HYPOHIDROTIC ECTODERMAL DYSPLASIA--A GENETIC ANALYSIS

外胚叶发育不良是一种临床和遗传上的疾病， 一组异质性疾病，伴X连锁少汗性外胚层 其中，先天性发育不良（XLHED）最为常见。 一种常染色体隐性 存在的疾病形式（ARHED），这是临床上 与XLHED难以区分，导致相同的牙齿异常， 头发和汗腺的发育临床分子检测不是 可用于区分ARHED和XLHED，也不用于识别 在许多XLHED家庭中携带者女性。 连同我们 我们已经成功地确定了XLHED（EDA）的基因 及其鼠同系物Tabby（Ta）。 我们建议分析光谱 在170多个XLHED家族中发现的突变， 为临床分子检测设计最佳策略， 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和标签的标识 基因提供了一个机会，探索这些新的 蛋白质在上皮间质信号传导和发展中的作用 牙齿头发和外泌汗腺 我们将开始定义 Ta/EDA蛋白的功能，使用了一些方法：分析 基因表达的组织特异性和发育模式， 使用转基因小鼠的蛋白质异构体的功能分析 技术，并使用酵母鉴定相互作用的蛋白质 双杂交试验 我们还将确定与这些基因相关的基因。 人类和小鼠中HED的常染色体隐性形式。 他们很可能 成为共同发展途径的成员，包括EDA/Ta proteins. 这一建议的总体假设是， 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）将鉴定出对于以下过程所必需的新基因： 形态发生，并协助理解功能和相互作用 它们的蛋白质。 与此同时，新知识应迅速 导致改善遗传诊断和咨询，甚至可能 为未来的治疗提供了途径。

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.