Endoglin-deficient mice, a unique model to study hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by dilated vessels and arteriovenous malformations. Phenotypi c heterogeneity, such as age of onset, severity of disease and organ involv ement, is explained in part by two genes being mutated, endoglin (HHT1) and ALK-1 (HHT2). Haploinsufficiency is the mechanism responsible for HHT. Thi s implies that position and type of mutations cannot explain heterogeneity, because mutant proteins are not expressed at the cell surface and conseque ntly cannot interfere with normal function. Based on this mode, we generate d mice expressing only one allele of endoglin, but in two different inbred strains, 129/Ola and C57BL/6. Phenotypic heterogeneity was also observed am ong the HHT mice and was very dependent on the genetic background. Our data strongly suggest that additional genes, contributed by the 129/Ola strain, are responsible for the vascular anomalies associated with HHT. The murine model is faithful to the human disease and should allow us to identify the modifier genes of HHT as well as to test potential therapeutic interventio ns. (Trends Cardiovasc Med 2000;10;279-285). (C) 2001, Elsevier Science Inc .