Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival

Common, J.E.

doi:10.1136/jmg.2003.017632

Cited by 49 publications

(30 citation statements)

References 11 publications

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“…Even carriers of a recessive GJB2 mutation have been found to have altered keratinocyte behavior. 8 We have found GJB2 variants in a small proportion of this series of 98 children with cholesteatoma, with 14% of children carrying at least one variant, including 3% with two variants. It is difficult to define a normal population by which this rate could be compared to determine whether it is higher than would be expected in children without cholesteatoma.…”

Section: Discussionmentioning

confidence: 99%

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Pediatric cholesteatoma and variants in the gene encoding connexin 26

et al. 2009

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Objectives/Hypothesis: Connexin 26 is a gap junction protein encoded by the GJB2 gene. It is expressed in cholesteatoma, and mutations cause proliferative skin disorders and sensorineural hearing loss (SNHL). Deletions of GJB6, which encodes connexin 30, cause SNHL in a digenic manner with a heterozygous GJB2 mutation. We hypothesize that GJB2 and GJB6 mutations might influence the development of cholesteatoma.Study Design: Prospective observational study to identify GJB mutations in pediatric cholesteatoma.Methods: Peripheral blood samples from 98 children with cholesteatoma were screened for mutations in the GJB2 gene by direct sequencing of the coding region (exon 2 and the intron/exon boundary). Deletions of the GJB6 gene were tested using multiple ligation probe amplification methods. GJB status was compared with other populations and patient age and extent of cholesteatoma at presentation.Results: Fourteen children had at least one GJB2 variant (14%). Of these, three had two variants. Two of the variants were neutral polymorphisms. One child with the GJB2 genotype 35delG/35delG also had SNHL. No correlation was found between GJB2 status and patient age or cholesteatoma severity at presentation. No GJB6 deletions were found.Conclusions: GJB2 gene variants are present in a minority of children with cholesteatoma, but may be more common than in normal populations. It is conceivable that alterations of connexin 26 expression could contribute to the multifactorial disease process in cholesteatoma by modifying the cell-to-cell communication that is important in proliferation and migration of keratinocytes.

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Section: Discussionmentioning

confidence: 99%

“…7 This has been attributed to prolonged keratinocyte survival. 8 Connexin 30 (encoded by the GJB6 gene) is also found in normal human epidermis. It often colocalizes with connexin 26 and is important in keratinocyte differentiation and wound healing.…”

Section: Introductionmentioning

confidence: 99%

Pediatric cholesteatoma and variants in the gene encoding connexin 26

et al. 2009

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“…25 This thickening of epidermis is perhaps due to increased cell survival mediated by R143W. 26 Future studies could test if W24X also confers a heterozygote advantage. Of the 530 individuals screened, one was a compound heterozygote for W24X and R143W.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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In a study of 530 individuals with non-syndromic, sensorineural hearing loss, we identified 18 mutations at connexin 26 (Cx26), four of which are novel (À23G4T, I33T, 377_383dupTCCGCAT, W172R) and the remaining 14 (ivs1 þ 1G4A, M1V, 35delG, W24X, I35S, V37I, R75W, W77X, 312del14, E120del, Q124X, Y136X, R143W, R184P) being mutations previously described. To gain insight into functional consequences of these mutations, cellular localization of the mutant proteins and their ability to permit lucifer yellow transfer between cells was studied in seven of them (W24X, I33T, I35S, R75W, E120del, W172R and R184P). I35S and R184P showed impaired trafficking of the protein to the plasma membrane. I33T, R75W, E120del and W172R showed predominantly membrane localization but did not form functional gap junction channels. Surprisingly, W24X, a protein-truncating mutation, apparently permits formation of a full-length protein, perhaps due to a stop codon read-through mechanism. These results provide further evidence that Cx26 mutations affect gap junction activity by mis-regulation at multiple levels.

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“…7, [26][27][28][29][30] Furthermore, novel hypotheses for the probable specific mechanism (combination of improved genetic fitness and assortative mating) for selective amplification of the commonest form of recessive deafness in the populations and of probable heterozygote advantage of GJB2 recessive mutations have been suggested. 31,32 Data on the mutation spectrum and prevalence of major mutations of the GJB2 gene in various ethnic groups are very important for the development of molecular diagnostics tools for identifying genetic causes of hereditary hearing loss; however, data on the prevalence of major GJB2 mutations in some populations are still not available.…”

Section: Introductionmentioning

confidence: 99%