Molecular Basis of Disease

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In 1994, Guilford et al. mapped the first locus for ARNSD to chromosome 13q12-13 and named it DFNB1 (Online Mendelian Inheritance in Man [OMIM; database online] #220290).4 Three years later, the deafness-causing gene at this locus was identified as GJB2.5 GJB2 encodes a transmembrane protein called Connexin 26 (Cx26) that oligomerizes with five other connexins to form a con-nexon. Connexons in adjoining cells join to form gap junctions, or conduits, that facilitate the rapid exchange of electrolytes, second messengers, and metabolites from one cytoplasm to another.6 Interestingly and unexpectedly, mutations in Cx26 have been found in approximately 50% of persons with severe-to-profound congenital ARNSD in several worldwide populations.711

Immunohistochemical studies of Cx26 expression in rat cochleae have demonstrated that two groups of cells are interconnected via gap junctions. The first group, nonsen-sory epithelial cells, includes interdental cells of the spiral limbus, inner and outer sulcus cells, sensory supporting cells, and cells within the root process of the spiral ligament. The second group, the connective tissue cell gap junction system, includes fibrocytes within the spiral ligament and spiral limbus, basal and intermediate cells of the stria vascularis, and mesenchymal cells, which line the scala vestibule and interconnect the two populations of cell types. Expression of Cx26 in the vestibular labyrinth is similar.12,13 These studies suggest that the Cx26 gap junction system plays a role in potassium recycling, facilitating the rapid transport of K+ ions through the supporting cell network to the stria vascularis, thereby helping to maintain the unique potassium-sodium endolymph balance.14

Although more than 80 different deafness-causing allele variants of GJB2 have been reported,15 in populations of European descent a single mutation predominates, 35delG. This mutation reflects the deletion of one deoxyguanosine from a string of 6, resulting in a shift in reading frame and premature protein truncation. Based on an analysis of single nucleotide polymorphisms (SNPs) tightly linked to the 35delG mutation, this mutation segregates on a common haplotype background and arose as a result of a founder effect about 10,000 years ago.16

Today, the carrier frequency for the 35delG mutation in the midwestern United States is approximately 2.5%, and in this population roughly two thirds of persons with Cx26-related deafness are 35delG homozygotes.2,17 Of the remaining persons with Cx26-related deafness, most are 35delG heterozygotes, and carry a second, noncomplemen-tary mutation. Consistent with a founder origination is the observation that in some populations the 35delG mutation is rare. For example, in the Ashkenazi Jewish and Japanese populations, the 167delT and 235delC mutations, respectively, are most common.18,19

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