A NOVEL MISSENSE MUTATION IN THE ENDOGLIN GENE IN HEREDITARY HEMORRHAGIC TELANGIECTASIA

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant d isorder characterized by multisystem vascular dysplasia and recurrent hemorrhage. Recent investigation has mapped one of the responsible gen es for HHT to chromosome 9q33-q34; subsequently, nine different mutati ons have been identified in the endoglin gene, which encodes a transfo rming growth factor beta (TGF-beta) binding protein, in nine unrelated families with HHT. We examined the endoglin gene in a Japanese patien t with HHT and her family members. Using PCR-SSCP analysis followed by sequencing, we identified a C to A missense mutation in exon 4 which changed an Ala(160) codon(GCT) to an Asp(160) codon (GAT). Since this mutation destroys one of three Fnu4H I sites in exon 4, the Fnu4H I di gestion patterns of the PCR-amplified exon 4 fragments from each famil y member were analyzed. In affected members, the restriction patterns were all consistent with a phenotype of HHT. PCR-amplified exon 4 frag ments from 150 normal individuals were also analyzed by allele-specifi c oligonucleotide hybridization analysis. As a result, the mutation wa s not found in any of them. We conclude that the C to A mutation in ex on 4 of the endoglin gene in this proband is responsible for the occur rence of HHT in this family.