MOLECULAR BASIS OF INHERITED DEAFNESS

在这项提案中，我们概述了三个基因的研究，遗传 耳聋：编码Norrie（Norrie病）、肌球蛋白VIIa的耳聋 （Usher 1B和shaker-1小鼠）和肌球蛋白-VIIb（候选者 对于旋转者和摇动者-2小鼠突变体）。 诺里研究 继续在他的赠款的头两年所做的工作，而 肌球蛋白研究启动了两个新项目。 诺里病是一种罕见的X连锁综合征性耳聋， 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;它编码一个小的， 分泌蛋白（Norrin），可能是生长因子。 的 一些流浪者的病理学表明， norrin允许血管过度生长-这是正常的 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定， 人类和小鼠的组织学研究， 基因 Usher 1B表现为先天性耳聋， 前庭功能和视力逐渐丧失 它是最 人类常见的遗传性耳聋 缺陷基因编码 肌球蛋白VIIa，一种连接和移动其他蛋白质的蛋白质， 行动上 我们已经关闭了人类肌球蛋白VIIa，并使用 抗体定位它在听觉感受器细胞与电子 显微镜 我们将测试一个特定的假设，即肌球蛋白VIIA 参与维持机械敏感纤毛的凝聚力， 通过使用一个突变小鼠，shaker-1，有缺陷的肌球蛋白VIIa， 并通过基因转移破坏正常人中的肌球蛋白VIIa， 小鼠 有证据表明，其他肌球蛋白-VII亚型存在于 他们也有可能在有缺陷的时候导致耳聋。 我们已经关闭了基因片段，并比较了它们的 染色体定位与遗传性耳聋的关系。 我们建议 克隆这些其他的同种型， 基因.

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.