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Homozygote loss-of-function variants in the human COCH gene underlie hearing loss

European Journal of Human Genetics volume 29, pages 338–342 (2021)Cite this article

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Abstract

Since 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 additional recessive variants in the COCH gene (DFNB110) have 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 have a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH.

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Fig. 1: Family AF101 pedigree, segregation of the COCH variant and audiograms.
Fig. 2: The c.984_985dup variant results in loss of cochlin protein expression.

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Data availability

The c.984_985dup variant is available on ClinVar (Accession # VCV000870100).

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Acknowledgements

We thank the families for their participation in this study. We also thank Dr. Zippora Brownstein for helpful comments throughout the research.

Funding

This work was supported by the National Institutes of Health/NIDCD R01DC011835 (K.B.A.)

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Authors and Affiliations

  1. Genetics Institute, Ha’emek Medical Center, Afula, Israel

    Nada Danial-Farran, Elena Chervinsky, Morad Khayat & Stavit A. Shalev

  2. Rappaport Faculty of Medicine Technion, Haifa, Israel

    Nada Danial-Farran, Eran Cohen Barak & Stavit A. Shalev

  3. Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Nada Danial-Farran, Prathamesh T Nadar-Ponniah, Shahar Taiber & Karen B. Avraham

  4. Department of Dermatology, Haʼemek Medical Center, Afula, Israel

    Eran Cohen Barak

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  1. Nada Danial-Farran
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  2. Elena Chervinsky
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Correspondence to Nada Danial-Farran.

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Danial-Farran, N., Chervinsky, E., Nadar-Ponniah, P.T. et al. Homozygote loss-of-function variants in the human COCH gene underlie hearing loss. Eur J Hum Genet 29, 338–342 (2021). https://doi.org/10.1038/s41431-020-00724-6

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