Familial combined hypolipidemia due to mutations in the ANGPTL3 gene

The role of ANGPTL3 in lipoprotein metabolism emerged from studies in a mutant mouse strain characterized by severe hypotriglyceridemia and carrying a loss-of-function (LOF) mutation of the ANGPTL3 gene. ANGPTL3 was found to inhibit lipoprotein lipase and endothelial lipase. Genome-wide association studies in humans demonstrated the association of ANGPTL3 variants with plasma triglyceride levels and LOF mutations of ANGPTL3 were found in hypotriglyceridemic subjects in population studies. Recently, individuals originally classified as affected by familial hypobetalipoproteinemia were found to be homozygotes/compound heterozygotes for rare LOF mutations of ANGPTL3. They show a striking reduction of all lipoprotein classes (VLDL, LDL and HDL), a condition defined as familial combined hypolipidemia. This disorder,transmitted as a recessive trait, does not seem to be associated with specific clinical manifestations, such as premature atherosclerosis or fatty liver disease.