MOLECULAR BASIS OF INHERITED DEAFNESS

诺里病是一种X连锁的隐性疾病，导致进行性 听力损失，并伴有失明和智力障碍。基因 诺里病缺陷，NDP，最近被确认为 我们马萨诸塞州综合医院的位置克隆，在 与英国的一个团体合作。Norrin的基因编码是一种 预测大小为15 kDa的蛋白质，与 粘蛋白是一种高度糖基化的分泌蛋白家族。了解以下内容 缺陷蛋白质的序列将使我们能够确定其 在听力中的正常作用，以及缺陷是如何导致听力障碍的 诺里病。去甲肾上腺素抗血清的初步结果表明 这种蛋白质是覆盖层膜的一个组成部分，它传递 对受体细胞的声刺激，以及突变可能 导致覆盖膜薄弱或缺失。 我们建议定义去甲肾上腺素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 免疫细胞化学以确定其最终位置。我们将确定它的 显微解剖耳蜗凝胶电泳法测定耳蜗体内分子量 结构，我们将研究其糖基的范围和性质 不同的，不同的。 我们还将评估诺里病听力损失的性质。诺丽 疾病患者将接受全面的听力测试，以了解 他们听力障碍的确切性质，以及他们携带的突变 将被确定为将特定的突变与病理相关联。我们希望 从诺里病或尸检流产的胎儿中获取材料 材料：研究内耳的组织病理学。 为了创造一个进一步研究的动物模型，我们将制作一个转基因 缺乏Norrin基因的小鼠。将对这些小鼠进行听力研究 有诱发电位和耳声发射，以及它们的内耳 将进行组织学研究。听证开始时间的相关性 形态改变的缺陷将有助于了解其病因 这种疾病。如果真的在转基因中没有覆盖膜， 这些小鼠也将是了解新一代 耳声发射。最后，遗传性疾病最终将是 通过某种形式的基因转移来治疗。继承的鼠标模型 稍后，耳聋将成为设计基因疗法的基础。

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.