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Title: Clinical and Molecular Genetic Features of Pulmonary Hypertension in Patients with Hereditary Hemorrhagic Telangiectasia
Authors: Trembath, Richard C.
Thomson, Jennifer R.
Machado, Rajiv D.
Morgan, Neil V.
Atkinson, C.
Winship, I.
Simonneau, G.
Galie, N.
Loyd, J. E.
Humbert, M.
Nichols, W. C.
Morrell, N. W.
First Published: 2-Aug-2001
Publisher: Massachusetts Medical Society
Citation: New England Journal of Medicine 2001; 345:325-334
Abstract: 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 b (TGF-b) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, 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 pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-b–receptor proteins, including endoglin and activin-receptor–like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. Results We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activinreceptor–like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. 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 hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension. (N Engl J Med 2001;345:325-34.)
DOI Link: 10.1056/NEJM200108023450503
ISSN: 0028-4793
eISSN: 1533-4406
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Archived with reference to SHERPA/RoMEO and publisher website.
Appears in Collections:Published Articles, Dept. of Genetics

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