A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families

López‐Bigas, Núria; Melchionda, Salvatore; Gasparini, Paolo; Borragán, Alfonso; Arbonés, María L.; Estivill, Xavier

doi:10.1002/humu.9023

Cited by 19 publications

(21 citation statements)

References 8 publications

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“…At least six Cx genes (Cx26, Cx29, Cx30, Cx30.3, Cx31 and Cx43) are known to be involved in human genetic deafness (Kelsell et al 1997;Xia et al 1998;Grifa et al 1999;López-Bigas et al 2002;Yang et al 2007;Wang et al 2010). The proteins they encode are located in gap junction-rich regions of the cochlear duct, suggesting that all six connexin proteins are essential components of gap junctions.…”

Section: Introductionmentioning

confidence: 99%

A novel mutation in the connexin 29 gene may contribute to nonsyndromic hearing loss

Hong

Yang

Su³

et al. 2009

Hum Genet

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Connexins (Cxs) are homologous four-transmembrane domain proteins and constitute the major components of gap junctions. Among a cohort of patients with nonsyndromic hearing loss, we recently identified a novel missense mutation, E269D, in the GJC3 gene encoding connexin 29 (Cx29), as being causally related to hearing loss. The functional alteration of Cx29 caused by the mutant GJC3 gene, however, remains unknown. This study compared the intracellular distribution and assembly of mutant Cx29 (Cx29E269D) with that of the wild-type Cx29 (Cx29WT) in HeLa cells and the effect the mutant protein had on those cells. Cx29TW showed continuous staining along apposed cell membranes in the fluorescent localization assay. In contrast, the p.E269D missense mutation resulted in accumulation of the Cx29 mutant protein in the endoplasmic reticulum (ER) rather than in the cytoplasmic membrane. Co-expression of Cx29WT and Cx29E269D proteins by a bi-directional tet-on expression system demonstrated that the heteromeric connexon accumulated in the cytoplasm, thereby impairing the formation of the gap junction. Based on these findings, we suggest that Cx29E269D has a dominant negative effect on the formation and function of the gap junction. These results provide a novel molecular explanation for the role Cx29 plays in the development of hearing loss.

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Section: Introductionmentioning

confidence: 99%

A novel mutation in the connexin 29 gene may contribute to nonsyndromic hearing loss

Hong

Yang

Su³

et al. 2009

Hum Genet

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“…The proportions of carrier variants for GJB2, GJB3, GJB4, GJC3, and GJA1 were 7.91% (20/253), 4.35% (11/253), 3.56% (9/253), 4.74% (12/253), and 0.40% (1/253), respectively. Twenty-six diVerent variants of the CX gene family were observed, of which 17 were novel variants and the rest were presented in previous reports, including 3 GJB2 variants (c.235delC, c.368C > A, and c.11G > A), 4 GJB4 variants (c.64C > T, c.109G > A, c.292C > T, and c.370C > T) and 2 GJC3 variants (c.*+2T > G, c.781 + 62G > A) (Park et al 2000;Wang et al 2002Wang et al , 2010López-Bigas et al 2002;Hwa et al 2003;Yang et al 2007). Of the 26 variants, 19…”

Section: Study Populationmentioning

confidence: 99%

“…Less frequently encountered are mutations in other CX genes, such as GJB6, GJB3, and GJB1 (Grifa et al 1999;Xia et al 1998;BergoVen et al 1993;Liu et al 2000). In addition, few studies have been conducted on the correlation of variants in the GJB4 (López-Bigas et al 2002;Yang et al 2007), GJA1 (Yang et al 2007) and GJC3 gene (Yang et al 2007;Wang et al 2010), and its phenotype in patients with nonsyndromic hearing loss. In current study, a genetic survey was made on 373 Taiwanese individuals, 253 with nonsyndromic deafness and 120 (Wang et al 2010).…”

Section: Prevalence Of Cxs Gene Variantsmentioning

confidence: 99%

“…Mutations in the CX gene family, including GJB2 (CX26), GJB3 (CX31), GJB4 (CX30.3), GJB6 (CX30), GJC3 (CX30.2/ CX31.3), and GJA1 (CX43), have been shown to underlie distinct genetic forms of HL (Kelley et al 1998;Grifa et al 1999;Xia et al 1998;López-Bigas et al 2002;Yang et al 2007;Wang et al 2010). Our previous genetic survey of 380 Taiwanese individuals, comprising 260 with nonsyndromic HL and 120 with normal hearing, found that 62 of the 260 deaf subjects (23.85%) had mutations in the CX gene family (Yang et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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Prospective variants screening of connexin genes in children with hearing impairment: genotype/phenotype correlation

et al. 2010

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The crucial role of gap junctions, which are composed of connexin (CX) protein, in auditory functions has been confirmed by numerous studies. In this study, we investigate the prevalence and phenotype/genotype correlation of connexin (CX) gene family variants in a cohort of children with nonsyndromic hearing loss (HL). A total of 253 unrelated children with nonsyndromic HL were screened for the presence of variants in 6 genes of the CX gene family. The prevalence of CX gene variants in 253 patients was 19.7% (50/253). We found the frequency of a sloping audiometric configuration was significantly higher for children with GJB2 and GJB3 variants than for those with GJB4 and GJC3 variants (Adjusted OR = 4.89, p < 0.001). Conversely, the frequency of a flat audiometric configuration was significantly higher for children with GJB4 and GJC3 variants than for those with GJB2 and GJB3 variants (adjusted OR = 7.76, p < 0.001). The relative frequencies of multiplex families was significantly higher for children with GJB3 variants than for those with GJB2, GJB4, and GJC3 variants (Adjusted OR = 11.33, p = 0.003). Our results suggest the variants of GJC3, GJB4, and GJB3 may be the common genetic risk factor, after variants of GJB2, for the development of nonsyndromic HL in Taiwan. These data can be effectively applied to direct the clinical evaluation of children with CX gene variants.

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“…Mutations in connexin-26 (Cx26), connexin-30 (Cx30), connexin 30.3 (Cx30.3) and connexin-31 (Cx31) are linked to both non-syndromic and syndromic deafness (Denoyelle et al, 1997;Kelsell et al, 1997;Zelante et al, 1997;Xia et al, 1998;Grifa et al, 1999;Lopez-Bigas et al, 2001, 2002b. Electrophysiological studies of Xenopus oocytes expressing different connexin mutants revealed that HI-associated Cx26 mutants failed to generate intercellular conductance (White et al, 1998;Bruzzone et al, 2001Bruzzone et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

Trafficking abnormality and ER stress underlie functional deficiency of hearing impairmentassociated connexin-31 mutants

Xia

Xiong

et al. 2010

Protein Cell

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Hearing impairment (HI) affects 1/1000 children and over 2% of the aged population. We have previously reported that mutations in the gene encoding gap junction protein connexin-31 (Cx31) are associated with HI. The pathological mechanism of the disease mutations remains unknown. Here, we show that expression of Cx31 in the mouse inner ear is developmentally regulated with a high level in adult inner hair cells and spiral ganglion neurons that are critical for the hearing process. In transfected cells, wild type Cx31 protein (Cx31wt) forms functional gap junction at cell-cell-contacts. In contrast, two HIassociated Cx31 mutants, Cx31R180X and Cx31E183K resided primarily in the ER and Golgi-like intracellular punctate structures, respectively, and failed to mediate lucifer yellow transfer. Expression of Cx31 mutants but not Cx31wt leads to upregulation of and increased association with the ER chaperone BiP indicating ER stress induction. Together, the HI-associated Cx31 mutants are impaired in trafficking, promote ER stress, and hence lose the ability to assemble functional gap junctions. The study reveals a potential pathological mechanism of HI-associated Cx31 mutations.

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A common frameshift mutation and other variants in GJB4 (connexin 30.3): Analysis of hearing impairment families

Cited by 19 publications

References 8 publications

A novel mutation in the connexin 29 gene may contribute to nonsyndromic hearing loss

A novel mutation in the connexin 29 gene may contribute to nonsyndromic hearing loss

Prospective variants screening of connexin genes in children with hearing impairment: genotype/phenotype correlation

Trafficking abnormality and ER stress underlie functional deficiency of hearing impairmentassociated connexin-31 mutants

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