Makishima Tomoko, Rodriguez Clara I, Robertson Nahid G, Morton Cynthia C, Stewart Colin L, Griffith Andrew J
Section on Gene Structure and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
Hum Genet. 2005 Oct;118(1):29-34. doi: 10.1007/s00439-005-0001-4. Epub 2005 Oct 28.
Dominant progressive hearing loss and vestibular dysfunction DFNA9 is caused by mutations of the human COCH gene. COCH encodes cochlin, a highly abundant secreted protein of unknown function in the inner ear. Cochlin has an N-terminal LCCL domain followed by two vWA domains, and all known DFNA9 mutations are either missense substitutions or an amino acid deletion in the LCCL domain. Here, we have characterized the auditory phenotype associated with a genomic deletion of mouse Coch downstream of the LCCL domain. Homozygous Coch (-/-) mice express no detectable cochlin in the inner ear. Auditory brainstem responses to click and pure-tone stimuli (8, 16, 32 kHz) were indistinguishable among wild type and homozygous Coch (-/-) mice. A Coch-LacZDeltaneo reporter allele detected Coch mRNA expression in nonsensory epithelial and stromal regions of the cochlea and vestibular labyrinth. These data provide functional evidence that DFNA9 is probably not caused by COCH haploinsufficiency, but via a dominant negative or gain-of-function effect, in nonsensory regions of the inner ear.
显性进行性听力损失和前庭功能障碍DFNA9是由人类COCH基因突变引起的。COCH编码耳蜗蛋白，这是一种在内耳中大量分泌但功能未知的蛋白质。耳蜗蛋白有一个N端LCCL结构域，后面跟着两个vWA结构域，所有已知的DFNA9突变都是LCCL结构域中的错义替换或氨基酸缺失。在这里，我们已经对与LCCL结构域下游的小鼠Coch基因组缺失相关的听觉表型进行了表征。纯合Coch（-/-）小鼠在内耳中不表达可检测到的耳蜗蛋白。野生型和纯合Coch（-/-）小鼠对点击声和纯音刺激（8、16、32kHz）的听觉脑干反应没有区别。一个Coch-LacZDeltaneo报告等位基因在耳蜗和前庭迷路的非感觉上皮和基质区域检测到Coch mRNA表达。这些数据提供了功能证据，表明DFNA9可能不是由COCH单倍体不足引起的，而是通过在内耳非感觉区域的显性负效应或功能获得效应引起的。
