A novel mutation in ALK-1 causes hereditary hemorrhagic telangiectasia type 2

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant bleeding disorder and has two variants, HHT1 and HHT2, associated with mutations in the ENG and ALK-1 genes, respectively. We identified one Chinese HHT2 family to investigate the pathogenic gene and its possible mechanism of action by mutation screening and functional study. One substitution mutation (1717C>T) in exon 10 of the ALK-1 was found by sequencing of all exons of ENG and ALK-1 and caused a R479X mutation in the ALK-1 protein. ALK-1 mRNA and plasma thrombomodulin were measured by real-time quantitative PCR and ELISA, respectively. There was no significant difference in the expression levels of ALK-1 mRNA between patients and healthy individuals. A significantly higher level of thrombomodulin was found in HHT patients. These findings indicate that the mutation causes truncation of the ALK-1 protein at the post-transcriptional level; the plasma thrombomodulin may provide an easy diagnostic indicator in HHT patients.