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

Nada Danial-Farran*, Elena Chervinsky, Prathamesh T. Nadar-Ponniah, Eran Cohen Barak, Shahar Taiber, Morad Khayat, Karen B. Avraham, Stavit A. Shalev

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)338-342
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number2
StatePublished - Feb 2021


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