Bi-allelic inactivating variants in the COCH gene cause autosomal recessive prelingual hearing impairment

JanssensdeVarebeke, Sebastien; Camp, Guy Van; Peeters, Nils; Elinck, Ellen; Widdershoven, Josine; Cox, Tony; Deben, Kristof; Ketelslagers, Katrien; Crins, T. T. H.; Wuyts, Wim

doi:10.1038/s41431-017-0066-2

Cited by 25 publications

(26 citation statements)

References 18 publications

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“…S1c, d). This is in contrast to the previously reported variant, c.292C>T, p.Arg98*, which was linked to activating nonsense mediated decay (NMD), where the mutant allele was not detectable [3] To investigate the consequences of protein expression, and possible accumulation of the mutant protein in the cells, we co-transfected the COS7 cell line with COCH-GFP plasmids containing both the wild-type and mutant forms of the cDNA, and a vector expressing TGNP-mCherry, a Golgi complex protein. Wild-type cochlin was detected in the cellular cytoplasm and co-localized in the Golgi complex, as previously reported [8].…”

Section: Resultscontrasting

confidence: 99%

“…The nonsense variants reported in the Iranian and Moroccan families are located in the second and third exon of the COCH gene (NG_008211.2), respectively, which may explain the activation of NMD as a result of the nonsense variant c.292C>T in the Moroccan family [3], unlike the variant detected in this study, located at exon 9 out of 11 exons (NG_008211.2). Investigating the in vivo expression of the wild-type and mutant alleles of the COCH gene, by examining mRNA extracted from leukocytes, excluded the option of NMD activation.…”

Section: Discussionmentioning

confidence: 51%

“…The COCH gene encodes the secreted cochlin protein, a major component of the extracellular matrix of the inner ear [1]. Variants affecting COCH gene function have been linked to the autosomal dominant hearing loss, DFNA9 [2], and recently, also to the autosomal recessive hearing loss, DFNB110 [3,4]. More than 20 dominant variants in the COCH gene are associated with progressive mild-toprofound hearing impairment and vestibular dysfunction in the second to seventh decade of life [5].…”

Section: Introductionmentioning

confidence: 99%

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Homozygote loss-of-function variants in the humanCOCHgene underlie hearing loss

Danial‐Farran

Chervinsky

Nadar‐Ponniah

et al. 2020

Preprint

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AbstractSince 1999, the COCH gene encoding cochlin, has been linked to the autosomal dominant non-syndromic hearing loss, DFNA9, with or without vestibular abnormalities. The hearing impairment associated with the variants affecting gene function has been attributed to a dominant-negative effect. Mutant cochlin was seen to accumulate intracellularly, with the formation of aggregates both inside and outside the cells, in contrast to the wild-type cochlin that is normally secreted. While an additional recessive variant in the COCH gene (DFNB110) has recently been reported, the mechanism of the loss-of-function (LOF) effect of the COCH gene product remains unknown. In this study, we used COS7 cell lines to investigate the consequences of a novel homozygous frameshift variant on RNA transcription, and on cochlin translation. Our results indicate a LOF effect of the variant and a major decrease in cochlin translation. This data has a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH.

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Section: Resultscontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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Homozygote loss-of-function variants in the humanCOCHgene underlie hearing loss

Danial‐Farran

Chervinsky

Nadar‐Ponniah

et al. 2020

Preprint

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“…Downregulation of the mutant allele, thereby alleviating the inner ear from the burden caused by the formation of cytotoxic cochlin dimers, therefore has high therapeutic potential. The lack of auditory and vestibular phenotypes in mice carrying a heterozygous protein-truncating mutation in Coch , 10 and in heterozygous family members of patients with early-onset hearing impairment due to homozygous protein-truncating mutations in COCH , 11 illustrate that sufficient functional cochlin proteins can be produced from a single healthy COCH allele. We speculate that a timely intervention might even prevent hearing impairment altogether.…”

Section: Introductionmentioning

confidence: 99%

AON-based degradation of c.151C>T mutant COCH transcripts associated with dominantly inherited hearing impairment DFNA9

Vrieze

Martín

Peijnenborg

et al. 2021

Molecular Therapy - Nucleic Acids

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The c.151C>T founder mutation in COCH is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9) in the Dutch/Belgian population. The initial clinical symptoms only manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The dominant inheritance pattern and established non-haploinsufficiency disease mechanism indicate that suppressing translation of mutant COCH transcripts has high therapeutic potential. Single-molecule real-time (SMRT) sequencing resulted in the identification of 11 variants with a low population frequency (<10%) that are specific to the c.151C>T mutant COCH allele. Proof of concept was obtained that gapmer antisense oligonucleotides (AONs), directed against the c.151C>T mutation or mutant allele-specific intronic variants, are able to induce mutant COCH transcript degradation when delivered to transgenic cells expressing COCH minigenes. The most potent AON, directed against the c.151C>T mutation, was able to induce a 60% decrease in mutant COCH transcripts without affecting wild-type COCH transcript levels. Allele specificity decreased when increasing concentrations of AON were delivered to the cells. With the proven safety of AONs in humans, and rapid advancements in inner ear drug delivery, our in vitro studies indicate that AONs offer a promising treatment modality for DFNA9.

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“…Each of these genes has a distinct genomic and mutational signatures 1 . For some genes, variant location and variant type correlate with specific phenotypic outcomes as a consequence of the pathogenic mechanism at play; such is the case with the COCH gene [2][3][4] . Cochlin, the protein product of the COCH gene, is a large secreted extracellular protein that contains an N-terminus LCCL domain and two von Willebrand factor A-like domains (vWFA1 and vWFA2).…”

Section: Introductionmentioning

confidence: 99%

Novel Loss-of-Function Mutations inCOCHCause Autosomal Recessive Nonsyndromic Deafness

Booth

Ghaffar

Rashid

et al. 2020

Preprint

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COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the wellestablished autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used mini-gene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA-splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA-splicing, and highlights the need to investigate the effect of coding variants on RNA-splicing.

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Bi-allelic inactivating variants in the COCH gene cause autosomal recessive prelingual hearing impairment

Cited by 25 publications

References 18 publications

Homozygote loss-of-function variants in the humanCOCHgene underlie hearing loss

Homozygote loss-of-function variants in the humanCOCHgene underlie hearing loss

AON-based degradation of c.151C>T mutant COCH transcripts associated with dominantly inherited hearing impairment DFNA9

Novel Loss-of-Function Mutations inCOCHCause Autosomal Recessive Nonsyndromic Deafness

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