A hereditary haemorrhagic telangiectasia family with pulmonary involvementis unlinked to the known HHT genes, endoglin and ALK-1

Background-Pulmonary arteriovenous malformations (PAVMs) occur in over 25% of patients with the autosomal dominant disorder hereditary haemorrhagic te langiectasia (HHT). Mutations in two genes, endoglin and ALK-1, are known t o cause HHT. Each encodes a protein expressed on vascular endothelial cells and involved in signalling by members of the transforming growth factor (T GF)-beta superfamily. To date, PAVMs have not been detected in ALK-1 famili es. There is evidence from a single HHT family without pulmonary involvemen t that a third HHT gene may exist. To establish the existence of a further HHT gene responsible for PAVMs, linkage analyses were performed on an expan ded PAVM-HHT family in which HHT did not result from endoglin mutations. Methods-Family members were assessed clinically to assign HHT disease statu s and were screened for PAVMs. DNA was extracted from blood obtained from 2 0 individuals of known disease status. Short tandem repeat polymorphic mark ers spanning the intervals containing the endoglin and ALK-1 genes were amp lified by the polymerase chain reaction using P-33-labelled oligonucleotide primers, separated by denaturing polyacrylamide gel electrophoresis (PAGE) , and the resultant autoradiographs were examined for allele sizes. Linkage analyses were performed using MLINK and GENE-HUNTER. Results-Twelve members spanning four generations were affected with HHT. Tw o had proven PAVMs, one with a classical appearance, the other exhibiting m icroscopic PAVMs exacerbated by pregnancy. Two point lod and multipoint lod scores significantly excluded linkage to endoglin and ALK-1 in this pedigr ee. Conclusions-This study confirms the existence of a third HHT locus that acc ounts for disease in some HHT patients with pulmonary involvement.