Mutations in the GJB2 gene (connexin 26) are the major cause of autosomal recessive non-syndromic hearing impairment in many populations. In contrast to the volume of information regarding the involvement of GJB2 mutations in hearing impairment in populations of European ancestry, less is known regarding other ethnic groups. In this study, we analyzed the GJB2 gene for mutations in 1227 hearing-impaired Japanese individuals. This revealed a unique spectrum of GJB2 mutations, different from that found in the Caucasian population. The most frequent mutation in Japanese, 235delC, has never been reported in Caucasians. To investigate a possible founder effect for the 235delC mutation, we analyzed single nucleotide polymorphisms in the vicinity of the GJB2 gene. Results were consistent with inheritance of the 235delC mutation from a common ancestor. The results of this study have important implications for genetic diagnostic testing for deafness in the Japanese population.

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Mutations in the GJB2 (connexin 26, Cx26) gene are the major cause of nonsyndromic hearing impairment in many populations. Genetic testing offers opportunities to determine the cause of deafness and predict the course of hearing, enabling the prognostication of language development. In the current study, we compared severity of hearing impairment in 60 patients associated with biallelic GJB2 mutations and assessed the correlation of genotypes and phenotypes. Within a spectrum of GJB2 mutations found in the Japanese population, the phenotype of the most prevalent mutation, 235delC, was found to show more severe hearing impairment than that of V37I, which is the second most frequent mutation. The results of the present study, taken together with phenotypes caused by other types of mutations, support the general rule that phenotypes caused by the truncating GJB2 mutations are more severe than those caused by missense mutations. The present in vitro study further confirmed that differences in phenotypes could be explained by the protein expression pattern.

The present study demonstrated that the prevalence of deafness in individuals with the A1555G mitochondrial mutation was likely to be high even in the absence of aminoglycoside exposure and clearly showed the association of severe to profound hearing loss with the onset of hearing loss before age 10 years.

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