Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene.
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Arnett J, Emery SB, Kim TB, Boerst AK, Lee K, Leal SM, Lesperance MM
Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene.
Arch Otolaryngol Head Neck Surg. 2011 Jan;137(1):54-9. doi: 10.1001/archoto.2010.234.
- PubMed ID
- 21242547 [ View in PubMed]
- Abstract
OBJECTIVE: To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss. DESIGN: Prospective molecular genetic research study. SETTING: Academic genetic research laboratory. PARTICIPANTS: Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses. INTERVENTIONS: Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis. MAIN OUTCOME MEASURES: Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation. RESULTS: 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. CONCLUSIONS: 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.