HYPOHIDROTIC ECTODERMAL DYSPLASIA--A GENETIC ANALYSIS

少汗性外胚层发育不良--遗传分析

• 批准号: 6176696
• 负责人: JONATHAN ZONANA
• 金额: $ 32.09万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176696
• 关键词: autosomal recessive trait; biological signal transduction; clinical research; complementary DNA; developmental genetics; ectoderm; epithelium; family genetics; gene expression; gene frequency; gene mutation; genetic disorder; genetic disorder diagnosis; genetic mapping; genetically modified animals; human subject; hyperplasia; intermolecular interaction; laboratory mouse; mesenchyme; molecular genetics; protein isoforms; protein structure function; sex linked trait; yeast two hybrid system

The ectodermal dysplasias (EDs) are a clinically and genetically heterogeneous group of disorders, with X-linked hypohidrotic ectodermal dysplasia (XLHED) being the most common of them. An autosomal recessive form of the disorder exists (ARHED), which is clinically indistinguishable from XLHED, causing identical abnormalities of tooth, hair, and sweat gland development. Clinical molecular testing is not available to distinguish ARHED from XLHED, nor for the identification of carrier females in many families with XLHED. Together with our collaborators, we have successfully identified the gene for XLHED (EDA) and its murine homolog Tabby (Ta). We propose to analyze the spectrum of mutations seen in over 170 families with XLHED, and from these data design an optimal strategy for clinical molecular testing to improve diagnosis. The analysis may also identify essential functional domains within the EDA protein. The Ta and EDA proteins are highly homologous proteins whose function are unknown. Identification of the EDA and Ta genes provides an opportunity to explore the role of these novel proteins in epithelial-mesenchymal signaling and in the development of teeth, hair and eccrine sweat glands. We will begin to define the functions of the Ta/EDA proteins using a number of approaches: analysis of tissue specific and developmental patterns of gene expression, functional analysis of protein isoforms using transgenic mouse technologies, and identification of interacting proteins using the yeast two-hybrid assay. We will also identify the genes associated with the autosomal recessive forms of HED in humans and mice. They are likely to be members of a common developmental pathway that include the EDA/Ta proteins. The overall hypothesis of this proposal is that a continued molecular genetic analysis of the human disorders, X-linked (XLHED) and autosomal recessive (ARHED) hypohidrotic ectodermal dysplasia, and of their murine homologs (Ta, cr, dl) will identify new genes essential for morphogenesis and assist in understanding the function and interactions of their proteins. At the same time, the new knowledge should rapidly result in improved genetic diagnosis and counseling, and may even suggest avenues for future therapies.

外胚层发育不良(EDS)是一种临床和遗传学表现。 异质性疾病组，伴有X连锁的少汗性外胚层 异型增生(XLHED)是其中最常见的。一种常染色体隐性遗传 存在形式的障碍(ARHED)，临床上 与XLHED无法区分，导致相同的牙齿畸形， 毛发和汗腺发育。临床分子检测不是 可用于区分ARHED和XLHED，也可用于识别 许多XLHED家庭中的携带者女性。与我们的 合作者们，我们成功地确定了XLHED(EDA)的基因 和它的小鼠同系物猫(Ta)。我们建议分析频谱 在170多个患有XLHED的家庭中发现的突变，以及从这些数据 设计临床分子检测的优化策略，以提高 诊断。该分析还可以识别基本功能域 在EDA蛋白中。Ta和EDA蛋白高度同源 功能未知的蛋白质。EDA和Ta的鉴定 基因为探索这些小说的作用提供了一个机会 上皮-间充质信号转导中的蛋白质及其在血管内皮细胞发育中的作用 牙齿、头发和汗腺分泌。我们将开始定义 用多种方法分析Ta/EDA蛋白的功能 基因表达的组织特异性和发育模式， 利用转基因小鼠进行蛋白质异构体的功能分析 酵母菌相互作用蛋白的技术和鉴定 双杂交试验。我们还将确定与基因相关的基因 人类和小鼠的常染色体隐性遗传性遗传病。他们很可能 成为包括EDA/Ta在内的共同发育途径的成员 蛋白质。这一提议的总体假设是，继续 人类X连锁疾病的分子遗传学分析(XLHED)和 常染色体隐性遗传性少汗性外胚层发育不良 他们的小鼠同源基因(Ta、cr、dl)将识别新的 形态发生和帮助理解功能和相互作用 它们的蛋白质。与此同时，新的知识应该迅速 结果改善了基因诊断和咨询，甚至可能 为未来的治疗提供建议。