Homozygote loss-of-function variants in the human COCH gene underlie hearing loss
| Autor: | Eran Cohen Barak, Morad Khayat, Nada Danial-Farran, Prathamesh T Nadar-Ponniah, Elena Chervinsky, Stavit A. Shalev, Shahar Taiber, Karen B. Avraham |
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| Rok vydání: | 2020 |
| Předmět: |
Hearing loss
Hearing Loss Sensorineural Mutant Biology Brief Communication Cell Line Frameshift mutation 03 medical and health sciences Genetics medicine Humans Frameshift Mutation Hearing Loss Gene Genetics (clinical) Loss function Extracellular Matrix Proteins 0303 health sciences Homozygote 030305 genetics & heredity Heterozygote advantage Translation (biology) Pedigree Vestibular Diseases medicine.symptom Function (biology) |
| Zdroj: | Eur J Hum Genet |
| ISSN: | 1476-5438 1018-4813 |
| DOI: | 10.1038/s41431-020-00724-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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