A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation

Fransén, Erik; Verstreken, M.; Bom, S. J. H.; Lemaire, F. X.; Kemperman, Martijn H; Kok, Y.J.M. de; Wuyts, Floris L.; Verhagen, W. I. M.; Huygen, P.L.M.; McGuirt, Wyman T.; Smith, Richard J.H.; Maldergem, Lionel Van; Declau, Frank; Cremers, C.W.R.J.; Heyning, Paul Van de; Cremers, Frans P.M.; Camp, Guy Van

doi:10.1136/jmg.38.1.61

Cited by 41 publications

(37 citation statements)

References 15 publications

(10 reference statements)

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“…Since the onset of DFNA9 hearing loss occurs from the second to fifth decades of life Eavey et al 2000;Fransen et al 1999Fransen et al , 2001Kamarinos et al 2001;Nagy et al 2004;Robertson et al 1998;Usami et al 2003;Verhagen et al 2000), a potential progressive hearing loss phenotype might start after 5 months of age in Coch À/À mice. Analysis at later time points on a different strain background (e.g., CBA) could reveal a hearing loss phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…All reported DFNA9 mutations result in either missense substitutions or an amino acid deletion in the LCCL domain de Kok et al 1999;Eavey et al 2000;Fransen et al 2001;Kamarinos et al 2001;Nagy et al 2004;Robertson et al 1998;Verhagen et al 2000;Verstreken et al 2001). DFNA9 mutations cause misfolding of the LCCL domain of cochlin expressed in bacteria (Liepinsh et al 2001), and the extracellular deposition of DFNA9 mutant cochlin expressed in mammalian cell lines is altered (Grabski et al 2003) even though it is synthesized, glycosylated and secreted in the same manner as wild-type cochlin (Robertson et al 2003).…”

Section: Introductionmentioning

confidence: 94%

“…Mutations in COCH cause dominant progressive hearing loss and vestibular dysfunction DFNA9 de Kok et al 1999;Fransen et al 1999Fransen et al , 2001Kamarinos et al 2001;Nagy et al 2004;Robertson et al 1998;Usami et al 2003;Verhagen et al 2000;Verstreken et al 2001). COCH encodes cochlin, a secreted protein with a signal peptide sequence and LCCL domain at its amino terminus, followed by two von Willebrand factor type A (vWA) domains (Robertson et al 1998).…”

Section: Introductionmentioning

confidence: 98%

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Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder

et al. 2005

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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-LacZDeltaneo 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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 98%

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Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder

et al. 2005

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“…We suggest that for nonsyndromic congenital or first decade onset HI it would be cost-effective to prescreen GJB2, because of its relatively frequent association with HI. For recognizable phenotypes (such as Pendred syndrome, Waardenburg syndrome and Usher syndrome) or for genes with a relatively common founder mutation in a specific population (such as mutations in COCH in the Dutch and Belgian population) 20 prescreening of specific genes might still be useful. This is supported by the relatively high diagnostic yield of targeted sequencing of GJB2 (7.2%) and COCH (36.8%).…”

Section: Discussionmentioning

confidence: 99%

“…For these three genes, founder or hotspot mutations occur in the Dutch population explaining the high incidence of mutations found in DNA diagnostics. [20][21][22] The diagnostic yield for COL11A1, DFNA5, EYA1, MYO7A, NDP, OTOF, SLC26A4 and USH2A was higher than 10%, but the number of requests was less than 10 times. Therefore, the diagnostic yield for these genes is not reliable.…”

Section: Prescreening Of Single Genesmentioning

confidence: 99%

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

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Speech Recognition Scores Related to Age and Degree of Hearing Impairment in DFNA2/KCNQ4 and DFNA9/COCH

Bom

Leenheer²,

Lemaire³

et al. 2001

Arch Otolaryngol Head Neck Surg

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A common ancestor for COCH related cochleovestibular (DFNA9) patients in Belgium and The Netherlands bearing the P51S mutation

Cited by 41 publications

References 15 publications

Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder

Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

Speech Recognition Scores Related to Age and Degree of Hearing Impairment in DFNA2/KCNQ4 and DFNA9/COCH

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