Characterization of Three Kindreds with Familial Combined Hypolipidemia Due to Loss of Function Mutations of ANGPTL3.

BACKGROUND: -Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knock out mice have a marked hypolipidemia and heterozygous carriers of ANGPLT3 loss of function (LOF) mutations were found among individuals in the lowest quartile of plasma triglyceride (TG) in population studies. Recently four related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 LOF mutations.METHODS AND RESULTS: -We resequenced ANGPTL3 in four members of three kindred originally identified for very low LDL-C and HDL-C levels (0.97±0.16 and 0.56±0.20 mmol/L), in whom no mutations of known candidate genes for monogenic hypobeta- and hypoalpha-lipoproteinemia had been detected. These subjects were found to be homozygous or compound heterozygous for ANGPTL3 LOF mutations (p.G400VfsX5, p.I19LfsX22/p.N147X), associated with the absence of ANGPTL3 in plasma. They had reduced plasma levels of TG containing lipoproteins and of LpA-I and preβ-HDL particles. In addition, their apoB-depleted sera had a reduced capacity to promote cell cholesterol efflux through the various pathways (ABCA1-, SR-BI- and ABCG1-mediated efflux). However, these subjects had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3, moderately reduced LDL-C (2.52±0.38 mmol/L) but normal plasma HDL-C.CONCLUSIONS: -Complete ANGPTL3 deficiency caused by LOF mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I containing lipoproteins, changes in HDL subclasses and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of LDL.