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.

自 1999 年以来，编码 cochlin 的COCH基因一直与常染色体显性遗传非综合征性听力损失 DFNA9 相关，有或没有前庭异常。与影响基因功能的变异相关的听力障碍被归因于显性负效应。与正常分泌的野生型 cochlin 相比，突变型 cochlin 在细胞内积累，在细胞内外形成聚集体。虽然最近报道了COCH基因 (DFNB110)中的其他隐性变异，但COCH的功能丧失 (LOF) 效应的机制基因产物仍然未知。在这项研究中，我们使用 COS7 细胞系来研究一种新型纯合移码变体对 RNA 转录和 cochlin 翻译的影响。我们的结果表明变体的 LOF 效应和 cochlin 翻译的主要减少。这些数据对COCH中 LOF 变异的杂合子和纯合子携带者遗传咨询的准确性产生了巨大影响。