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1.
Seyed Basir Hashemi Mohamad Javad Ashraf Mohamad Saboori Negar Azarpira Masumeh Darai 《Molecular biology reports》2012,39(12):10481-10487
Hereditary hearing loss is a genetically heterogeneous disorder. Mutations in connexin 26 (CX26), are a major cause in many countries and are largely dependent on ethnic groups. The purpose of our study was to evaluate the prevalence of GJB2 mutations among affected individuals from south of Iran. Fifty patients presenting with autosomal recessive non-syndromic hearing loss from Fars, province in south of Iran, were studied for mutations in GJB2 gene and screened by direct sequencing. Mutations were detected in 15 out of 50 patients (30?%). Eight different mutations were identified; six of them were previously identified (35delG, V27I M34V, V153I, A149T, V198M). The remaining two alleles, L28I and N169T, were novel variants. The most common mutations were 35delG followed by V153I with an allele frequency of 7 and 6?%, respectively. In this study, 30?% of our subjects were found to have the causative variants or polymorphisms in GJB2 and the c.35delG mutation was the most common cause in our patients. However, more study with larger sample size as well as in vitro functional study for these new variants in Xenopus oocytes is required. 相似文献
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Alessandro Terrinoni Andrea Codispoti Valeria Serra Biagio Didona Steven Nisticò Bianca Napolitano Gerry Melino 《Biochemical and biophysical research communications》2010,395(1):25-30
KID syndrome (MIM 148210) is an ectodermal dysplasia characterized by the occurrence of localized erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. KID syndrome is inherited as an autosomic dominant disease, due to mutations in the gene encoding gap junction protein GJB2 (connexin 26, Cx26). Cx26 is a component of gap junction channels in the epidermis and in the stria vascularis of the cochlea. These channels play a role in the coordinated exchange of molecules and ions occurring in a wide spectrum of cellular activities. In this paper we describe two patients with Cx26 mutations cause cell death by the alteration of protein trafficking, membrane localization and probably interfering with intracellular ion concentrations. We discuss the pathogenesis of both the hearing and skin phenotypes. 相似文献
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Tekin M Duman T Boğoçlu G Incesulu A Cin S Akar N 《Genetic counseling (Geneva, Switzerland)》2003,14(4):379-386
Mutations in the GJB2 (connexin 26-Cx26) gene are responsible for 20-50% of cases with prelingual non-syndromic deafness in a large part of the world including Turkey. Although most of the cases with Cx26 deafness have a recessive mode of inheritance, a small group of families demonstrated dominant or pseudodominant inheritance. In this report we present a Turkish family in which the proband had congenital profound deafness and was found to be homozygous for the 35delG mutation, whereas the father and a paternal uncle who had milder, late-onset sensorineural hearing loss had compound heterozygous 35delG and L90P mutations. This family and previous reports with the L90P mutation demonstrate that the hearing loss associated with the L90P/35delG genotype is consistently milder than that of 35delG homozygotes. GJB2 gene screening should be considered in families with seemingly dominant inheritance and late-onset moderate hearing loss. 相似文献
6.
Utrera R Ridaura V Rodríguez Y Rojas MJ Mago L Angeli S Henríquez O 《Genetic testing》2007,11(4):347-352
Severe to profound hearing impairment affects 1 of every 1000 newborn children each year. Inheritance accounts for 60% of these cases, of which 70% are nonsyndromic. The most common cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) is mutation in GJB2, a gene on chromosome 13, which encodes a gap junction protein named Connexin 26. Mutations in GJB2 are responsible for 40% of genetic childhood deafness. The most common mutation, 35delG, predominates in many ethnic groups. Some families with linkage to the DFNB1 locus have none or only one mutated allele in GJB2, however, some subjects can exhibit a large deletion in another connexin gene, GJB6, resulting in a monogenic or digenic pattern of inheritance in this complex DFNB1 locus that contains both genes (GJB2 and GJB6). The aim of the study was to determine (1) the frequency for the 35delG (27.5%), del(GJB6-D13S1830) (2.5%) and del(GJB6-D13S1854) (0.0%) mutations in a cohort of 40 Venezuelan patients with ARNSHL and (2) the carrier frequency 35delG (4%), del(GJB6-D13S1830) (0%) and del(GJB6-D13S1854) (0%) in the Venezuelan population with no familial history of hearing impairment. One patient (2.5%) was detected as double heterozygote for the deletion del(GJB6-D13S1830) and 35delG mutation. This result has direct clinical implications because we include the molecular detection of the deletion del(GJB6-D13S1830) during the evaluation of the diagnosis of deafness in the Venezuelan population. 相似文献
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Liu XZ Xia XJ Ke XM Ouyang XM Du LL Liu YH Angeli S Telischi FF Nance WE Balkany T Xu LR 《Human genetics》2002,111(4-5):394-397
Mutations in GJB2, encoding gap junction beta 2 protein (connexin 26), are responsible for the commonest form of non-syndromic recessive deafness in many populations. It has been reported recently that the most common 35delG mutation in GJB2 is exceptionally low in Japanese and Korean populations, but another deletion, 235delC, is relatively frequent. Since the Chinese constitute approximately one fifth of the global population, the frequency of GJB2 mutations in the population has important implications for understanding worldwide causes of genetic deafness. To determine whether GJB2 mutations are an important cause of deafness in Chinese, we conducted mutation screening for GJB2 in 118 deaf Chinese probands, including 60 from simplex and 58 from multiplex families with non-syndromic deafness, and 150 normal hearing Chinese controls. Four mutations, including 235delC, 299-300delAT, V37I, and 35delG, were found in the patients. Thirty-nine percent of the probands had a GJB2mutation. Of the 118 probands, 19 carried two definitely pathogenic mutations: three among the 58 multiplex cases (5.2%) and 16 among the 60 simplex cases (26.7%). Twenty-seven probands (22.9%) were found to carry only single GJB2 mutations. None of them had mutations in exon 1 of GJB2 and or the 342-kb deletion of GJB6. The 235delC mutation was the most prevalent mutation (20.3% of alleles), accounting for 81% of the pathologic alleles in multiplex cases and 67% in simplex cases. Analysis of the affected haplotypes in the patients with the homozygous 235delC mutation yielded evidence for a single origin of the mutation. The carrier frequency of the 235delC mutation in control subjects with normal hearing was 1.3%. The 35delG mutation was only noted as a heterozygous change in two simplex cases (1.2% of alleles). These results indicated that mutations in GJB2 are a major cause of inherited and sporadic congenital deafness in the Chinese population. The 235delC mutation, rather than 35delG, is the most common mutation found in the Chinese deaf population. Our data support the view that specific combinations of GJB2 mutation exist in different populations. 相似文献
8.
Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT 总被引:2,自引:0,他引:2
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Griffith AJ Chowdhry AA Kurima K Hood LJ Keats B Berlin CI Morell RJ Friedman TB 《American journal of human genetics》2000,67(3):745-749
Previous studies of the gap-junction beta-2 subunit gene GJB2 (connexin 26) have suggested that the 101T-->C (M34T) nucleotide substitution may be a mutant allele responsible for recessive deafness DFNB1. This hypothesis was consistent with observations of negligible intercellular coupling and gap-junction assembly of the M34T allele product expressed in Xenopus oocytes and HeLa cells. The results of our current study of a family cosegregating the 167delT allele of GJB2 and severe DFNB1 deafness demonstrate that this phenotype did not cosegregate with the compound-heterozygous genotype M34T/167delT. Since 167delT is a null allele of GJB2, this result indicates that the in vivo activity of a single M34T allele is not sufficiently reduced to cause the typical deafness phenotype associated with DFNB1. This observation raises the possibility that other GJB2 missense substitutions may not be recessive mutations that cause severe deafness and emphasizes the importance of observing cosegregation with deafness in large families to confirm that these missense alleles are mutant DFNB1 alleles. 相似文献
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High frequency hearing loss correlated with mutations in the GJB2 gene 总被引:18,自引:0,他引:18
Wilcox SA Saunders K Osborn AH Arnold A Wunderlich J Kelly T Collins V Wilcox LJ McKinlay Gardner RJ Kamarinos M Cone-Wesson B Williamson R Dahl HH 《Human genetics》2000,106(4):399-405
Genetic hearing impairment affects approximately 1/2000 live births. Mutations in one gene, GJB2, coding for connexin 26 cause 10%-20% of all genetic sensorineural hearing loss. Mutation analysis in the GJB2 gene and audiology were performed on 106 families presenting with at least one child with congenital hearing loss. The families were recruited from a hospital-based multidisciplinary clinic, which functions to investigate the aetiology of sensorineural hearing loss in children and which serves an ethnically diverse population. In 74 families (80 children), the aetiology was consistent with non-syndromic recessive hearing loss. Six different connexin 26 mutations, including one novel mutation, were identified. We show that GJB2 mutations cause a range of phenotypes from mild to profound hearing impairment and that loss of hearing in the high frequency range (4000-8000 Hz) is a characteristic feature in children with molecularly diagnosed connexin 26 hearing impairment. We also demonstrate that this type of audiology and high frequency hearing loss is found in a similar-sized group of deaf children in whom a mutation could only be found in one of the connexin 26 alleles, suggesting connexin 26 involvement in the aetiology of hearing loss in these cases. In our study of the M34T mutation, only compound heterozygotes exhibited hearing loss, suggesting autosomal recessive inheritance. 相似文献
10.
Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29 总被引:27,自引:0,他引:27
Wilcox ER Burton QL Naz S Riazuddin S Smith TN Ploplis B Belyantseva I Ben-Yosef T Liburd NA Morell RJ Kachar B Wu DK Griffith AJ Riazuddin S Friedman TB 《Cell》2001,104(1):165-172
Tight junctions in the cochlear duct are thought to compartmentalize endolymph and provide structural support for the auditory neuroepithelium. The claudin family of genes is known to express protein components of tight junctions in other tissues. The essential function of one of these claudins in the inner ear was established by identifying mutations in CLDN14 that cause nonsyndromic recessive deafness DFNB29 in two large consanguineous Pakistani families. In situ hybridization and immunofluorescence studies demonstrated mouse claudin-14 expression in the sensory epithelium of the organ of Corti. 相似文献
11.
Hui-Mei Hong Jiann-Jou Yang Jia-Ching Shieh Mei-Ling Li Shuan-Yow Li 《Human genetics》2010,127(5):545-551
Connexins (CXs), a large family of membrane proteins, are key components of gap junction channels. Among a cohort of patients
with nonsyndromic hearing loss, we have recently identified three novel missense mutations in the GJA1 gene and GJA1 pseudogene (ρGJA1) as likely being causally related to hearing loss. However, the functional alteration of CX43 caused by the mutations of
GJA1 and ρGJA1 gene remains unclear. This study compares the intracellular distribution and assembly of three CX43 mutants expressed in
HeLa cells with their wild-type (WT) counterparts and the effects of the mutant proteins on those cells. Localization assay
of WT CX43 reveals a typical punctuate fluorescence pattern of a gap junction channel between neighboring expression cells.
Additionally, immunoblotting analysis of the transfectants confirms the production of mutant proteins, in which their distributions
along appositional membranes are determined using immunofluorescent staining procedures. Furthermore, dye transfer assay results
demonstrate that gap junctional intercellular communication is less in HeLa cells carrying mutant GJA1 or ρGJA1 gene than in WT-expressing cells. The results of this study suggest that the three mutations in GJA1 or ρGJA1 that we previously reported result in at least partial loss of normal functions carried out by CX43, which may form a basis
for the mechanism contributing to hearing loss in patients. 相似文献
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Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations 总被引:3,自引:0,他引:3
Cryns K Pfister M Pennings RJ Bom SJ Flothmann K Caethoven G Kremer H Schatteman I Köln KA Tóth T Kupka S Blin N Nürnberg P Thiele H van de Heyning PH Reardon W Stephens D Cremers CW Smith RJ Van Camp G 《Human genetics》2002,110(5):389-394
Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment. 相似文献
13.
Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy 总被引:12,自引:0,他引:12
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Raffaele Di Barletta M Ricci E Galluzzi G Tonali P Mora M Morandi L Romorini A Voit T Orstavik KH Merlini L Trevisan C Biancalana V Housmanowa-Petrusewicz I Bione S Ricotti R Schwartz K Bonne G Toniolo D 《American journal of human genetics》2000,66(4):1407-1412
Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function. 相似文献
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Zied Riahi Hassen Hammami Houyem Ouragini Habib Messai Rim Zainine Yosra Bouyacoub Lilia Romdhane Donia Essaid Rym Kefi Mohsen Rhimi Monia Bedoui Afef Dhaouadi Delphine Feldmann Laurence Jonard Ghazi Besbes Sonia Abdelhak 《Gene》2013
Hearing loss is the most frequent sensory disorder. It affects 3 in 1000 newborns. It is genetically heterogeneous with 60 causally-related genes identified to date. Mutations in GJB2 gene account for half of all cases of non-syndromic deafness. The aim of this study was to determine the relative frequency of GJB2 allele variants in Tunisia. In this study, we screened 138 patients with congenital hearing loss belonging to 131 families originating from different parts of Tunisia for mutations in GJB2 gene. GJB2 mutations were found in 39% of families (51/131). The most common mutation was c.35delG accounting for 35% of all cases (46/131). The second most frequent mutation was p.E47X present in 3.8% of families. Four identified mutations in our cohort have not been reported in Tunisia; p.V37I, c.235delC, p.G130A and the splice site mutation IVS1+1G>A (0.76%). These previously described mutations were detected only in families originating from Northern and not from other geographical regions in Tunisia. In conclusion we have confirmed the high frequency of c.35delG in Tunisia which represents 85.4% of all GJB2 mutant alleles. We have also extended the mutational spectrum of GJB2 gene in Tunisia and revealed a more pronounced allelic heterogeneity in the North compared to the rest of the country. 相似文献
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Hassan MJ Santos RL Rafiq MA Chahrour MH Pham TL Wajid M Hijab N Wambangco M Lee K Ansar M Yan K Ahmad W Leal SM 《Human genetics》2006,118(5):605-610
Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. Autosomal recessive (AR) forms of prelingual
HI account for ~75% of cases with a genetic etiology. A novel AR non-syndromic HI locus (DFNB47) was mapped to chromosome 2p25.1-p24.3, in two distantly related Pakistani kindreds. Genome scan and fine mapping were carried
out using microsatellite markers. Multipoint linkage analysis resulted in a maximum LOD score of 4.7 at markers D2S1400 and
D2S262. The three-unit support interval was bounded by D2S330 and D2S131. The region of homozygosity was found within the
three-unit support interval and flanked by markers D2S2952 and D2S131, which corresponds to 13.2 cM according to the Rutgers
combined linkage-physical map. This region contains 5.3 Mb according to the sequence-based physical map. Three candidate genes,
KCNF1, ID2 and ATP6V1C2 were sequenced, and were found to be negative for functional sequence variants. 相似文献
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Azeem Z Jelani M Naz G Tariq M Wasif N Kamran-Ul-Hassan Naqvi S Ayub M Yasinzai M Amin-Ud-Din M Wali A Ali G Chishti MS Ahmad W 《Human genetics》2008,123(5):515-519
Autosomal recessive hypotrichosis (LAH3) is a rare hair disorder characterized by sparse hair on scalp and the rest of the
body of affected individuals. Recently mutations in a G protein-coupled receptor gene, P2RY5, located at LAH3 locus, have been reported in several families with autosomal recessive hypotrichosis simplex and woolly
hair. For the present study, 22 Pakistani families with autosomal recessive hypotrichosis were enrolled. Genotyping using
microsatellite markers linked to three autosomal recessive forms of hypotrichosis (LAH1, LAH2, LAH3) showed the linkage of
2 families to the LAH2 locus and 14 to the LAH3 locus. The remaining 6 families were not linked to any of the three loci.
Families linked to LAH3 locus were further subjected to screening of the P2RY5 gene with direct DNA sequencing. Three previously reported variants, c.69insCATG (p.24insHfs52), c.188A > T (p.D63V) and
c.565G > A (p.E189K) were observed in eight families. Four novel nonsynonymous sequence variants, c.8G > C (p.S3T), c.36insA
(p.D13RfsX16), c.160insA (p.N54TfsX58) and c.436G > A (p.G146R) were found to segregate within six families.
Z. Azeem, M. Jelani, G. Naz, M. Tariq, N. Wasif, S. Kamran-ul-Hassan Naqvi contributed equally to this work. 相似文献
20.
Janecke AR Hirst-Stadlmann A Günther B Utermann B Müller T Löffler J Utermann G Nekahm-Heis D 《Human genetics》2002,111(2):145-153
Mutations of GJB2 (encoding connexin 26) are the most common cause of hearing loss (HL) in different populations, and a broad spectrum of GJB2 mutations has been identified. We screened 204 consecutive patients with non-syndromic sensorineural hearing loss for GJB2 mutations. Causative GJB2mutations were identified in 31 (15.2%) patients, and two common mutations, c.35delG and L90P (c.269T>C), accounted for 72.1% and 9.8% of GJB2 disease alleles. In four additional patients (2.0%) only one recessive GJB2 mutation was identified, making genetic counselling difficult. No genotype-phenotype correlation was established. We found, however, that homozygotes for truncating mutations were more likely to have a more severe degree of HL compared with other genotypes. Moreover, we showed by co-segregation studies that L90P is a GJB2 disease allele, and that compound heterozygotes for L90P and any recessive mutation share a mild to moderate phenotype. GJB2-associated HL was linked with progressive HL or with recurrent sudden sensorineural hearing loss (SSNHL) in three of 15 cases being analysed retrospectively. We extended the phenotypic spectrum of GJB2-related disease and recommend GJB2 mutation screening also in cases of progressive HL, and recurrent SSNHL. In addition, a carrier frequency of 1/110 (0.9%) for the most common Caucasian mutation in this gene, c.35delG, was determined in 1,212 blood donors from West-Austria, supporting the prevailing hypothesis of a Mediterranean founder mutation. Based on population and patient data, an overall GJB2 mutation carrier frequency of 1.3% was estimated for West-Austria. 相似文献