M34T and V37I mutations in <i>GJB2</i> associated hearing impairment: Evidence for pathogenicity and reduced penetrance

Pollak, Agnieszka; Skórka, Agata; Mueller-Malesińska, Małgorzata; Kostrzewa, Grażyna; Kisiel, Bartłomiej; Waligora, J; Krajewski, Paweł; Ołdak, Monika; Korniszewski, L; Skarżyńśki, Henryk; Płoski, Rafał

doi:10.1002/ajmg.a.31982

Cited by 103 publications

(87 citation statements)

References 45 publications

(56 reference statements)

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“…28 Previous studies demonstrated that mutation IVS1+1G4A was predominantly registered among Caucasian populations. 14,38,40,41,[47][48][49] Relatively high rates of this mutation in Eastern Europe (Czech Republic, Poland and Hungary) have been supposed to be specific for Slavic populations. 47 In recent study of Tekin et al, 50 identification of this mutation in homozygous state in Turks and Mongolians and reconstruction of common haplotype with IVS1+1G4A proposes Central Asian origin for this mutation followed by the migration of its carriers to the territories of Middle East.…”

Section: Discussionmentioning

confidence: 99%

Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect

Barashkov¹,

Dzhemileva

Fedorova³

et al. 2011

J Hum Genet

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Section: Discussionmentioning

confidence: 99%

Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect

Barashkov¹,

Dzhemileva

Fedorova³

et al. 2011

J Hum Genet

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“…For example, a p.V37I mutation in Cx26 causes various phenotypes from mild to severe hearing loss. Therefore, functional studies using cell lines are critical to understand the pathogenicities of the GJB2 mutations (Han et al, 2008;Mani et al, 2008;Pollak et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Different functional consequences of two missense mutations in theGJB2gene associated with non-syndromic hearing loss

Choi

Park²,

Lee

et al. 2009

Hum. Mutat.

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Mutations in the GJB2 gene, which encodes the gap junction (GJ) protein connexin26 (Cx26), are the most common cause of inherited non-syndromic hearing loss (NSHL). We identified two missense mutations, p.D46E (c.138T>G) and p.T86R (c.257C>G), of GJB2 in Korean HL families. The novel p.D46E mutation exhibited autosomal dominant inheritance, while the p.T86R mutation, which is exclusively found in Asians, segregated with an autosomal recessive pattern. Thus, we sought to elucidate the pathogenic nature of such different inherited patterns of HL. We studied protein localization and gap junction functions in cells transfected with wild-type or mutant Cx26 tagged with fluorescent proteins, which allowed visual confirmation of homozygous or heterozygous mutant GJs. The Cx26-D46E mutant was targeted to the plasma membrane, but this mutant protein failed to transfer Ca 2+ or propidium iodide intercellularly, suggesting disruption of both ionic and biochemical coupling. Heterozygous GJs also showed dysfunctional intercellular couplings and hemichannel opening, confirming the dominant-negative nature of the p.D46E mutation. The Cx26-T86R mutant protein did not form GJs, since the mutated protein was confined in the cytoplasm and not transported to the cell membrane. When Cx26-T86R was co-expressed with Cx26-WT, ionic and biochemical coupling was normal, consistent with the recessive nature of the mutation. These studies revealed distinct pathogenic mechanisms of two GJB2 mutations identified in Korean families.

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“…Three mutations,c.35delG,c.167delT,and c.235delC, are found to be the most frequent mutations in Caucasian, Ashkenazi Jews, and East Asian populations, respectively (Morell et al, 1998;Roux et al, 2004;Tsukada et al, 2010). The polymorphisms are diverse and complex as well; p.V27I and p.E114G are commonly described as polymorphic variants in East Asian countries (Han et al, 2008) while the p.V37I variant, originally described as an innocent polymorphism, was recently suggested to contribute to the pathogenesis of moderate hearing loss in a Korean population (Pollak et al, 2007;Kim et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Update of the Spectrum ofGJB2Mutations in 107 Patients with Nonsyndromic Hearing Loss in the Fujian Population of China

Chen

Jiang

Liu

et al. 2014

Annals of Human Genetics

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SummaryMutations in the GJB2 gene, encoding connexin26, which is expressed in the inner ear, have been shown to be responsible for the majority of nonsyndromic hearing loss (NSHL) cases. To update and evaluate the spectrum and prevalence of GJB2 mutations in the Fujian population, we screened exon 2 (coding), exon 1, and flanking introns of GJB2 in 107 NSHL probands and 61 individuals with normal hearing. Twelve different variants were identified, including three pathogenic mutations (c.235delC, c.299_300delAT, and c.508insAACG), one hypomorphic allele (p

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M34T and V37I mutations in GJB2 associated hearing impairment: Evidence for pathogenicity and reduced penetrance

Cited by 103 publications

References 45 publications

Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect

Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect

Different functional consequences of two missense mutations in theGJB2gene associated with non-syndromic hearing loss

Update of the Spectrum ofGJB2Mutations in 107 Patients with Nonsyndromic Hearing Loss in the Fujian Population of China

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