In a 4-generation Turkish family segregating for autosomal dominant deafness and palmoplantar keratoderma (148350), Uyguner et al. (2002) identified a 224G-A transition in the GJB2 gene resulting in an arg75-to-gln (R75Q) mutation. The age of onset and progression of hearing loss were variable among affected family members, but they all had more severe impairment at higher hearing frequencies. Mutation in the same amino acid (R75W; 121011.0011) is associated with profound prelingual hearing loss and palmoplantar keratoderma.
Feldmann et al. (2005) reported 2 French families presenting with autosomal dominant hearing loss (DFNA3A; 601544) caused by the R75Q mutation of the GJB2 gene. In 1 family, a mother and son presented with hearing loss with no skin disease. The hearing defect was profound in the child and moderate/severe in his mother. Both were heterozygous for the R75Q mutation. The R75Q mutation was not found in either of the mother's parents. In the second family reported by Feldmann et al. (2005), a father and his 2 daughters presented with a sensorineural hearing loss associated with skin abnormalities. Bilateral mild hearing loss of the father had been diagnosed at age 18 years, and a palmoplantar keratosis had developed during infancy. His elder daughter had a mild bilateral hearing loss detected at age 10 years.
In 4 individuals over 3 generations of a Turkish family with autosomal dominant nonsyndromic congenital profound hearing loss, Piazza et al. (2005) identified heterozygosity for the R75Q mutation in the GJB2 gene. Cell transfection and fluorescence imaging, dye transfer experiments, and dual patch-clamp recording showed that the mutant protein completely prevents the formation of functional channels.
