The pathogenesis of primary pulmonary arterial hypertension (PAH) is unknown. The main goal of this project continues to be the identification of genes that cause PAH and how these genes contribute to the pathophysiology of the disease and its clinical subsets. The familial form of primary pulmonary hypertension (FPPH), inherited as an autosomal dominant disease with incomplete penetrance, was known to have a gene, PPH1 located on chromosome 2q32,33. After narrowing this large locus, our studies found mutations of bone morphogenetic protein receptor 2 (BMPR2) caused disease in 9 of 21 FPPH families. Others found BMPR2 mutations in 26% of sporadic PPH. BMPR2 mutations were also found 9% of fenfluramine appetite-associated PAH whereas no mutations were found in PAH patients with HIV-infection or with scleroderma spectrum of disease. BMPR2 mutations remain to be determined in large PAH cohorts of children and adults with anatomically large congenital pulmonary to systemic communications and with sporadic PPH. Our clinical resources include 100 FPPH families and 5 hereditary hemorrhagic telangiectasia (HHT1) families, four have mutations in activin-like receptor 1 (ALK-1), another gene associated with PPH. The identification of BMPR2 gene, a member of the TGF-B superfamly has focused the BMP/TGF-B signaling pathway for new explorations into the pathogenesis of PPH. Our newer aims will investigate the mechanism by which BMPR2 mutations cause disease, identify genetic mutations that cause disease in the 50% of FPPH cases that do not contain mutations in the exons of BMPR2, and identify DNA variations that alter the penetrance of BMPR2 mutations. We are most interested in the long C-terminal tail of BMPR2, which is unique in the TGF-B superfamily. Hopefully, these aims and the large available clinical material should provide pathophysiological information on the functional relevance of BMPR2 mutations, provide an in vitro method of BMPR2 evaluation, and provide the identification of additional risk factors and genes required for disease penetrance. Longitudinal follow of the FPPH and sporadic cases and of the HHT families should give information on the natural history of disease. The results could also define further avenues for therapeutic interventions and potentially provide in vitro models for drug testing. ? ?
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