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Paolo Gasparini - One of the best experts on this subject based on the ideXlab platform.
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GJB2 and gjb6 genes and the a1555g mitochondrial mutation are only minor causes of nonsyndromic hearing loss in the qatari population
International Journal of Audiology, 2012Co-Authors: Khalifa M Alkowari, Giorgia Girotto, Khalid Abdulhadi, Savina Dipresa, R Siam, Nihal Najjar, Ramin Badii, Paolo GaspariniAbstract:AbstractObjective: This study reports results from the first survey of the genetic causes of nonsyndromic sensorineural hearing loss (NSHHL) in the Qatari population. Design and Study samples: Data were collected from 126 Qatari patients (58 males and 68 females) belonging to inbred families (56%), showing an autosomal recessive pattern of inheritance (96%). Fifty-three patients were less than 10 years old, 55 in the age range of 10 to 20 years, while 18 were aged between 20 and 30 years. All subjects had moderate to severe sensorineural hearing loss and were screened for GJB2 mutations, GJB6 deletion, and for A1555G mitochondrial mutation. Results: Four patients were homozygous and one was heterozygous for c.35delG; five were homozygous for the IVS1 + 1G C. Only 8.3% of the pathogenic alleles were detected. No patients were positive for GJB6 deletion or for A1555G . Conclusions: These findings: (1) demonstrate that GJB2, GJB6 deletion and A1555G mutation accou...
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Mutations in GJB2, GJB6 and mDNA 1555A>G variant explain only a minority of cases of nonsyndromic hearing loss in the Qatari population
Qatar Foundation Annual Research Forum Proceedings, 2010Co-Authors: Moza Khalifa Al Kowari, Paolo Gasparini, Khalid Abdulhadi, Savina Dipresa, Nihal Najjar, Ramin Badii, Rowa Siam, Maha Al-sulaiteen, G. GirottoAbstract:AbstractHereditary hearing loss is a common genetic disorder accounting for at least 60% of prelingual deafness in children. Most cases (70%) are nonsyndromic and are not associated to other signs or symptoms, while the remaining 30% are syndromic. Nonsyndromic hereditary hearing loss has different patterns of inheritance. The most common one is autosomal recessive. This accounts for 75%-85% of the cases. Another 15%-25% of cases are inherited in an autosomal dominant (DNFA) pattern, while the remaining 1%-2% is inherited as X-linked disorder. Several mitochondrial mutations are also reported of which 1555A>G in the 12S rRNA gene is a common cause of mitochondrial-associated deafness in nonsyndromic progressive sensory neural hearing loss and its aminoglycoside induced state.The two major genes for recessive forms are GJB2 and GJB6, which belong to the connexin family. GJB2 and GJB6 code for connexin 26 and connexin 30 proteins, respectively.Here, we report for the first time results of a study in which a...
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a common frameshift mutation and other variants in gjb4 connexin 30 3 analysis of hearing impairment families
Human Mutation, 2002Co-Authors: Nuria Lopezbigas, Salvatore Melchionda, Alfonso Borragan, Paolo Gasparini, Maria L Arbones, Xavier EstivillAbstract:Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment. © 2002 Wiley-Liss, Inc.
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A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families.
Human mutation, 2002Co-Authors: Nuria Lopez-bigas, Salvatore Melchionda, Alfonso Borragan, Paolo Gasparini, Maria L Arbones, Xavier EstivillAbstract:Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment.
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Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins
Human mutation, 2000Co-Authors: Raquel Rabionet, Paolo Gasparini, Xavier EstivillAbstract:Deafness is a complex disorder that involves a high number of genes and environmental factors. There has been enormous progress in non-syndromic deafness research during the last five years, with the identification of over 50 loci and 15 genes. Among these, three genes, GJB2, GJB3, and GJB6, encode for connexin proteins (Connexin26, Connexin31, and Connexin30, respectively). Another connexin (Connexin32, encoded by GJB1) is involved in X-linked peripheral neuropathy and hearing impairment. Mutations in these genes cause autosomal recessive (GJB2 and GJB3), autosomal dominant (GJB2, GJB3, and GJB6) or X-linked (GJB1) hearing impairment, both syndromic (GJB2, keratoderma; GJB3 erythrokeratodermia variabilis; and GJB1, peripheral neuropathy), and non-syndromic (GJB2, GJB3, and GJB6). Among these genes, mutations in GJB2 account for about 50% of all congenital cases of hearing impairment. Three mutations in GJB2 (35delG, 167delT, and 235delC) are particularly common in specific populations (Caucasoid, Jewish Ashkenazi, and Oriental, respectively), leading to carrier frequencies between one in 30 and one in 75. Over 50 mutations have been identified in the GJB2 gene, of which some missense changes (M34T, W44C, G59A, D66H, and R75W) have a negative dominant action in hearing impairment, with partial to full penetrance. Functional studies for some missense mutations in connexins 26, 30, and 32 have indicated abnormal gap junction conductivity. Expression patterns in mouse and rat cochlea indicate that Connexin26 and Connexin30 are expressed in the supportive cells of the cochlea, suggesting a potential role in endolymph potassium recycling. The high prevalence of mutations in GJB2 in some populations provides the tools for molecular diagnosis, carrier detection, and prenatal diagnosis of congenital hearing impairment. Hum Mutat 16:190–202, 2000. © 2000 Wiley-Liss, Inc.
Philine Wangemann - One of the best experts on this subject based on the ideXlab platform.
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k cycling and its regulation in the cochlea and the vestibular labyrinth
Audiology and Neuro-otology, 2002Co-Authors: Philine WangemannAbstract:Potassium (K + ) plays a very important role in the cochlea. K + is the major cation in endolymph and the charge carrier for sensory transduction and the generation of the endocochlear potential. The importance of K + handling in the cochlea is marked by the discovery of several forms of hereditary deafness that are due to mutations of K + channels. Deafness results from mutations of KCNQ4, a K + channel in the sensory hair cells, as well as from mutations of the gap junction proteins GJB2, GJB3 and GJB6 that may facilitate cell-to-cell movements of K + . Deafness results also from mutations of KCNQ1 or KCNE1, subunits of a K + channel that carries K + from strial marginal cells and vestibular dark cells into endolymph. Further, deafness results from mutations of KCNJ10, a K + channel that generates the endocochlear potential in conjunction with the high K + concentration in strial intermediate cells and the low K + concentration in the intrastrial fluid spaces. This review details recent advances in the understanding of K + transport and its regulation in the cochlea and the vestibular labyrinth.
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K(+) cycling and its regulation in the cochlea and the vestibular labyrinth.
Audiology & neuro-otology, 2002Co-Authors: Philine WangemannAbstract:Potassium (K + ) plays a very important role in the cochlea. K + is the major cation in endolymph and the charge carrier for sensory transduction and the generation of the endocochlear potential. The importance of K + handling in the cochlea is marked by the discovery of several forms of hereditary deafness that are due to mutations of K + channels. Deafness results from mutations of KCNQ4, a K + channel in the sensory hair cells, as well as from mutations of the gap junction proteins GJB2, GJB3 and GJB6 that may facilitate cell-to-cell movements of K + . Deafness results also from mutations of KCNQ1 or KCNE1, subunits of a K + channel that carries K + from strial marginal cells and vestibular dark cells into endolymph. Further, deafness results from mutations of KCNJ10, a K + channel that generates the endocochlear potential in conjunction with the high K + concentration in strial intermediate cells and the low K + concentration in the intrastrial fluid spaces. This review details recent advances in the understanding of K + transport and its regulation in the cochlea and the vestibular labyrinth.
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K+ cycling and the endocochlear potential.
Hearing research, 2002Co-Authors: Philine WangemannAbstract:Sensory transduction in the cochlea and the vestibular labyrinth depends on the cycling of K+. In the cochlea, endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells into perilymph via basolateral K+ channels including KCNQ4. K+ may be taken up by fibrocytes in the spiral ligament and transported from cell to cell via gap junctions into strial intermediate cells. Gap junctions may include GJB2, GJB3 and GJB6. K+ is released from the intermediate cells into the intrastrial space via the KCNJ10 K+ channel that generates the endocochlear potential. From the intrastrial space, K+ is taken up across the basolateral membrane of strial marginal cells via the Na+/2Cl-/K+ cotransporter SLC12A2 and the Na+/K+-ATPase ATP1A1/ATP1B2. Strial marginal cells secrete K+ across the apical membrane into endolymph via the K+ channel KCNQ1/KCNE1, which concludes the cochlear cycle. A similar K+ cycle exists in the vestibular labyrinth. Endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells via basolateral K+ channels including KCNQ4. Fibrocytes connected by gap junctions including GJB2 may be involved in delivering K+ to vestibular dark cells. Extracellular K+ is taken up into vestibular dark cells via SLC12A2 and ATP1A1/ATP1B2 and released into endolymph via KCNQ1/KCNE1, which concludes the vestibular cycle. The importance of K+ cycling is underscored by the fact that mutations of KCNQ1, KCNE1, KCNQ4, GJB2, GJB3 and GJB6 lead to deafness in humans and that null mutations of KCNQ1, KCNE1, KCNJ10 and SLC12A2 lead to deafness in mouse models.
Ambroise Wonkam - One of the best experts on this subject based on the ideXlab platform.
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GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana.
Frontiers in Genetics, 2019Co-Authors: Samuel Mawuli Adadey, Noluthando Manyisa, Khuthala Mnika, Victoria Nembaware, Gordon A. Awandare, Osbourne Quaye, Carmen De Kock, Geoggrey Kwabla Amedofu, Ambroise WonkamAbstract:Our study aimed to investigate GJB2 (connexin 26) and GJB6 (connexin 30) mutations associated with non-syndromic childhood hearing impairment (HI) as well as the environmental causes of HI in Ghana. Medical reports of 1104 students attending schools for the deaf were analyzed. Families segregating HI, as well as isolated cases of HI of putative genetic origin were recruited. DNA was extracted from peripheral blood followed by Sanger sequencing of the entire coding region of GJB2. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of GJB6-D3S1830 deletion. Ninety-seven (97) families segregating HI were identified, with 235 affected individuals; and a total of 166 isolated cases of putative genetic causes, were sampled from 11 schools for the deaf in Ghana. The environmental factors, particularly meningitis, remain a major cause of HI impairment in Ghana. The male/female ratio was 1.49. Only 59.6% of the patients had their first comprehensive HI test between 6 to 11 years of age. Nearly all the participants had sensorineural HI (99.5%; n = 639). The majority had pre-lingual HI (68.3%, n = 754), of which 92.8% were congenital. Pedigree analysis suggested autosomal recessive inheritance in 96.9% of the familial cases. GJB2-R143W mutation, previously reported as founder a mutation in Ghana accounted for 25.9% (21/81) in the homozygous state in familial cases, and in 7.9% (11/140) of non-familial non-syndromic congenital HI cases, of putative genetic origin. In a control population without HI, we found a prevalent of GJB2-R143W carriers of 1.4% (2/145), in the heterozygous state. No GJB6-D3S1830 deletion was identified in any of the HI patients. GJB2-R143W mutation accounted for over a quarter of familial non-syndromic HI in Ghana and should be investigated in clinical practice. The large connexin 30 gene deletion (GJB6-D3S1830 deletion) does not account for of congenital non-syndromic HI in Ghana. There is a need to employ Next Generation Sequencing approaches and functional genomics studies to identify the other genes involved in most families and isolated cases of HI in Ghana.
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in search of genetic markers for nonsyndromic deafness in africa a study in cameroonians and black south africans with the gjb6 and gja1 candidate genes
Omics A Journal of Integrative Biology, 2014Co-Authors: Jason Bosch, Kamogelo Lebeko, Jean Jacques Noubiap Nziale, Nomlindo Makubalo, Collet Dandara, Ambroise WonkamAbstract:Abstract Deafness is the most common sensory disability in the world and has a variety of causes. Globally, mutations in GJB2 have been shown to play a major role in nonsyndromic deafness, but this has not been seen in Africans. Two other connexin genes, GJB6 and GJA1, have been implicated in hearing loss but have seldom been investigated in African populations. We set out to investigate the role of genetic variation in GJB6 and GJA1 in a group of Cameroonian and South African Blacks with nonsyndromic recessive hearing loss. A subset of 100 patients, affected with nonsyndromic hearing loss, from a cohort that was previously shown not to have GJB2 mutation, was analyzed by Sanger sequencing of the entire coding regions of GJB6 and GJA1. In addition, the large-scale GJB6-D3S1830 deletion was also investigated. No pathogenic mutation was detected in either GJB6 or GJA1, nor was the GJB6-D3S1830 deletion detected. There were no statistically significant differences in sequence variants between patients and co...
Iris Schrijver - One of the best experts on this subject based on the ideXlab platform.
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Allele-specific impairment of GJB2 expression by GJB6 deletion del(GJB6-D13S1854).
PloS one, 2011Co-Authors: Juan Rodriguez-paris, Marta L. Tamayo, Nancy Gelvez, Iris SchrijverAbstract:Mutations in the GJB2 gene, which encodes connexin 26, are a frequent cause of congenital non-syndromic sensorineural hearing loss. Two large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854), which truncate GJB6 (connexin 30), cause hearing loss in individuals homozygous, or compound heterozygous for these deletions or one such deletion and a mutation in GJB2. Recently, we have demonstrated that the del(GJB6-D13S1830) deletion contributes to hearing loss due to an allele-specific lack of GJB2 mRNA expression and not as a result of digenic inheritance, as was postulated earlier. In the current study we investigated the smaller del(GJB6-D13S1854) deletion, which disrupts the expression of GJB2 at the transcriptional level in a manner similar to the more common del(GJB6-D13S1830) deletion. Interestingly, in the presence of this deletion, GJB2 expression remains minimally but reproducibly present. The relative allele-specific expression of GJB2 was assessed by reverse-transcriptase PCR and restriction digestions in three probands who were compound heterozygous for a GJB2 mutation and del(GJB6-D13S1854). Each individual carried a different sequence variant in GJB2. All three individuals expressed the mutated GJB2 allele in trans with del(GJB6-D13S1854), but expression of the GJB2 allele in cis with the deletion was almost absent. Our study clearly corroborates the hypothesis that the del(GJB6-D13S1854), similar to the larger and more common del(GJB6-D13S1830), removes (a) putative cis-regulatory element(s) upstream of GJB6 and narrows down the region of location.
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The digenic hypothesis unraveled: the GJB6 del(GJB6-D13S1830) mutation causes allele-specific loss of GJB2 expression in cis.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Juan Rodriguez-paris, Iris SchrijverAbstract:Abstract Connexin 26 and connexin 30 are the major connexins expressed in the cochlea, where they are co-localized and form heteromeric gap junctions. Mutations in the GJB2 gene, which encodes connexin 26, are the most common cause of prelingual non-syndromic sensorineural hearing loss. The large del( GJB6 -D13S1830) mutation which involves GJB6 (connexin 30), causes hearing loss in homozygous individuals, or when compound heterozygous with a GJB2 mutation. Until now, it remained unresolved whether this phenomenon results from digenic inheritance or because of lack of GJB2 mRNA expression. After RNA extraction from buccal epithelium, a tissue known to express connexin 26 as well as connexin 30, allele-specific expression of GJB2 was investigated by reverse-transcriptase PCR and restriction digestions in three unrelated individuals compound heterozygous for a GJB2 mutation and del( GJB6 -D13S1830). Each proband carried a different sequence change in GJB2 . The mutated GJB2 allele in trans with del( GJB6 -D13S1830) was expressed in all three individuals whereas the GJB2 allele located in c is with the deletion was not expressed at all. Thus, mutations in these two genes do not cause hearing loss through a digenic mechanism of inheritance alone, as was postulated previously, but instead GJB2 expression is abolished through an effect in cis with the deletion. Our study provides unequivocal support for the hypothesis that del( GJB6 -D13S1830) eliminates a putative cis -regulatory element located within the deleted region.
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The digenic hypothesis unraveled: the GJB6 del(GJB6-D13S1830) mutation causes allele-specific loss of GJB2 expression in cis.
Biochemical and Biophysical Research Communications, 2009Co-Authors: Juan Rodriguez-paris, Iris SchrijverAbstract:Abstract Connexin 26 and connexin 30 are the major connexins expressed in the cochlea, where they are co-localized and form heteromeric gap junctions. Mutations in the GJB2 gene, which encodes connexin 26, are the most common cause of prelingual non-syndromic sensorineural hearing loss. The large del( GJB6 -D13S1830) mutation which involves GJB6 (connexin 30), causes hearing loss in homozygous individuals, or when compound heterozygous with a GJB2 mutation. Until now, it remained unresolved whether this phenomenon results from digenic inheritance or because of lack of GJB2 mRNA expression. After RNA extraction from buccal epithelium, a tissue known to express connexin 26 as well as connexin 30, allele-specific expression of GJB2 was investigated by reverse-transcriptase PCR and restriction digestions in three unrelated individuals compound heterozygous for a GJB2 mutation and del( GJB6 -D13S1830). Each proband carried a different sequence change in GJB2 . The mutated GJB2 allele in trans with del( GJB6 -D13S1830) was expressed in all three individuals whereas the GJB2 allele located in c is with the deletion was not expressed at all. Thus, mutations in these two genes do not cause hearing loss through a digenic mechanism of inheritance alone, as was postulated previously, but instead GJB2 expression is abolished through an effect in cis with the deletion. Our study provides unequivocal support for the hypothesis that del( GJB6 -D13S1830) eliminates a putative cis -regulatory element located within the deleted region.
Xavier Estivill - One of the best experts on this subject based on the ideXlab platform.
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a common frameshift mutation and other variants in gjb4 connexin 30 3 analysis of hearing impairment families
Human Mutation, 2002Co-Authors: Nuria Lopezbigas, Salvatore Melchionda, Alfonso Borragan, Paolo Gasparini, Maria L Arbones, Xavier EstivillAbstract:Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment. © 2002 Wiley-Liss, Inc.
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A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families.
Human mutation, 2002Co-Authors: Nuria Lopez-bigas, Salvatore Melchionda, Alfonso Borragan, Paolo Gasparini, Maria L Arbones, Xavier EstivillAbstract:Mutations in GJB1, GJB2, GJB3 and GJB6 are involved in hearing impairment. GJB2, GJB3 and GJB6 are also mutated in patients with hyperproliferative skin disorders. The human GJB4 gene has been deduced in silico and a mutation in a family with erythrokeratodermia variabilis has been reported. We describe here the analysis of the GJB4 gene in hearing impairment patients and control subjects. We have identified a common (4%) frameshift mutation (154del4) in GJB4 in both affected and hearing subjects, one patient being homozygous for the mutation. We have also detected five amino acid variants (R103C, R124Q, R160C, C169W and E204A) in individuals that have not skin disorders. While mutation 154del4 is not associated with hearing impairment the involvement of some of the amino acid variants detected here is uncertain. These GJB4 variants should help to define the putative role of connexin 30.3 in both skin disorders and hearing impairment.
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Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins
Human mutation, 2000Co-Authors: Raquel Rabionet, Paolo Gasparini, Xavier EstivillAbstract:Deafness is a complex disorder that involves a high number of genes and environmental factors. There has been enormous progress in non-syndromic deafness research during the last five years, with the identification of over 50 loci and 15 genes. Among these, three genes, GJB2, GJB3, and GJB6, encode for connexin proteins (Connexin26, Connexin31, and Connexin30, respectively). Another connexin (Connexin32, encoded by GJB1) is involved in X-linked peripheral neuropathy and hearing impairment. Mutations in these genes cause autosomal recessive (GJB2 and GJB3), autosomal dominant (GJB2, GJB3, and GJB6) or X-linked (GJB1) hearing impairment, both syndromic (GJB2, keratoderma; GJB3 erythrokeratodermia variabilis; and GJB1, peripheral neuropathy), and non-syndromic (GJB2, GJB3, and GJB6). Among these genes, mutations in GJB2 account for about 50% of all congenital cases of hearing impairment. Three mutations in GJB2 (35delG, 167delT, and 235delC) are particularly common in specific populations (Caucasoid, Jewish Ashkenazi, and Oriental, respectively), leading to carrier frequencies between one in 30 and one in 75. Over 50 mutations have been identified in the GJB2 gene, of which some missense changes (M34T, W44C, G59A, D66H, and R75W) have a negative dominant action in hearing impairment, with partial to full penetrance. Functional studies for some missense mutations in connexins 26, 30, and 32 have indicated abnormal gap junction conductivity. Expression patterns in mouse and rat cochlea indicate that Connexin26 and Connexin30 are expressed in the supportive cells of the cochlea, suggesting a potential role in endolymph potassium recycling. The high prevalence of mutations in GJB2 in some populations provides the tools for molecular diagnosis, carrier detection, and prenatal diagnosis of congenital hearing impairment. Hum Mutat 16:190–202, 2000. © 2000 Wiley-Liss, Inc.