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

G ap junctions composed of connexins (Cx) are intercellular channels that provide a mechanism of synchronised cellular response facilitating the metabolic and electronic functions of the cell. At least 20 human Cx genes have been described, many of which harbour germline mutations that are associated with a variety of human diseases. Recessive mutations in the coding region of GJB2 encoding Cx26 are associated with non-syndromic hearing loss (NSHL) and, indeed, account for a significant proportion of NSHL worldwide. Within different ethnic groups, there are specific common founder mutations that account for the majority of GJB2-related hearing loss, for example, 35delG, 235delC, and R143W in the European, Japanese, and African populations, respectively. The relatively high carrier frequency of recessive GJB2 mutations residing in the human genetic pool suggests there may be phenotypic advantages counterbalancing NSHL. Examination of skin histology has revealed that individuals homozygous and heterozygous for the common African GJB2 mutation, R143W, had significantly thicker epidermis plus higher sodium and chloride sweat secretions than wildtype family members. The authors suggested these GJB2-associated epidermal phenotypes may provide a protective mechanism against pathogen invasion. Although clinically defined skin disease is not described with these or other NSHL alleles, it should be noted that specific dominant GJB2 mutations result in ectodermal disorders in which hyperkeratosis is a common feature. Here, we describe in vitro analysis of deafness-associated missense GJB2 mutations that provide further evidence of a physiological mechanism that could provide GJB2-phenotypic advantage in vivo.