Abstract
Dominant progressive hearing loss and vestibular dysfunction DFNA9 is caused by mutations of the human COCH gene. COCH encodes cochlin, a highly abundant secreted protein of unknown function in the inner ear. Cochlin has an N-terminal LCCL domain followed by two vWA domains, and all known DFNA9 mutations are either missense substitutions or an amino acid deletion in the LCCL domain. Here, we have characterized the auditory phenotype associated with a genomic deletion of mouse Coch downstream of the LCCL domain. Homozygous Coch −/− mice express no detectable cochlin in the inner ear. Auditory brainstem responses to click and pure-tone stimuli (8, 16, 32 kHz) were indistinguishable among wild type and homozygous Coch −/− mice. A Coch-LacZΔneo reporter allele detected Coch mRNA expression in nonsensory epithelial and stromal regions of the cochlea and vestibular labyrinth. These data provide functional evidence that DFNA9 is probably not caused by COCH haploinsufficiency, but via a dominant negative or gain-of-function effect, in nonsensory regions of the inner ear.
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References
Bom SJ, Kemperman MH, De Kok YJ, Huygen PL, Verhagen WI, Cremers FP, Cremers CW (1999) Progressive cochleovestibular impairment caused by a point mutation in the COCH gene at DFNA9. Laryngoscope 109:1525–1530
Colombatti A, Bonaldo P (1991) The superfamily of proteins with von Willebrand factor type A-like domains: one theme common to components of extracellular matrix, hemostasis, cellular adhesion, and defense mechanisms. Blood 77:2305–2315
Colombatti A, Bonaldo P, Doliana R (1993) Type A modules: interacting domains found in several nonfibrillar collagens and in other extracellular matrix proteins. Matrix 13:297–306
de Kok YJ, Bom SJ, Brunt TM, Kemperman MH, van Beusekom E, van der Velde-Visser SD, Robertson NG, Morton CC, Huygen PL, Verhagen WI, Brunner HG, Cremers CW, Cremers FP (1999) A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects. Hum Mol Genet 8:361–366
Eavey RD, Manolis EN, Lubianca J, Merchant S, Seidman JG, Seidman C (2000) Mutations in COCH (formerly Coch5b2) cause DFNA9. Adv Otorhinolaryngol 56:101–102
Fransen E, Verstreken M, Verhagen WI, Wuyts FL, Huygen PL, D’Haese P, Robertson NG, Morton CC, McGuirt WT, Smith RJ, Declau F, Van de Heyning PH, Van Camp G (1999) High prevalence of symptoms of Meniere’s disease in three families with a mutation in the COCH gene. Hum Mol Genet 8:1425–1429
Fransen E, Verstreken M, Bom SJ, Lemaire F, Kemperman MH, De Kok YJ, Wuyts FL, Verhagen WI, Huygen PL, McGuirt WT, Smith RJ, Van Maldergem LV, Declau F, Cremers CW, Van De Heyning PH, Cremers FP, Van Camp G (2001) A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation. J Med Genet 38:61–65
Grabski R, Szul T, Sasaki T, Timpl R, Mayne R, Hicks B, Sztul E (2003) Mutations in COCH that result in non-syndromic autosomal dominant deafness (DFNA9) affect matrix deposition of cochlin. Hum Genet 113:406–416
Griffith AJ, Szymko YM, Kaneshige M, Quinonez RE, Kaneshige K, Heintz KA, Mastroianni MA, Kelley MW, Cheng SY (2002) Knock-in mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor beta gene disrupts cochlear morphogenesis. J Assoc Res Otolaryngol 3:279–288
Ikezono T, Omori A, Ichinose S, Pawankar R, Watanabe A, Yagi T (2001) Identification of the protein product of the Coch gene (hereditary deafness gene) as the major component of bovine inner ear protein. Biochim Biophys Acta 1535:258–265
Ikezono T, Shindo S, Li L, Omori A, Ichinose S, Watanabe A, Kobayashi T, Pawankar R, Yagi T (2004) Identification of a novel Cochlin isoform in the perilymph: insights to Cochlin function and the pathogenesis of DFNA9. Biochem Biophys Res Commun 314:440–446
Kamarinos M, McGill J, Lynch M, Dahl H (2001) Identification of a novel COCH mutation, I109N, highlights the similar clinical features observed in DFNA9 families. Hum Mutat 17:351
Khetarpal U (2000) DFNA9 is a progressive audiovestibular dysfunction with a microfibrillar deposit in the inner ear. Laryngoscope 110:1379–1384
Liepinsh E, Trexler M, Kaikkonen A, Weigelt J, Banyai L, Patthy L, Otting G (2001) NMR structure of the LCCL domain and implications for DFNA9 deafness disorder. EMBO J 20:5347–5353
Merchant SN, Linthicum FH, Nadol JB Jr (2000) Histopathology of the inner ear in DFNA9. Adv Otorhinolaryngol 56:212–217
Nagy I, Horvath M, Trexler M, Repassy G, Patthy L (2004) A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss. J Med Genet 41:E9
Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, Nadol JB Jr, Miyamoto RT, Linthicum FH Jr, Lubianca Neto JF, Hudspeth AJ, Seidman CE, Morton CC, Seidman JG (1998) Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat Genet 20:299–303
Robertson NG, Resendes BL, Lin JS, Lee C, Aster JC, Adams JC, Morton CC (2001) Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9. Hum Mol Genet 10:2493–2500
Robertson NG, Hamaker SA, Patriub V, Aster JC, Morton CC (2003) Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. J Med Genet 40:479–486
Rodriguez CI, Cheng JG, Liu L, Stewart CL (2004) Cochlin, a secreted von Willebrand factor type a domain-containing factor, is regulated by leukemia inhibitory factor in the uterus at the time of embryo implantation. Endocrinology 145:1410–1418
Szymko-Bennett YM, Kurima K, Olsen B, Seegmiller R, Griffith AJ (2003) Auditory function associated with Col11a1 haploinsufficiency in chondrodysplasia (cho) mice. Hear Res 175:178–182
Thorne M, Salt AN, DeMott JE, Henson MM, Henson OW Jr, Gewalt SL (1999) Cochlear fluid space dimensions for six species derived from reconstructions of three-dimensional magnetic resonance images. Laryngoscope 109:1661–1668
Trexler M, Banyai L, Patthy L (2000) The LCCL module. Eur J Biochem 267:5751–5757
Usami S, Takahashi K, Yuge I, Ohtsuka A, Namba A, Abe S, Fransen E, Patthy L, Otting G, Van Camp G (2003) Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere’s disease. Eur J Hum Genet 11:744–748
Verhagen WI, Bom SJ, Huygen PL, Fransen E, Van Camp G, Cremers CW (2000) Familial progressive vestibulocochlear dysfunction caused by a COCH mutation (DFNA9). Arch Neurol 57:1045–1047
Verstreken M, Declau F, Wuyts FL, D’Haese P, Van Camp G, Fransen E, Van den Hauwe L, Buyle S, Smets RE, Feenstra L, Van der Stappen A, Van de Heyning PH (2001) Hereditary otovestibular dysfunction and Meniere’s disease in a large Belgian family is caused by a missense mutation in the COCH gene. Otol Neurotol 22:874–881
Acknowledgements
We thank Tom Friedman and Rob Morell for helpful discussion and critical review of the manuscript, and Rachel McNamara for excellent technical assistance This work was supported by NIDCD/NIH intramural research fund Z01-DC-000060-03 (to AJG) and NIH grant DC03402 (to CCM). TM was supported in part by a Japan Society for the Promotion of Science Research Fellowship for Japanese biomedical and behavioral researchers at the National Institutes of Health.
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Tomoko Makishima, Clara I. Rodriguez contributed equally
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Makishima, T., Rodriguez, C.I., Robertson, N.G. et al. Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder. Hum Genet 118, 29–34 (2005). https://doi.org/10.1007/s00439-005-0001-4
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DOI: https://doi.org/10.1007/s00439-005-0001-4