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.

Cochlin in the eye: Functional implications

“…The FCH domain is the site of at least seven known mutations in COCH gene (Usami et al, 2003;Nagy et al, 2004;Street et al, 2005;Robertson et al, 2006), all located within exons 4 or 5. These mutations were observed in patients carrying the diagnosis of DFNA9 (Grabski et al, 2003;Robertson et al, 2006), Meniere's disease and presbyacusis (Fransen et al, 1999).…”

“…Abnormal central oculomotor functions have been reported in family members with the c.1625G > T COCH alteration implying a possible central nervous system change due to cochlin mutation (Street et al, 2005). Geographical distribution of patients, lack of comprehensive medical record and other regulatory statues have prohibited an efficient retrospective study to assess the frequency and severity of glaucoma in DFNA9 patients.…”

Clinical Characteristics of a Dutch DFNA9 Family with a Novel <i>COCH</i> Mutation, G87W

“…Including the novel G87W mutation, nine different mutations have been identified, of which eight occur in the LCCL domain (V66G, W117R, G88E, P51S, I109N, A119T, V104del, G87W [Collin et al, 2006;de Kok et al, 1999;Kamarinos et al, 2001;Nagy et al, 2004;Robertson et al, 1998;Usami et al, 2003]). A recent study reported on the first DFNA9 mutation in the vWFA2 domain (C542F) [Street et al, 2005]. Liepinsh and colleagues showed that, except for W117R, all the other then-known mutations (P51S, V66G, G88E, I109N, W117R) in the LCCL domain disrupt its normal structure and lead to protein misfolding of this domain [Liepinsh et al, 2001].…”

Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice

“…COCH was chosen as a candidate for hearing loss due to its high expression in the Morton fetal cochlear cDNA library (Robertson et al, 1994;Robertson et al, 1997). Mutations in the gene have since been found to be responsible for DFNA9 in a number of families around the world (Robertson et al, 1998;de Kok et al, 1999;Fransen et al, 1999;Kamarinos et al, 2001;Usami et al, 2003;Nagy et al, 2004;Kemperman et al, 2005;Street et al, 2005;Collin et al, 2006;Pauw et al, 2007). But, although this relationship is well-established, mice deficient in Coch do not exhibit hearing loss (Makishima et al, 2005).…”