MOLECULAR BASIS OF INHERITED DEAFNESS

遗传性耳聋的分子基础

• 批准号: 2127552
• 负责人: DAVID P COREY
• 金额: $ 16.73万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2127552
• 关键词: MOLECULAR; BASIS; INHERITED; DEAFNESS

Norrie disease is an X-linked recessive disorder that causes a progressive hearing loss, along with blindness and mental retardation. The gene defective in Norrie disease, NDP, has recently been identified by positional cloning by our group at Massachusetts General Hospital, in collaboration with a group in England. The gene codes for norrin, a protein of 15 kDa predicted size, which has partial homology to the mucins, a family of highly g1ycosylated, secreted proteins. Knowledge of the sequence of the defective protein will enable us to determine its normal role in hearing, and how the defect contributes to the etiology of Norrie disease. Preliminary results with an antiserum to norrin suggests that the protein is a constituent of the tectorial membrane, which conveys the acoustic stimulus to the receptor cells, and that mutations might cause a weak or absent tectorial membrane. We propose to define the cellular distribution of norrin in the inner ear, by in situ hybridization to determine the cells that make it and by immunocytochemistry to locate its final position. We will determine its molecular weights vivo by gel electrophoresis of micro-dissected cochlear structures, and we will investigate the extent and nature of its glycosylat n. We will also evaluate the nature of hearing loss in Norrie disease. Norrie disease patients will be given complete audiological testing to understand the exact nature of their hearing deficit, and the mutation they carry will be determined to correlate specific mutations with pathology. We hope to obtain material from aborted fetuses with Norrie disease or autopsy material to study the histological pathology of the inner ear. To create an animal model for further study, we will make a transgenic mouse lacking the norrin gene. These mice will be studied audiologically with evoked potentials and otoacoustic emissions, and their inner ears will be studied histologically. Correlation of the onset of the hearing deficit with changes in morphology will help understand the etiology of the disease. If the tectorial membrane is in fact absent in transgenics, these mice will also be a useful tool to understand generation of otoacoustic emissions. Finally, inherited diseases will ultimately be treated by some form of gene transfer. A mouse model for an inherited deafness will later serve as a basis for designing gene therapy.

诺里病是一种 X 连锁隐性遗传病，可导致进行性进展 听力丧失、失明和智力障碍。基因 诺里病（NDP）缺陷，最近被鉴定为 我们的团队在马萨诸塞州总医院进行的定位克隆 与英国的一个团体合作。该基因编码诺里蛋白， 15 kDa 预测大小的蛋白质，与 粘蛋白，一类高度糖基化的分泌蛋白。知识 有缺陷的蛋白质的序列将使我们能够确定其 听力的正常作用，以及该缺陷如何导致听力损失的病因学 诺里病。诺林抗血清的初步结果表明 该蛋白质是盖膜的组成部分，负责传递 对受体细胞的声刺激，突变可能 导致盖膜薄弱或缺失。 我们建议定义诺里蛋白在内耳中的细胞分布， 通过原位杂交来确定制造它的细胞，并通过 免疫细胞化学来定位其最终位置。 我们将确定其 通过微解剖耳蜗凝胶电泳测定体内分子量 结构，我们将研究其糖基化的程度和性质 名词 我们还将评估诺里病听力损失的性质。诺里 疾病患者将接受完整的听力学测试以了解 他们听力缺陷的确切性质以及他们携带的突变 将确定特定突变与病理学的关联。我们希望 从患有诺里病的流产胎儿或尸检中获取材料 研究内耳组织病理学的材料。 为了创建动物模型以供进一步研究，我们将制作转基因动物 缺乏诺里蛋白基因的小鼠。这些小鼠将接受听力学研究 具有诱发电位和耳声发射，以及他们的内耳 将进行组织学研究。 听证会开始的相关性 形态学变化的缺陷将有助于理解 这种疾病。如果转基因中实际上不存在盖膜， 这些小鼠也将成为了解生成的有用工具 耳声发射。最后，遗传性疾病最终将 通过某种形式的基因转移进行治疗。遗传性小鼠模型 耳聋将成为设计基因疗法的基础。