Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

Background: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of rec eptors. Because patients with hereditary hemorrhagic telangiectasia may hav e lung disease that is indistinguishable from primary pulmonary hypertensio n, we investigated the genetic basis of lung disease in these patients. Methods: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmo nary hypertension. In the two largest families, we used microsatellite mark ers to test for linkage to genes encoding TGF-beta -receptor proteins, incl uding endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In sub jects with hereditary hemorrhagic telangiectasia and pulmonary hypertension , we also scanned ALK1 and BMPR2 for mutations. Results: We identified suggestive linkage of pulmonary hypertension with he reditary hemorrhagic telangiectasia on chromosome 12q13, a region that incl udes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and his tologic features indistinguishable from those of primary pulmonary hyperten sion. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. Conclusions: Pulmonary hypertension in association with hereditary hemorrha gic telangiectasia can involve mutations in ALK1. These mutations are assoc iated with diverse effects, including the vascular dilatation characteristi c of hereditary hemorrhagic telangiectasia and the occlusion of small pulmo nary arteries that is typical of primary pulmonary hypertension.