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.
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