Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss

Mani, Ram S.; Ganapathy, Aparna; Jalvi, Rajeev; Srisailapathy, C. R. Srikumari; Malhotra, Vikas; Chadha, Shelly; Agarwal, Arun; Ramesh, A.; Rangasayee, R.; Anand, Anuranjan

doi:10.1038/ejhg.2008.179

Cited by 71 publications

(81 citation statements)

References 33 publications

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“…The p.T86R mutation is located in the second transmembrane domain of Cx26 and converts an uncharged amino acid to a positively charged amino acid. The Cx26-T86R phenotype is consistent with previous studies suggesting that transmembrane domains are important for oligomerization and membrane targeting of Cxs (Mani et al, 2008). In addition, several mutations in the transmembrane domains have been shown to cause recessively inherited patterns of hearing loss (Bruzzone et al, 2003;Man et al, 2007) in accord with the p.T86R mutation and its observed recessive inheritance in Korean family.…”

Section: Discussionsupporting

confidence: 76%

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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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Section: Discussionsupporting

confidence: 76%

“…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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“…[3] and Mani et al [2] but with low ethnic and geographic variation in Cx 26 mutations across the continents has been reported earlier, for example, 35delG mutation is predominant in Europeans [9], 167delT in Ashkenazi Jews [10] and 235delC in Japanese [11] etc.…”

Section: Discussionmentioning

confidence: 99%

“…Indian data on the genetics of non-syndromic hearing NSHL is limited and is based on several small studies except a recent larger study by Mani et al [2]. India is a huge obtained from one part of the country to other regions.…”

Section: Introductionmentioning

confidence: 99%

Low prevalence of GJB2 mutations in non-syndromic hearing loss in Western India

Godbole¹,

Hemavathi

Vaid³

et al. 2010

Indian J Otolaryngol Head Neck Surg

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Objectives To identify the prevalence of GJB2 (Cx 26)and GJB6 (Cx 30) mutations in hearing impaired individuals from Western and South India.Study design Cross-sectional study.Methods Families with hearing impaired individuals (prelingual, non-syndromic, sensori-neural hearing loss) were enrolled and genomic DNA was extracted. Primers were designed for amplifying the coding and non-coding Probands heterozygous or negative for Cx 26 mutations were further analyzed for the 342Kb deletion encompassing D13S1830 microsatellite marker on Cx 30.Results Two hundred and eighty-eight patients were enrolled in the study and 116 (40.3%) were diagnosed to have mutations in the coding exon 2 of Cx 26 gene. Fiftyfour (18.8%) probands were found to have mutations in both the alleles while the remaining 62 (21.5%) were heterozygous for Cx 26 mutations. W24X, and W77X were deafness was similar in both consanguineous and nonconsanguineous families (33% and 34.9% respectively).Mutations in the non-coding exon 1 and intron 1 as well as the 342 kb deletion involving D13S1830 marker on Cx 30 were ruled out in two hundred and thirty-four deaf individuals carrying none or only one mutation in the exon 2 of Cx 26 gene.Conclusion Cx 30 mutations do not contribute to the autosomal recessive non-syndromic hearing loss (NSHL) in the Indian population. Homozygous Cx26 mutations account only for about 1/5th (18.8%) of autosomal recessive non-syndromic hearing implying the need to explore other contributory loci.

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“…The residues in the intracellular loop region and C-terminus are very different among different connexins and are hence thought to be responsible for regulation. These residues could thus impart unique properties to the various connexin molecules [14]. According to ConSeq [15] the mutation p.Leu213X affects a highly conserved residue that has evolved slowly ( fig.…”

Section: Methodsmentioning

confidence: 99%

A novel p.Leu213X mutation in GJB2 gene in a Portuguese family

Gonçalves

Chora

Matos

et al. 2013

International Journal of Pediatric Otorhinolaryngology

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A novel p.Leu213X mutation in GJB2 gene in a Portuguese familyDear Sirs, Herewith we are submitting an Article, focused on a new mutation found in the GJB2 gene. This mutation, p.Leu213X, introduces a premature STOP codon avoiding the formation of the functional connexin 26 protein and in the present study was found in compound heterozygosity with another GJB2 mutation already identified (c.333-334delAA), being this genotype responsible for the hearing impairment observed in the two patients. We would like to inform that there is no conflict of interest regarding this study.Thanking you in advance for your prompt attention to our submission. There is no conflict of interest 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Abstract Introduction: Hearing loss is the most common sensory disability and is present in about 1.9 *Manuscript

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Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss

Cited by 71 publications

References 33 publications

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

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

Low prevalence of GJB2 mutations in non-syndromic hearing loss in Western India

A novel p.Leu213X mutation in GJB2 gene in a Portuguese family

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