The Activin Receptor-Like Kinase 1 Gene: Genomic Structure and Mutations in Hereditary Hemorrhagic Telangiectasia Type 2

• Published in: American journal of human genetics Vol. 61; no. 1; pp. 60 - 67
• Main Authors: Berg, Jonathan N., Gallione, Carol J., Stenzel, Timothy T., Johnson, David W., Allen, William P., Schwartz, Charles E., Jackson, Charles E., Porteous, Mary E.M., Marchuk, Douglas A.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.07.1997; University of Chicago Press
• Subjects: Activin Receptors; Alleles; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 9; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Genetic Linkage; Genome, Human; Humans; Male; Medical sciences; Mice; Molecular Sequence Data; Mutation; Pedigree; Protein-Serine-Threonine Kinases - genetics; Telangiectasia, Hereditary Hemorrhagic - genetics; Human; Skin disease; Genetic inheritance; Enzyme; Transferases; Cardiovascular disease; Osler Rendu disease; Genetic disease; Telangiectasia; Vascular disease; Angioma; Kinase; Mutation; Activin; Biological receptor
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/513903

The activin receptor-like kinase 1 gene (ALK-1) is the second locus for the autosomal dominant vascular disease hereditary hemorrhagic telangiectasia (HHT). In this paper we present the genomic structure of the ALK-1 gene, a type I serine-threonine kinase receptor expressed predominantly in endothelial cells. The coding region is contained within nine exons, spanning < 15 kb of genomic DNA. All introns follow the GT-AG rule, except for intron 6, which has a TAG|gcaag 5′ splice junction. The positions of introns in the intracellular domain are almost identical to those of the mouse serine-threonine kinase receptor TSK-7L. By sequencing ALK-1 from genomic DNA, mutations were found in six of six families with HHT either shown to link to chromosome 12q13 or in which linkage of HHT to chromosome 9q33 had been excluded. Mutations were also found in three of six patients from families in which available linkage data were insufficient to allow certainty with regard to the locus involved. The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established. In two cases in which premature termination codons were found in genomic DNA, the mutant m RNA was either not present or present at barely detectable levels. These data suggest that mutations in ALK-1 are functionally null alleles.