Nature Genetics
13, 189 - 195 (1996)
doi:10.1038/ng0696-189
Mutations in the activin receptor−like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2D.W. Johnson1, J.N. Berg1, 2, M.A. Baldwin1, C.J. Gallione1, I. Marondel3, S.-J. Yoon3, T.T. Stenzel1, 4, M. Speer5, M.A. Pericak-Vance5, A. Diamond6, A.E. Guttmacher7, C.E. Jackson8, L. Attisano9, R. Kucherlapati3, M.E.M. Porteous2
& D.A. Marchuk1
1Department of Genetics, Duke University Medical Center, Box 3175, Durham, North Carolina 27710, USA
2Department of Human Genetics, University of Edinburgh, Edinburgh EH4 2XU, UK
3Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10461, USA
4Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
5Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA
6Department of Immunology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4AA,UK
7Department of Pediatrics, University of Vermont, Burlington, VT 05401, USA
8Departmentof Medicine, Division of Clinical and Molecular Genetics, Henry Ford Hospital, Detroit, Michigan 48202, USA
9Department of Anatomy and Cell Biology, The University of Toronto, Toronto, Ontario M5S1A8, Canada Correspondence should be addressed to D.A.M. Hereditary haemorrhagic telangiectasia, or Osler−Rendu−Weber (ORW) syndrome, is an autosomal dominant vascular dysplasia. So far, two loci have been demonstrated for ORW. Linkage studies established an ORW locus at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. Here we report a new 4 cM interval for ORW2 that does not overlap with any previously defined. A 1.38−Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALKI), a member of the serine−threonine kinase receptor family expressed in endothelium. We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12. Our data suggest a critical role for ALK1 in the control of blood vessel development or repair.
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