Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene.

ABSTRACT: To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss.Prospective molecular genetic research study.Academic genetic research laboratory.Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses.Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis.Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation.Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single-nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34-p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate-binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation.Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4.

SUBMITTER: Arnett J 

PROVIDER: S-EPMC3278911 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature