title: A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction.
abstract: Mutations within the COCH gene (encoding the cochlin protein) lead to auditory and vestibular impairment in the DFNA9 disorder. In this study, we describe the genetic mapping of progressive autosomal dominant sensorineural hearing loss first affecting high-frequency auditory thresholds within a human pedigree to the long arm of chromosome 14 in band q12. A maximal pairwise LOD score of 7.08 was obtained with marker D14S1021. We identified a c.1625G > T mutation in exon 12 of COCH that co-segregates with auditory dysfunction in the pedigree. The mutation results in a predicted p.C542F substitution at an evolutionarily conserved cysteine residue in the C-terminus of cochlin. The c.1625G > T transversion in COCH exon 12 represents the first reported mutation outside of the LCCL domain which is encoded by exons 4 and 5. The 542F mutant cochlin is translated and secreted by transfected mammalian cells. Western blot analysis under non-reducing and reducing conditions suggests that the 542F mutation alters intramolecular cochlin disulfide bond formation. In the vestibular system, a progressive horizontal canal hypofunction and a probable saccular otolith challenge were detected in family members with the c.1625G > T COCH alteration. Abnormal central oculomotor test results in family members with the c.1625G > T COCH alteration imply a possible central nervous system change not previously noted in DFNA9 pedigrees harboring mutations within the LCCL domain.
authors.affiliation: V.M. Bloedel Hearing Research Center, Otolaryngology-HNS Department, University of Washington, Seattle, Washington 98195, USA. vastreet@u.washington.edu
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Street
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Kallman
authors.forename: Nahid G
authors.initials: NG
authors.lastname: Robertson
authors.forename: Sharon F
authors.initials: SF
authors.lastname: Kuo
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: James O
authors.initials: JO
authors.lastname: Phillips
mesh_terms: D000595:Amino Acid Sequence; D001299:Audiometry; D015153:Blotting, Western; D004220:Disulfides / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D008040:Genetic Linkage; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D009154:Mutation; D009801:Oculomotor Muscles / Q000503:physiopathology*; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015837:Vestibular Diseases / Q000235:genetics*
chemical_list: C110668:COCH protein, human; D004220:Disulfides; D016326:Extracellular Matrix Proteins; D011506:Proteins