HYPOHIDROTIC ECTODERMAL DYSPLASIA--A GENETIC ANALYSIS

少汗性外胚层发育不良--遗传分析

• 批准号: 2897069
• 负责人: JONATHAN ZONANA
• 金额: $ 32万
• 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/2897069
• 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 (ED) 是一种临床和遗传性疾病 一组异质性疾病，伴有 X 连锁外胚层少汗症 其中最常见的是发育不良（XLHED）。 常染色体隐性遗传 该疾病的形式存在（ARHED），临床上 与 XLHED 无法区分，导致相同的牙齿异常， 头发和汗腺的发育。临床分子检测不 可用于区分 ARHED 和 XLHED，也可用于识别 许多患有 XLHED 的家庭中女性携带者的比例。 与我们一起 合作者，我们已经成功鉴定了 XLHED (EDA) 基因 及其鼠同源物虎斑猫 (Ta)。 我们建议分析频谱 在 170 多个 XLHED 家族中发现的突变，以及这些数据 设计临床分子检测的最佳策略以改善 诊断。 该分析还可以确定重要的功能域 EDA 蛋白内。 Ta和EDA蛋白高度同源 功能未知的蛋白质。 EDA和Ta的鉴定 基因提供了探索这些新奇作用的机会 上皮间质信号传导和发育中的蛋白质 牙齿、头发和小汗腺。 我们将开始定义 使用多种方法研究 Ta/EDA 蛋白的功能：分析 基因表达的组织特异性和发育模式， 使用转基因小鼠进行蛋白质亚型的功能分析 技术，以及使用酵母鉴定相互作用蛋白质 双杂交测定。 我们还将鉴定与 人类和小鼠常染色体隐性遗传形式的 HED。 他们很可能 成为包括 EDA/Ta 在内的共同发展途径的成员 蛋白质。 该提案的总体假设是，持续 人类疾病的分子遗传学分析，X连锁（XLHED）和 常染色体隐性遗传（ARHED）少汗性外胚层发育不良，以及 它们的鼠同源物（Ta、cr、dl）将识别出对于 形态发生并协助理解功能和相互作用 他们的蛋白质。 同时，新知识也应该快速吸收。 改善基因诊断和咨询，甚至可能 为未来的治疗提出建议。