Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multi-systemic vascular lesions resulting from dysplastic growth of the venules and arterioles. Recurrent hemorrhage, serious morbidity, and 10% mortality are the result. The pathophysiology of this disorder suggests a critical role for the HHT gene(s) in angiogenesis. Genetic heterogeneity has been established for HHT with loci mapping to 9q33 (HHT 1), 12q13 (HHT 2), and a yet unmapped location (HHT 3). Thus HHT is a group of related genetic disorders of improper regulation of vascular growth. The HHT 1 locus has been identified as endoglin, a transforming growth factor (TGF)-beta receptor of endothelial cells, suggesting a role for the TGF-beta signal transduction pathway in angiogenesis. The molecular genetic characterization of the other types of HHT will reveal other genes causing this disorder and in addition, other genes involved in angiogenesis. The candidate region for HHT 2 has been narrowed to an 8 cM interval. This proposal aims to identify the HHT 2 gene by a positional cloning strategy. The interval will first be narrowed by collection of more HHT 2 families and subsequent haplotype analysis to identify key recombinant chromosomes. Once the interval is narrowed sufficiently, the existing physical and transcript map of this region will be augmented by cDNA selection using genomic clones from the region. Candidate genes will be investigated for their potential involvement in HHT by a combination of tissue expression study and sequence analysis. DNA sequence analysis of genes from patients will uncover mutations which identify the HHT 2 gene. For the HHT 3 gene, which is yet unmapped, a positional-candidate approach will be used. From what is known about the role of endoglin in HHT 1 and the effects of TGF-beta on endothelial cells, a number of candidate genes are suggested. Linkage analysis will be performed to the regions where these genes map. If this approach fails, a whole genome linkage approach will be used. Subsequent work will parallel that used for the identification of the HHT 1 and HHT 2 genes, in a positional cloning effort. The identification of the HHT 2 and HHT 3 genes will provide insight into the pathology of this disorder and the biology of the vascular system, and become the framework for future studies on the role of the gene products in angiogenesis.