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A novel type of myosin encoded by the mouse deafness gene shaker-2

小鼠耳聋基因shaker-2编码的新型肌球蛋白

基本信息

批准号：
09470029
负责人：
KOMINAMI Ryo
金额：
$ 8.51万
依托单位：
NIIGATA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470029/
关键词：
GENETIC DEAFNESS POSITIONAL CLONING GENOME ANALYSIS MYOSIN GENE

项目摘要

Genetic hearing impairment affects about one in 2,000 children at birth. The majority of genetic deafness is non-syndromic, in which hearing loss is not associated with any other abnormalities. Autosomal recessive forms of non-syndromic deafness (DFNB) account for most profound deafness and are almost exclusively due to abnormalities of the sensory neuroepithelia of the inner ear. Ten loci for such deafness have been mapped and mutations in two genes encoding unconventional myosin VIIA and connexin 26 have been identified. One locus, DFNB3, is assigned to 17p11.2-17q12 which is homologous to the shaker-2 (sh-2) locus on mouse chromosome 11. Homozygous sh-2 mice exhibit the circling, headtossing, deafness, and hyperactivity seen in mice with inner ear defects and some of these symptoms resemble those of DFNB3, implying that the same unidentified gene underlies DFNB3 and sh-2.We constructed a contig consisting of 21 BAC clones across an approximately 700-kb region which covers the entire nonrecombinant region of sh-2. With this genetic and physical maps, we carried out a positional cloning approach to identify the sh-2 mutation. Here we report the use of a positional cloning approach to show that the gene mutated in sh-2 mice encodes a novel type of unconventional myosin. A G-to-A transition changing cysteine to tyrosine in the conserved actin binding domain is detected in sh-2 but absent in laboratory strains and wild mice belonging to different mouse subspecies and species. Based on conserved synteny and the mutation, the novel myosin gene is a strong candidate for DFNB3.

遗传性听力障碍在出生时大约每2000名儿童中就有一名受到影响。大多数遗传性耳聋是非综合征性的，听力损失与任何其他异常无关。常染色体隐性遗传性非综合征性耳聋(DFNB)是最严重的耳聋，几乎完全是由于内耳感觉神经上皮细胞的异常所致。已经定位了这种耳聋的10个基因座，并确定了编码非传统肌球蛋白VIIA和连接蛋白26的两个基因的突变。DFNB3基因定位于17p11.2-17q12，与小鼠11号染色体上的Shaker-2(sh-2)基因座同源。纯合子sh-2小鼠表现出内耳缺陷小鼠的打圈、头晕、耳聋和多动等症状，其中一些症状与DFNB3相似，这意味着DFNB3和sh-2背后有相同的未知基因。利用这个遗传图谱和物理图谱，我们进行了定位克隆的方法来鉴定sh-2突变。在这里，我们报告了一种位置克隆方法的使用，以表明在sh-2小鼠中突变的基因编码一种新型的非传统肌球蛋白。在sh-2中检测到保守的肌动蛋白结合区的半胱氨酸到酪氨酸的G-A转换，但在不同小鼠亚种和物种的实验室菌株和野鼠中没有。基于保守的共性和突变，新的肌球蛋白基因是DFNB3的有力候选者。