title: Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology.
abstract: Hearing loss is a common communication disorder caused by various environmental and genetic factors. Hereditary hearing loss is very heterogeneous, and most of such cases involve sensorineural defects in the auditory pathway. There are currently 57 known autosomal dominant non-syndromic hearing loss (DFNA) loci, and the causative genes have been identified at 22 of these loci. In the present study, we performed a genome-wide linkage analysis in a Korean family segregating autosomal dominant hearing loss. We observed linkage on chromosome 1p34, and at this locus, we detected a novel mutation consisting of an 18 nucleotide deletion in exon 4 of the KCNQ4 gene, which encodes a voltage-gated potassium channel. We carried out a functional in vitro study to analyze the effects of this mutation (c.664_681del) along with two previously described KCNQ4 mutations, p.W276S and p.G285C. Although the c.664_681del mutation is located in the intercellular loop and the two previously described mutations, p.W276S and p.G285C, are located in the pore region, all mutants inhibit normal channel function by a dominant negative effect. Our analysis indicates that the intercellular loop is as significant as the pore region as a potential site of pathogenic effects on KCNQ4 channel function.
authors.affiliation: Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 702-701, South Korea.
authors.forename: Jeong-In
authors.initials: JI
authors.lastname: Baek
authors.forename: Hong-Joon
authors.initials: HJ
authors.lastname: Park
authors.forename: Kyungjoon
authors.initials: K
authors.lastname: Park
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Kyu-Yup
authors.initials: KY
authors.lastname: Lee
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Yi
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Dennis
authors.initials: D
authors.lastname: Drayna
authors.forename: Ki Soon
authors.initials: KS
authors.lastname: Shin
authors.forename: Un-Kyung
authors.initials: UK
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D005799:Genes, Dominant; D008040:Genetic Linkage; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics*; D051656:KCNQ Potassium Channels / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017384:Sequence Deletion
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human