The DFNA2 locus for hearing impairment: two genes regulating K+ ion recycling in the inner ear

DFNA2 is a locus for autosomal dominant non-syndromal hearing impairment (ADNSHI) located on chromosome 1p34 and six linked families have been identified. An audiometric study of these families showed that despite small differences in the phenotype all families suffer from progressive hearing impairment starting in the high frequencies. A detailed genetic analysis revealed that this deafness locus contains more than one gene responsible for hearing impairment. Thus far, two genes on chromosome 1p34 have been implicated in ADNSHI. The first, connexin 31 (GJB3), is a member of the connexin gene family. Connexins form gap junctions. These are connections between neighbouring cells that allow transport of small molecules. GJB3 mutations were found in two small Chinese families with ADNSHI. The second is KCNQ4, a voltage-gated K+ channel. Mutations in KCNQ4 were first found in a small French family, later in five of the six linked DFNA2 families. No GJB3 or KCNQ4 mutations were detected in patients of an extended Indonesian DFNA2 family. Two pathways have been proposed for the recycling of K+ from the hair cells back to the endolymph. These pathways involve the use of gap junctions, K+ pumps and K+ channels. The expression of GJB3 and KCNQ4 in the inner ear and their functions suggest that both DFNA2 genes may play a role in K+ homeostasis.