Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment

Xia, Jia; Liu, Chunyu; Tang, Bei; Pan, Qian; Huang, Lei; Dai, He; Zhang, Bao Rong; Xie, Wei; Hu, Dong Xu; Zheng, Duo; Shi, Xiaoliu; Wang, De An; Xia, Kun; Yu, Kuan Ping; Liao, Xiao Dong; Feng, Yong; Yang, Youyun; Xiao, Jian Yun; Xie, Dongdong; Huang, Jian

doi:10.1038/3845

Cited by 400 publications

(242 citation statements)

References 14 publications

(7 reference statements)

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“…The importance of Cxs in hearing has been revealed by genetic studies showing that mutations in Cx genes are among the most common forms of human genetic defects, resulting in hearing impairments in millions of patients with either autosomal dominant or recessive deafness (1)(2)(3). In many ethnic populations, mutations in Cx26 (1,4), Cx30 (5,6), and other Cx genes (7,8) have been linked to approximately half of inherited prelingual nonsyndromic deafness cases. The most commonly found mutations are deletions of either Cx26 (e.g., 35delG or 235delC; refs.…”

mentioning

confidence: 99%

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Ahmad

Tang²,

Chang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

132

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Mutations in genes coding for connexin26 (Cx26) and/or Cx30 are linked to approximately half of all cases of human autosomal nonsyndromic prelingual deafness. Cx26 and Cx30 are the two major Cx isoforms found in the cochlea, and they coassemble to form hybrid (heteromeric and heterotypic) gap junctions (GJs). This molecular arrangement implies that homomeric GJs would remain in the cochlea if one of the coassembly partners were mutated resulting in null expression. We generated mice in which extra copies of the Cx26 gene were transgenically expressed from a modified bacterial artificial chromosome in a Cx30 ؊/؊ background. In the absence of the Cx30 gene, Cx26 expressed from extra alleles completely restored hearing sensitivity and prevented hair cell death in deaf Cx30 ؊/؊ mice. The results indicated that hybrid GJs consisting of Cx26 and Cx30 were not essential for normal hearing in mice and suggested that up-regulation of Cx26 or slowing down its protein degradation might be a therapeutic strategy to prevent and treat deafness caused by Cx30 mutations.gap junction ͉ hearing rescue ͉ hereditary deafness

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mentioning

confidence: 99%

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Ahmad

Tang²,

Chang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

132

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“…Certain mutational alterations of individual connexins are known to be associated with some human hereditary diseases. Thus mutations of Cx32 are associated with Charcot-Marie-Tooth Xlinked peripheral neuropathy (CMTX) (Bergoffen et al, 1993;Nelis et al, 1999;, mutations of Cx26 (White et al, 1998) and Cx31 (Xia et al, 1998) with deafness, and those of Cx31 (Richard et al, 1998) and Cx30 (Lamartine et al, 2000) with skin disorders. It has also been found that autosomal mutations of Cx43 involving phosphorylatable serine or threonine residues in the carboxyl-terminal tail of the protein are associated with complex human heart malformations (Britz-Cunningham et al, 1995).…”

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confidence: 99%

Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer

et al. 2002

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The membrane-spanning connexin proteins form microscopic intercellular channels that directly connect the cytoplasms of adjacent cells and as such have been implicated in maintenance of tissue homeostasis. They are considered to act as tumor suppressors since their function or expression is frequently aberrant in tumor cells. Several mechanisms appear to be involved in this, but irreversible mutational alterations have not yet been proved to be among them. In this study we have demonstrated for the first time that connexin 43 but not connexin 32 is specifically and quite frequently mutated in human colon sporadic adenocarcinomas. All tumor-associated mutations led to a shift of reading frame and were located in the multifunctional carboxylterminal domain of the protein. Expression of mutated connexin 43 protein was restricted to invasive structures of tumors. These findings suggest that mutational alterations of connexin 43 are involved in advanced stages of progression of human colon cancer towards malignancy.

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“…Richard et al [1998a] identified three mutations in the Connexin31 gene (GJB3) in four families with erythrokeratodermia variabilis (EKV). Independently, Xia et al [1998] presented the cloning of the human GJB3 gene on chromosome 1p33-p35 and found mutations in two small deafness families. In both cases the disorders were inherited in an autosomal dominant pattern with partial penetrance (female carriers have either subclinical deafness or normal hearing).…”

Section: Of Gjb2 Mutationsmentioning

confidence: 99%

“…During the last three years 15 of the genes involved in NSHI have been identified by positional cloning or positional candidate gene approaches. Seven genes are responsible for ARNSHI: GJB2 (GDB: 125247; MIM# 121011, 220290, 601544; GenBank: M86849, U43932; URL: http://www.iro.es/ cx26deaf.html) [Kelsell et al, 1997;Zelante et al, 1997], PDS [Li et al, 1998], MYO7A [Liu et al, 1997], MYO15 , TECTA , OTOF [Yasunaga et al, 1999], and GJB3 (GDB: 127820; MIM# 600101, 603324, 133200; GenBank: AF099730, AF052692, AJ004856) [Xia et al, 1998]; 10 for ADNSHI: GJB2 [Kelsell et al, 1997;Denoyelle et al, 1998], HDIA1 [Lynch et al, 1997], MYO7A [Liu et al, 1997], GJB3 [Xia et al, 1998], DFNA5 , TECTA [Verhoeven et al, 1998], COCH [Robertson et al, 1998], POU4F3 [Vahava et al, 1998], KCNQ4 [Kubisch et al, 1999], and GJB6 (GDB: 9958357; GenBank: AJ005585) [Grifa et al, 1999]; one for X-linked non-syndromic hearing impairment: POU3F4 [de Kok et al, 1995]; and one for maternal (mitochondrial) inheritance of non-syndromic hearing loss: 12S rRNA [Prezant et al, 1993;Estivill et al, 1998a] (for details see Hereditary Hearing Loss Homepage).…”

Section: Introductionmentioning

confidence: 99%

Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins

Rabionet¹,

Gasparini

Estivill³

2000

Hum. Mutat.

185

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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.

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Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment

Cited by 400 publications

References 14 publications

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

Connexin 43, but not connexin 32, is mutated at advanced stages of human sporadic colon cancer

Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins

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