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Previous Volume 345:325-334 August 2, 2001 Number 5 Next

	Full Text PDF Editorial by Loscalzo, J. Editorial by Welch, C. A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

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 (TGF-) 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-–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 activin-receptor–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.

Source Information

From the Division of Medical Genetics, Departments of Medicine and Genetics, University of Leicester, Leicester, United Kingdom (R.C.T., J.R.T., R.D.M., N.V.M.); the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom (C.A., N.W.M.); the Department of Molecular Medicine, School of Medicine, University of Auckland, Auckland, New Zealand (I.W.); the Service de Pneumologie, Hôpital Antoine Béclère, Assistance Publique–Hôpitaux de Paris, Université Paris-Sud, Clamart, France (G.S., M.H.); the Institute of Cardiology, University of Bologna, Bologna, Italy (N.G.); Vanderbilt University Medical Center, Nashville (J.E.L.); and the Division of Human Genetics, Children's Hospital Medical Center, Cincinnati (W.C.N.).

Other authors were Jonathan Berg, M.D., Department of Clinical Genetics, Guy's Hospital Campus, King's College, London; Alessandra Manes, M.D., Institute of Cardiology, University of Bologna, Bologna, Italy; Julie McGaughran, M.D., Department of Molecular Medicine, School of Medicine, University of Auckland, Auckland, New Zealand; Michael Pauciulo, B.Sc., Division of Human Genetics, Children's Hospital Medical Center, Cincinnati; and Lisa Wheeler, B.Sc., Vanderbilt University Medical Center, Nashville.

Address reprint requests to Dr. Trembath at the Division of Medical Genetics, Departments of Medicine and Genetics, Adrian Bldg., University of Leicester, Leicester LE1 7RH, United Kingdom, or at rtrembat{at}hgmp.mrc.ac.uk.

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