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

The activin receptor-like kinase 1 gene (ALK-1) is the second locus fo r the autosomal dominant vascular disease hereditary hemorrhagic telan giectasia (HI-IT). In this paper we present the genomic structure of t he ALK-1 gene, a type I serine-threonine kinase receptor expressed pre dominantly 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 junctio n. The positions of introns in the intracellular domain are almost ide ntical to those of the mouse serine-threonine kinase receptor TSK-7L. By sequencing ALK-1 from genomic DNA, mutations were found in six of s ix families with HHT either shown to link to chromosome 12q13 or in wh ich linkage of HHT to chromosome 9q33 had been excluded. Mutations wer e 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 seq uencing of ALK-1 suggests that this will be a useful diagnostic test f or HHT2, particularly where preliminary linkage to chromosome 12q13 ca n be established. In two cases in which premature termination codons w ere found in genomic DNA, the mutant mRNA was either not present or pr esent at barely detectable levels. These data suggest that mutations i n ALK-1 are functionally null alleles.