MOLECULAR BASIS OF INHERITED DEAFNESS

遗传性耳聋的分子基础

基本信息

批准号：
6379335
负责人：
DAVID P COREY
金额：
$ 21.19万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2003-06-30
项目状态：
已结题

项目摘要

In this proposal we outline studies on three genes for inherited deafness: those encoding Norrie (Norrie disease), myosin-VIIa (Usher 1B and the shaker-1 mouse), and myosin-VIIb (a candidate for the twirler and shaker-2 mouse mutants). The Norrie studies continue work done in the first two years of t his grant, while the myosin studies initiate two new programs. Norrie disease is a rare X-linked syndromic deafness, with congenital blindness and progressive hearing loss. We have cloned the gene defective in this disease; it encodes a small, secreted protein (norrin) that my be a growth factor. The pathology in some vagrants of the disease suggest that a defective norrin allows excessive growth of blood vessels - that it isnorally an angiogenesis inhibitor. We propose several methods to test this hypothesis, and propose to initiate or continue audiometric and histological studies of both humans and mice with this defective gene. Usher 1B presents with congenial deafness and absence of vestibular function, and progressive loss of vision. It is the most common genetic deafness in humans. The gene defective encodes myosinVIIa, a protein that connects and moves other proteins on action. We have closed human myosin-VIIa, and have used antibodies to locate it in auditory receptor cells with electron microscopy. We will test a specific hypotheses that myosin-VIIA is involved in maintaining cohesion of the mechanosensitive cilia, by using a mutant mouse, shaker-1, that has defective myosin-VIIa and by using gene transfers to disrupt myosin-VIIa in normal mice. There is evidence that other myosin-VII isoforms exist in the cochlea, and that they may also cause deafness when defective. We have closed fragments of the genes and have compared their chromosomal location to genetic deafness in mice. We propose to clone these other isoforms, and to test them as candidate deafness genes.

在本提案中，我们概述了对遗传性的三个基因的研究耳聋：编码 Norrie（诺里病）、肌球蛋白-VIIa 的基因（Usher 1B 和 shaker-1 小鼠）和肌球蛋白-VIIb（候选对于 twirler 和 shaker-2 小鼠突变体）。诺里研究继续该拨款的前两年所做的工作，同时肌球蛋白研究启动了两个新项目。诺里病是一种罕见的 X 连锁耳聋综合征，先天性失明和进行性听力损失。我们有克隆了这种疾病的缺陷基因；它编码一个小，分泌的蛋白质（诺林）是一种生长因子。这一些疾病流浪者的病理学表明，有缺陷的 Norrin 会导致血管过度生长 - 这实际上是正常的血管生成抑制剂。我们提出了几种方法来测试这一点假设，并建议启动或继续听力测试和对具有这种缺陷的人类和小鼠进行的组织学研究基因。 Usher 1B 患有先天性耳聋和失神前庭功能和进行性视力丧失。这是最人类常见的遗传性耳聋。基因缺陷编码肌球蛋白VIIa，一种连接并移动其他蛋白质的蛋白质行动。我们已经封闭了人肌球蛋白-VIIa，并使用了抗体用电子将其定位在听觉受体细胞中显微镜。我们将测试肌球蛋白-VIIA 的具体假设参与维持机械敏感纤毛的凝聚力，使用肌球蛋白-VIIa 有缺陷的突变小鼠 shaker-1 并通过使用基因转移来破坏正常细胞中的肌球蛋白-VIIa 老鼠。有证据表明，其他肌球蛋白 VII 亚型存在于耳蜗，当它们有缺陷时也可能导致耳聋。我们已经关闭了基因片段并比较了它们小鼠遗传性耳聋的染色体位置。我们建议克隆这些其他亚型，并测试它们作为候选耳聋基因。