targeted knockout of Slc7a14 in mice results in retinal degeneration with abnormal ERG response. This suggests that SLC7A14 has an important role in retinal development and visual function. PMID:24670872

Jin, Zi-Bing; Huang, Xiu-Feng; Lv, Ji-Neng; Xiang, Lue; Li, Dong-Qing; Chen, Jiangfei; Huang, Changjiang; Wu, Jinyu; Lu, Fan; Qu, Jia

2014-01-01

392

The malformations of the urinary system in autosomal disorders.  

PubMed

Data from the world literature about the pathology of the urinary system in autosomal chromosomal disorders are analyzed and compared with our own morphological investigations of this system in 63 cases of chromosomal disorders (Patau's, Edwards', Down's, Orbeli's, Wolf-Hirschhorn's syndromes, partial trisomy B and inversion of chromosome 2). The urinary system is most frequently involved in "cat-eye", triploidy, Orbeli's, Patau's and Edwards' syndromes. All known malformations of the urinary system are observed in children with chromosomal diseases, except infantile polycystic kidney and medullary "sponge" kidney. The authors recognize specific and nonspecific abnormalities of the urinary system. Nonspecific abnormalities, as simple renal dysgenesis, may be observed in all chromosomal disorders. Specific abnormalities are found only in certain chromosomal diseases. These malformations are an excess of embryonal lobulation of the kidney with the increase of its weight and cystic changes (Patau's syndrome), crossed renal ectopy with fusion and horseshoe kidney (Edwards' syndrome), unilateral renal agenesis (Orbeli's syndrome), hypospadia (Wolf-Hirschhorn's syndrome). A possible pathogenesis of malformations of the urinary system in chromosomal disorders is discussed. PMID:127413

Kravtzova, G I; Lazjuk, G I; Lurie, I W

1975-10-20

393

Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q  

SciTech Connect

The authors have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of the enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.

Russell, L.J.; Compton, J.G.; Bale, S.J. [National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (United States); DiGiovanna, J.J. [National Cancer Institute, Bethesda, MD (United States); Hashem, N. [Ains-Shams Univ. Medical Genetics Center, Cairo (Egypt)

1994-12-01

394

A Novel Loss-of-Function Mutation, Gln459Arg, of the Calcium-Sensing Receptor Gene Associated with Apparent Autosomal Recessive Inheritance of Familial Hypocalciuric Hypercalcemia  

PubMed Central

Context: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism. Objective: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred. Design: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR. Results: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband’s parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30–50% of the calcium-dependent activity of the wild-type CaSR. Conclusion: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions. PMID:19789209

Lietman, Steven A.; Tenenbaum-Rakover, Yardena; Jap, Tjin Shing; Yi-Chi, Wu; De-Ming, Yang; Ding, Changlin; Kussiny, Najat; Levine, Michael A.

2009-01-01

395

Mutations in NSUN2 Cause Autosomal- Recessive Intellectual Disability  

PubMed Central

With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227?] and c.1114C>T [p.Gln372?], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs?192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development. PMID:22541559

Abbasi-Moheb, Lia; Mertel, Sara; Gonsior, Melanie; Nouri-Vahid, Leyla; Kahrizi, Kimia; Cirak, Sebahattin; Wieczorek, Dagmar; Motazacker, M. Mahdi; Esmaeeli-Nieh, Sahar; Cremer, Kirsten; Weißmann, Robert; Tzschach, Andreas; Garshasbi, Masoud; Abedini, Seyedeh S.; Najmabadi, Hossein; Ropers, H. Hilger; Sigrist, Stephan J.; Kuss, Andreas W.

2012-01-01

396

Rapid detection of autosomal aneuploidy using microsatellite markers  

SciTech Connect

Trisomy occurs in at least 4% of all clinically recognized pregnancies, making it the most common type of chromosome abnormality in humans. The most commonly occurring trisomies are those of chromosomes 13, 18, 21 and aneuploidy of X and Y, accounting for about 0.3% of all newborns and a much higher percentage of conceptuses. In Canada, prenatal chromosome analysis by amniocentesis is offered to those women {ge} 35 years of age at the time of delivery or equivalent risk by maternal serum screen. We are developing a rapid molecular diagnostic test to detect the most common autosomal aneuploidies in prenatal and neonatal samples. The tests makes use of highly polymorphic short tandem repeat markers labeled with fluorescent tags which allow analysis on a GENESCANNER automated fragment analyzer (ABI). Multiple polymorphic markers have been selected on each of chromosomes 13, 18 and 21. At a given locus, trisomic fetuses/neonates will have either three alleles or two alleles with one allele having twice the intensity of the other. Unaffected individuals have two equal intensity alleles. We are conducting a blind study that will compare the detection efficiencies of FISH analysis on uncultured cells and the molecular method on confirmation amniotic fluid samples collected at the time of termination of affected fetuses. Results on cultured amniocytes from one such patient confirmed that trisomy 21 can be detected. FISH was not done on this sample. In addition, detection efficiency of the molecular method in whole blood samples from affected neonates is also being studied. To date, two such samples have been tested, one with trisomy 13 and one with trisomy 18, and both samples were diagnosed correctly. Preliminary results suggest that this method may provide a valuable tool for the rapid diagnosis of aneuploidy.

Ray, P.N.; Teshima, I.E. [Hospital for Sick Children, Ontario (Canada); Winsor, E.J.T. [Toronto Hospital, Ontario (Canada)] [and others

1994-09-01

397

An exome sequencing strategy to diagnose lethal autosomal recessive disorders.  

PubMed

Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies. PMID:24961629

Ellard, Sian; Kivuva, Emma; Turnpenny, Peter; Stals, Karen; Johnson, Matthew; Xie, Weijia; Caswell, Richard; Lango Allen, Hana

2015-03-01

398

Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene  

Microsoft Academic Search

Axonal forms of Charot-Marie-Tooth disease, either dominantly or recessively inherited, are clinically and genetically heterogeneous. We describe the clinical and electrophysiological characteristics of an axonal autosomal recessive form of Charot-Marie-Tooth disease in a French family, associated with a new mutation of the ganglioside-induced differentiation-associated protein-1 gene (GDAP1). Two sisters, born to non-consanguineous parents, presented severe proximal and distal sensorimotor deficit,

Tanya Stojkovic; Philippe Latour; Ghislaine Viet; Jérôme de Seze; Jean-François Hurtevent; Antoon Vandenberghe; P. Vermersch

2004-01-01

399

Close genetic relationships in vast territories: autosomal and X chromosome Alu diversity in Yakuts from Siberia.  

PubMed

Twelve autosomal and 8 X chromosome Alu markers were genotyped for the first time in 161 Central and West Yakuts to test their ability to reconstruct the genetic history of these populations, the northernmost Turkic-speaker ethnic group living in Siberia. Autosomal data revealed that both groups showed extremely close genetic distances to other populations of Siberian origins that occupied areas from Lake Baikal, the ancestral place of origin of Yakuts, to North Siberia, their current territories. Autosomal and X chromosome data revealed some discrepancies on the genetic differentiation and the effective sizes of Central and West Yakuts. Such discrepancies could be related to the patrilineal and occasionally polygamous structure of these populations. Autosomal and X Alu markers are informative markers to reconstruct population past demography and history, but their utility is limited by the available data. This study represents a contribution for further investigations on these populations. PMID:24466640

Rocañín-Arjó, Ares; Rodríguez-Botigué, Laura; Esteban, Esther; Theves, Catherine; Evdokimova, Larissa E; Fedorova, Sardana A; Gibert, Morgane; Crubezy, Eric; Moral, Pedro

2013-01-01

400

Autosomal spindle fibres influence subsequent sex-chromosome movement in crane-fly spermatocytes.  

PubMed

In meiosis-I crane-fly spermatocytes 3 autosomal half-bivalents move to each pole in anaphase while the 2 sex-chromosomal univalents remain at the equator. The sex chromosomes move to opposite poles only after the autosomes reach the poles; the sex chromosomes start to move polewards about 25 min after the autosomal half-bivalents have begun to move. We irradiated portions of single autosomal spindle fibres with an ultraviolet microbeam and found that these irradiation altered the subsequent sex-chromosome movements. Two effects were observed. In one, one of the sex chromosomes did not move at all; the sex cin after the autosomal half-bivalents have begun to move. We irradiated portions of single autosomal spindle fibres with an ultraviolet microbeam and found that these irradiation altered the subsequent sex-chromosome movements. Two effects were observed. In one, one of the sex chromosomes did not move at all; the sex cin after the autosomal half-bivalents have begun to move. We irradiated portions of single autosomal spindle fibres with an ultraviolet microbeam and found that these irradiation altered the subsequent sex-chromosome movements. Two effects were observed. In one, one of the sex chromosomes did not move at all; the sex chromosome that remained at the equator would normally have moved to the pole associated with the irradiated autosomal spindle fibre. In the second, both sex chromosomes moved to the same pole, always that of the non-irradiated side. These effects occurred whether or not autosomal anaphase movement was blocked by the irradiation. There was no wavelength dependence for altering sex-chromosome movements. Sex-chromosome movements were altered only when at least one sex-chromosomal spindle fibre was adjacent to the irradiated autosomal spindle fibre; when neither sex chromosome had a spindle fibre adjacent to the irradiated autosomal spindle fibres the chromosomes always moved normally. Irradiation of sex-chromosomal spindle fibres during sex-chromosomal anaphase showed short blockages of movement (usually 5-8 min), and then complete recovery. Direct irradiation of sex-chromosomal spindle fibres (without irradiating autosomal spindle fibres) when the autosomes were in anaphase but the sex chromosomes were in metaphase never caused abnormal sex-chromosome movements. These results eliminate the possibility that when we irradiated autosomal spindle fibres that were adjacent to sex-chromosomal spindle fibres the sex-chromosomal spindle fibres were irradiated inadvertently and were unable to recover from the damage. We suggest that the irradiations of autosomal spindle fibres alter a control system involved in "turning on' sex-chromosomal spindle fibre motors, rather than directly altering the motors. We suggest that interactions between spindle fibres are somehow involved in this control system. PMID:7198129

Sillers, P J; Forer, A

1981-06-01

401

Announcement of Population Data Allele frequencies for 70 autosomal SNP loci with  

E-print Network

Interstate Blood Bank, Inc. (Memphis, TN) and Millennium Biotech, Inc. (Ft. Lauderdale, FL). All samples were. SNP markers The 70 autosomal SNP markers are listed in Table 1 (see also http://www.cstl.nist.gov/biotech

402

Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy.  

PubMed Central

Inherited optic neuropathies are a significant cause of childhood and adult blindness and dominant optic atrophy (DOA) is the most common form of autosomally inherited (non-glaucomatous) optic neuropathy. Patients with DOA present with an insidious onset of bilateral visual loss and they characteristically have temporal optic nerve pallor, centrocaecal visual field scotoma, and a colour vision deficit, which is frequently blue-yellow. Evidence from histological and electrophysiological studies suggests that the pathology is confined to the retinal ganglion cell. A gene for dominant optic atrophy (OPA1) has been mapped to chromosome 3q28-qter, and studies are under way to refine the genetic interval in which the gene lies, to map the region physically, and hence to clone the gene. A second locus for dominant optic atrophy has recently been shown to map to chromosome 18q12.2-12.3 near the Kidd blood group locus. The cloning of genes for dominant optic atrophy will provide important insights into the pathophysiology of the retinal ganglion cell in health and disease. These insights may prove to be of great value in the understanding of other primary ganglion cell diseases, such as the mitochondrially inherited Leber's hereditary optic neuropathy and other diseases associated with ganglion cell loss, such as glaucoma. Images PMID:9783700

Votruba, M; Moore, A T; Bhattacharya, S S

1998-01-01

403

Cytological study of Searle's X-autosome translocation in Mus musculus  

Microsoft Academic Search

Genetic studies on Searle'S X-autosome translocation of Mus musculus have shown that a segment of the X carrying the loci for two sex-linked genes, Ta and Blo, has been translocated to an autosome. Females heterozygous for Tabby normally have variegated hair structures, with transverse Ta bands visible against a background of wildtype fur. When the wild-type allele of Ta or

Susumu Ohno; Mary F. Lyon

1965-01-01

404

Genetically enhanced asynapsis of autosomal chromatin promotes transcriptional dysregulation and meiotic failure.  

PubMed

During meiosis, pairing of homologous chromosomes and their synapsis are essential prerequisites for normal male gametogenesis. Even limited autosomal asynapsis often leads to spermatogenic impairment, the mechanism of which is not fully understood. The present study was aimed at deliberately increasing the size of partial autosomal asynapsis and analysis of its impact on male meiosis. For this purpose, we studied the effect of t(12) haplotype encompassing four inversions on chromosome 17 on mouse autosomal translocation T(16;17)43H (abbreviated T43H). The T43H/T43H homozygotes were fully fertile in both sexes, while +/T43H heterozygous males, but not females, were sterile with meiotic arrest at late pachynema. Inclusion of the t(12) haplotype in trans to the T43H translocation resulted in enhanced asynapsis of the translocated autosome, ectopic phosphorylation of histone H2AX, persistence of RAD51 foci, and increased gene silencing around the translocation break. Increase was also on colocalization of unsynapsed chromatin with sex body. Remarkably, we found that transcriptional silencing of the unsynapsed autosomal chromatin precedes silencing of sex chromosomes. Based on the present knowledge, we conclude that interference of meiotic silencing of unsynapsed autosomes with meiotic sex chromosome inactivation is the most likely cause of asynapsis-related male sterility. PMID:22002499

Homolka, David; Jansa, Petr; Forejt, Jiri

2012-02-01

405

From the Cover: KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway  

Microsoft Academic Search

Mutations in the potassium channel gene KCNQ4 underlie DFNA2, an autosomal dominant form of progressive hearing loss in humans. In the mouse cochlea, the transcript has been found exclusively in the outer hair cells. By using specific antibodies, we now show that KCNQ4 is situated at the basal membrane of these sensory cells. In the vestibular organs, KCNQ4 is restricted

Tatjana Kharkovets; Jean-Pierre Hardelin; Saaid Safieddine; Michaela Schweizer; Aziz El-Amraoui; Christine Petit; Thomas J. Jentsch

2000-01-01

406

Dominant optic atrophy  

PubMed Central

Definition of the disease Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Prognosis Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. Management To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation. PMID:22776096

2012-01-01

407

Prospect and Markowitz Stochastic Dominance  

Microsoft Academic Search

Levy and Levy (2002, 2004) develop the Prospect and Markowitz stochastic dominance theory with S-shaped and reverse S-shaped utility functions for investors. In this paper, we extend Levy and Levy’s Prospect Stochastic Dominance theory (PSD) and Markowitz Stochastic Dominance theory (MSD) to the first three orders and link the corresponding S-shaped and reverse S-shaped utility functions to the first three

Wing-Keung Wong; Raymond H. Chan

2005-01-01

408

A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.  

PubMed

Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex. PMID:20164846

Groves, Richard W; Liu, Lu; Dopping-Hepenstal, Patricia J; Markus, Hugh S; Lovell, Patricia A; Ozoemena, Linda; Lai-Cheong, Joey E; Gawler, Jeffrey; Owaribe, Katsushi; Hashimoto, Takashi; Mellerio, Jemima E; Mee, John B; McGrath, John A

2010-06-01

409

Modulation of penetrance by the wild-type allele in dominantly inherited erythropoietic protoporphyria and acute hepatic porphyrias  

Microsoft Academic Search

We have recently demonstrated that in an autosomal dominant porphyria, erythropoietic protoporphyria (EPP), the coinheritance of a ferrochelatase ( FECH) gene defect and of a wild-type low-expressed FECH allele is generally involved in the clinical expression of EPP. This mechanism may provide a model for phenotype modulation by minor variations in the expression of the wild-type allele in the other

Laurent Gouya; Hervé Puy; Anne-Marie Robreau; Said Lyoumi; Jérome Lamoril; Vasco Da Silva; Bernard Grandchamp; Jean-Charles Deybach

2004-01-01