The Experts below are selected from a list of 24747 Experts worldwide ranked by ideXlab platform
Marc Thiry - One of the best experts on this subject based on the ideXlab platform.
-
Actin-independent trafficking of cochlear Connexin 26 to non-lipid raft gap junction plaques.
Hearing Research, 2019Co-Authors: Jean Defourny, Nicolas Thelen, Marc ThiryAbstract:Abstract Hereditary hearing loss affects about 1 per 1000 children. Mutations in GJB2, which encodes the Connexin 26 protein (Cx26) involved in cochlear homeostasis, are found in about 50% of patients with autosomal recessive non-syndromic hearing loss. Deciphering the trafficking pathway of cochlear Cx26 in situ should represent an advance in understanding the pathogenic significance of many of these mutations. Connexins trafficking and delivery to lipid raft-associated gap junction plaques usually requires successively microtubule and actin networks. Here we show that cochlear Cx26 exhibits an unusual trafficking pathway. We observed that Cx26 assembly occurs in non-lipid raft membrane domains and that junctional plaques are devoid of actin and associated zonula occludens proteins. Using cytoskeleton-disrupting drugs in organotypic culture, we found that cochlear Cx26 gap junction assembly requires microtubules but not actin filaments. Altogether, our data provide an unexpected insight into Cx26 trafficking pathway and gap junction assembly in the cochlea.
Arti Pandya - One of the best experts on this subject based on the ideXlab platform.
-
Does universal newborn hearing screening identify all children with GJB2 (Connexin 26) deafness? Penetrance of GJB2 deafness.
Ear and hearing, 2006Co-Authors: Virginia W. Norris, Walter E Nance, Kathleen S. Arnos, Wendy D. Hanks, X. J. Xia, Arti PandyaAbstract:Objective:Deafness is the most common neurosensory defect at birth, and GJB2 (Connexin 26) mutations are the most frequent genetic cause of hearing loss in many populations. The hearing loss caused by GJB2 mutations is usually congenital in onset and moderate to profound in degree. Considerable phen
-
Audiological features of GJB2 (Connexin 26) deafness.
Ear and hearing, 2005Co-Authors: Xue Zhong Liu, Walter E Nance, Fred F Telischi, Arti Pandya, Kathleen S. Arnos, Simon I. Angeli, Thomas BalkanyAbstract:Objective: The aim of the present study was to characterize audiological profiles in patients with GJB2 deafness Design: We screened DNA from 399 individuals with nonsyndromic deafness for mutations in the Connexin 26 gene (GJB2) by sequence analysis. A total of 77 (19%) of these deaf individuals were biallelic GJB2 mutations (either homozygous or compound heterozygous mutations) (GJB2 deafness). Using the audiological classification criteria of genetic deafness proposed by the European Workshop on Genetic Hearing Loss, we analyzed audiograms of these patients to characterize audiological features of the GJB2 deafness. In addition, we reviewed audiological data of 411 deafness cases from the literature providing details of audiological data (including 157 with GJB2 deafness). Results: All categories of hearing loss severity were found, with significant differences in the findings from GJB2 cases: 1 (4.5%) of 22 individuals with mild hearing loss, 10 (13.3%) of 75 with moderate loss, 14 (14.9%) of 94 with severe loss, and 52 (25%) of 208 with profound deafness (Chi-square test, 3 df, p = 0.016). 81.6% of patients with GJB2 mutations had severe to profound loss, 18.4% with mild to moderate loss (Chi-square test, p = 0.014). The 235delC mutation was always associated with profound deafness. The main audiogram shapes found were residual/sloping (72.7%) and flat (23.4%). There were no differences in the severity and audiogram shapes of the hearing impairment between homozygous and compound heterozygous GJB2 deafness (Chi-square test, p > 0.05). Conclusions: Our study shows that the probability of finding biallelic GJB2 mutations increases with the severity of hearing loss. Audiograms associated with GJB2 deafness were usually nonspecific. Patients with unknown causes of severe or profound hearing loss should be routinely tested for GJB2 mutations, but due to the variability in hearing loss, individuals with lesser degrees of hearing loss should not be precluded from testing.
-
evidence of a founder effect for the 235delc mutation of gjb2 Connexin 26 in east asians
Human Genetics, 2003Co-Authors: Denise Yan, Walter E Nance, Andrew J Griffith, Xiaomei Ouyang, Arti Pandya, Hong Joon Park, Katsumi Doi, Raadnabazar Erdenetungalag, Naoki Matsushiro, Xue Zhong LiuAbstract:Mutations in the GJB2 gene encoding Connexin 26 (Cx26) are a major cause of autosomal recessive and sporadic cases of congenital deafness in most populations. The 235delC mutation of GJB2 is the most frequent known mutation in some east Asian populations, with a carrier frequency of approximately 1%. In order to study the origin of 235delC among east Asians, we analyzed single-nucleotide polymorphisms (SNPs) within the coding region of GJB2 and flanking the 235delC mutation. We observed significant linkage disequilibrium between 235delC and five linked polymorphic markers, suggesting that 235delC arose from a common founder. The detection of 235delC only in east Asians, but not in Caucasians, and the small chromosomal interval of the shared haplotype suggest that 235delC is an ancient mutation that arose after the divergence of Mongoloids and Caucasians. Similarly, the finding that this mutation appears on a single haplotype provides no support for the possibility that recurrent mutation is the explanation for the high frequency of the allele.
-
Connexin 26 gjb2 mutations in the turkish population implications for the origin and high frequency of the 35delg mutation in caucasians
Human Genetics, 2001Co-Authors: Mustafa Tekin, Walter E Nance, X. J. Xia, Nejat Akar, şukru Cin, Susan H Blanton, Xue Liu, Arti PandyaAbstract:Mutations in the Connexin 26 (GJB2/Cx26) gene are responsible for more than half of all cases of prelingual non-syndromic recessive deafness in many Caucasian populations. To determine the importance of Cx26 mutations as a cause of deafness in Turks we screened 11 families with prelingual non-syndromic deafness, seven (64%) of which were found to carry the 35delG mutation. We subsequently screened 674 Turkish subjects with no known hearing loss and found twelve 35delG heterozygotes (1.78%; 95% confidence interval: 0.9%-3%) but no examples of the 167delT mutation. To search for possible founder effects, we typed chromosomes carrying the 35delG mutation for closely linked polymorphic markers in samples from Turkey and United States and compared the allele frequencies with those of hearing subjects. The data showed a modest degree of disequilibrium in both populations. Analyses of two pedigrees from Turkey demonstrated both conserved and different haplotypes, suggesting possible founder effects and multiple origins of the 35delG mutation.
-
relation between choice of partner and high frequency of Connexin 26 deafness
The Lancet, 2000Co-Authors: Walter E Nance, Xue Zhong Liu, Arti PandyaAbstract:Recessive mutations at the Connexin-26 gene locus are now recognised as the cause of nearly half of all cases of genetic deafness in many populations. We suggest that this high frequency is only seen in populations with a long tradition of intermarriage among deaf people. Available data are consistent with the hypothesis that such marriages might well have contributed to the high frequency of Connexin-26 deafness in the USA, and could represent a novel mechanism for maintaining specific genotypes at unexpectedly high frequencies.
Walter E Nance - One of the best experts on this subject based on the ideXlab platform.
-
Does universal newborn hearing screening identify all children with GJB2 (Connexin 26) deafness? Penetrance of GJB2 deafness.
Ear and hearing, 2006Co-Authors: Virginia W. Norris, Walter E Nance, Kathleen S. Arnos, Wendy D. Hanks, X. J. Xia, Arti PandyaAbstract:Objective:Deafness is the most common neurosensory defect at birth, and GJB2 (Connexin 26) mutations are the most frequent genetic cause of hearing loss in many populations. The hearing loss caused by GJB2 mutations is usually congenital in onset and moderate to profound in degree. Considerable phen
-
Audiological features of GJB2 (Connexin 26) deafness.
Ear and hearing, 2005Co-Authors: Xue Zhong Liu, Walter E Nance, Fred F Telischi, Arti Pandya, Kathleen S. Arnos, Simon I. Angeli, Thomas BalkanyAbstract:Objective: The aim of the present study was to characterize audiological profiles in patients with GJB2 deafness Design: We screened DNA from 399 individuals with nonsyndromic deafness for mutations in the Connexin 26 gene (GJB2) by sequence analysis. A total of 77 (19%) of these deaf individuals were biallelic GJB2 mutations (either homozygous or compound heterozygous mutations) (GJB2 deafness). Using the audiological classification criteria of genetic deafness proposed by the European Workshop on Genetic Hearing Loss, we analyzed audiograms of these patients to characterize audiological features of the GJB2 deafness. In addition, we reviewed audiological data of 411 deafness cases from the literature providing details of audiological data (including 157 with GJB2 deafness). Results: All categories of hearing loss severity were found, with significant differences in the findings from GJB2 cases: 1 (4.5%) of 22 individuals with mild hearing loss, 10 (13.3%) of 75 with moderate loss, 14 (14.9%) of 94 with severe loss, and 52 (25%) of 208 with profound deafness (Chi-square test, 3 df, p = 0.016). 81.6% of patients with GJB2 mutations had severe to profound loss, 18.4% with mild to moderate loss (Chi-square test, p = 0.014). The 235delC mutation was always associated with profound deafness. The main audiogram shapes found were residual/sloping (72.7%) and flat (23.4%). There were no differences in the severity and audiogram shapes of the hearing impairment between homozygous and compound heterozygous GJB2 deafness (Chi-square test, p > 0.05). Conclusions: Our study shows that the probability of finding biallelic GJB2 mutations increases with the severity of hearing loss. Audiograms associated with GJB2 deafness were usually nonspecific. Patients with unknown causes of severe or profound hearing loss should be routinely tested for GJB2 mutations, but due to the variability in hearing loss, individuals with lesser degrees of hearing loss should not be precluded from testing.
-
evidence of a founder effect for the 235delc mutation of gjb2 Connexin 26 in east asians
Human Genetics, 2003Co-Authors: Denise Yan, Walter E Nance, Andrew J Griffith, Xiaomei Ouyang, Arti Pandya, Hong Joon Park, Katsumi Doi, Raadnabazar Erdenetungalag, Naoki Matsushiro, Xue Zhong LiuAbstract:Mutations in the GJB2 gene encoding Connexin 26 (Cx26) are a major cause of autosomal recessive and sporadic cases of congenital deafness in most populations. The 235delC mutation of GJB2 is the most frequent known mutation in some east Asian populations, with a carrier frequency of approximately 1%. In order to study the origin of 235delC among east Asians, we analyzed single-nucleotide polymorphisms (SNPs) within the coding region of GJB2 and flanking the 235delC mutation. We observed significant linkage disequilibrium between 235delC and five linked polymorphic markers, suggesting that 235delC arose from a common founder. The detection of 235delC only in east Asians, but not in Caucasians, and the small chromosomal interval of the shared haplotype suggest that 235delC is an ancient mutation that arose after the divergence of Mongoloids and Caucasians. Similarly, the finding that this mutation appears on a single haplotype provides no support for the possibility that recurrent mutation is the explanation for the high frequency of the allele.
-
The prevalence of Connexin 26 ( GJB2) mutations in the Chinese population.
Human genetics, 2002Co-Authors: Xue Zhong Liu, Walter E Nance, Xiaomei Ouyang, Xia Juan Xia, Yu He Liu, Simon Angeli, Fred F Telischi, Thomas BalkanyAbstract: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.
-
Connexin 26 gjb2 mutations in the turkish population implications for the origin and high frequency of the 35delg mutation in caucasians
Human Genetics, 2001Co-Authors: Mustafa Tekin, Walter E Nance, X. J. Xia, Nejat Akar, şukru Cin, Susan H Blanton, Xue Liu, Arti PandyaAbstract:Mutations in the Connexin 26 (GJB2/Cx26) gene are responsible for more than half of all cases of prelingual non-syndromic recessive deafness in many Caucasian populations. To determine the importance of Cx26 mutations as a cause of deafness in Turks we screened 11 families with prelingual non-syndromic deafness, seven (64%) of which were found to carry the 35delG mutation. We subsequently screened 674 Turkish subjects with no known hearing loss and found twelve 35delG heterozygotes (1.78%; 95% confidence interval: 0.9%-3%) but no examples of the 167delT mutation. To search for possible founder effects, we typed chromosomes carrying the 35delG mutation for closely linked polymorphic markers in samples from Turkey and United States and compared the allele frequencies with those of hearing subjects. The data showed a modest degree of disequilibrium in both populations. Analyses of two pedigrees from Turkey demonstrated both conserved and different haplotypes, suggesting possible founder effects and multiple origins of the 35delG mutation.
R F Mueller - One of the best experts on this subject based on the ideXlab platform.
-
a common founder for the 35delg gjb2 gene mutation in Connexin 26 hearing impairment
Journal of Medical Genetics, 2001Co-Authors: Lut Van Laer, R F Mueller, Mark J Houseman, Graham R Taylor, Paul Coucke, Goele Caethoven, Kris Flothmann, Suyash Prasad, G P Chamberlin, C M Van De HeyningAbstract:Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein Connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder effect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for different single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant differences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder.
-
genetic analysis of the Connexin 26 m34t variant identification of genotype m34t m34t segregating with mild moderate non syndromic sensorineural hearing loss
Journal of Medical Genetics, 2001Co-Authors: Mark J Houseman, Amelia H Osborn, Hans Henrik M Dahl, Lucy A Ellis, Alistair T Pagnamenta, Sarah Rickard, Graham R Taylor, Maria Bitnerglindzicz, William Reardon, R F MuellerAbstract:Mutations in the human gap junction β-2 gene (GJB2) that encodes Connexin-26 have been shown to cause non-syndromic sensorineural hearing loss (NSSNHL) at the DFNB1 locus on 13q11. Functional and genetic data regarding the disease causing potential of one particular GJB2 sequence variant, 101 T→C (M34T), have proven contradictory. In this study, we found the prevalence of the M34T allele in a cohort of white sib pairs and sporadic cases with NSSNHL from the United Kingdom and Ireland to be 3.179% of chromosomes screened. Significantly, we identified the first M34T/M34T genotype cosegregating in a single family with mid to high frequency NSSNHL. Screening a control population of 630 subjects we identified 25 M34T heterozygotes; however, no M34T homozygotes were detected. Surprisingly, the majority of M34T alleles (88%) were in cis with a 10 bp deletion in the 5' non-coding sequence. This non-coding deletion was also homozygous in the homozygous M34T subjects. Microsatellite analysis of flanking loci in M34T heterozygotes and controls does not define an extensive ancestral haplotype but preliminary data suggest two common alleles in subjects with the M34T allele. In summary, we provide data that support M34T acting as a recessive GJB2 allele associated with mild-moderate prelingual hearing impairment. Keywords: GJB2; Connexin-26; M34T; hearing loss
-
Connexin 26 mutations in sporadic non syndromal sensorineural deafness
The Lancet, 1998Co-Authors: N J Lench, Guy Van Camp, Mark J Houseman, Valerie Newton, R F MuellerAbstract:Congenital or childhood-onset sensorineural deafness affects about one in 1000 children and is especially important since it impedes oral language acquisition. Most cases (about 70%) are non-syndromal—ie, they occur in the absence of associated features. Although non-syndromal sensorineural deafness usually occurs sporadically, a genetic cause is responsible in up to 60% of cases, most (about 75%) of which are inherited in an autosomal recessive manner. Clinical and audiological features such as age of onset and severity do not usually allow reliable discrimination between acquired and genetic causes when providing estimates of recurrence risk for genetic counselling in an individual family. Recurrence risks for subsequent offspring are therefore based on empirical data. Non-syndromal sensorineural deafness is genetically heterogeneous with, to date, 20 autosomal recessive and 13 autosomal dominant loci mapped. 1 Recently, mutations in the Connexin-26 gene (Cx26) have been shown to result in autosomal recessive (DFNB1) and dominant (DFNA3) non-syndromal sensorineural deafness. 2 In addition, a single mutation in the Connexin-26 gene, 30delG, accounts for most (about 70%) of Cx26 mutant alleles in families that originate from the UK, France, Italy, Spain, Tunisia, Lebanon, Australia, and New Zealand. 3,4 To determine the prevalence of Cx26 mutations in sporadic non-syndromal sensorineural deafness, we studied a cohort of 68 non-consanguineous UK and Belgian singletons. Detailed clinical histories and physical examinations excluded obvious syndromal or acquired causes of hearing loss/deafness. Genomic DNA was extracted from blood or buccal scrapes. The entire Cx26 coding region was amplified on two overlapping fragments (285 bp and 520 bp, respectively). 1 Samples were screened for mutations by both single-strand conformation polymorphism analysis and direct DNA sequencing of PCR products. Cx26 gene mutations were identified in four of 43 UK and two of 25 Belgian singletons. Three of six individuals with Cx26 mutations were homozygous for the 30delG mutation and three of six were heterozygous for the mutation. DNA sequencing of the entire Cx26 coding region of the other allele of affected individuals heterozygous for the 30delG mutation failed to reveal a second mutation. This could be explained by a mutation in the 5' (exon 1 and the promoter region) or 3' non-coding regions of the Cx26 gene or a digenic mode of inheritance—ie, mutations occurring in two different genes—as has been shown in retinitis pigmentosa. 5
-
a moroccan family with autosomal recessive sensorineural hearing loss caused by a mutation in the gap junction protein gene Connexin 26 gjb2
Journal of Medical Genetics, 1998Co-Authors: N J Lench, Richard J H Smith, A F Markham, R F Mueller, David P Kelsell, P J Willems, Isabelle Schatteman, H Capon, P J Van De Heyning, G Van CampAbstract:We report a mutation in the Connexin 26 gene (Cx26) in a consanguineous Moroccan family linked to the DFNA3/DFNB1 locus on human chromosome 13q11-q12. Affected subjects display congenital, bilateral, sensorineural hearing loss. We have previously identified Cx26 mutations in consanguineous Pakistani families. This current finding indicates that Cx26 mutations are not restricted to ethnically and geographically distinct populations. This is an important observation since it will help to determine the overall contribution of Connexin 26 mutations to autosomal deafness in different populations.
-
Connexin 26 mutations in hereditary non syndromic sensorineural deafness
Nature, 1997Co-Authors: David P Kelsell, N J Lench, R F Mueller, J Dunlop, Howard P Stevens, J N Liang, Gareth Parry, I M LeighAbstract:Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein Connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.
Tomitake Tsukihara - One of the best experts on this subject based on the ideXlab platform.
-
structure of the Connexin 26 gap junction channel at 3 5 a resolution
Nature, 2009Co-Authors: Shoji Maeda, Atsunori Oshima, Yoshinori Fujiyoshi, So Nakagawa, Michihiro Suga, Eiki Yamashita, Tomitake TsukiharaAbstract:Gap junctions consist of arrays of intercellular channels between adjacent cells that permit the exchange of ions and small molecules. Here we report the crystal structure of the gap junction channel formed by human Connexin 26 (Cx26, also known as GJB2) at 3.5 A resolution, and discuss structural determinants of solute transport through the channel. The density map showed the two membrane-spanning hemichannels and the arrangement of the four transmembrane helices of the six protomers forming each hemichannel. The hemichannels feature a positively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance. The structure of the Cx26 gap junction channel also has implications for the gating of the channel by the transjunctional voltage.