MUTATIONS IN THE ACTIVIN RECEPTOR-LIKE KINASE-1 GENE IN HEREDITARY HEMORRHAGIC TELANGIECTASIA TYPE-2

Hereditary haemorrhagic telangiectasia, or Osler-Rendu-Weber (ORW) syn drome, is an autosomal dominant vascular dysplasia. So far, two loci h ave been demonstrated for ORW. Linkage studies established an ORW locu s at chromosome 9q3; endoglin was subsequently identified as the ORW1 gene. A second locus, designated ORW2, was mapped to chromosome 12. He re we report a new 4 cM interval for ORW2 that does not overlap with a ny previously defined. A 1.38-Mb YAC contig spans the entire interval. It includes the activin receptor like kinase 1 gene (ACVRLK1 or ALK1) , 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 contr ol of blood vessel development or repair.