BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by 
inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout 
mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, 
loss-of-function mutations were found among individuals in the lowest quartile 
of plasma triglycerides in population studies. Recently, 4 related individuals 
with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 
loss-of-function mutations.
METHODS AND RESULTS: We resequenced ANGPTL3 in 4 members of 3 kindreds 
originally identified for very low levels of low-density lipoprotein cholesterol 
and high-density lipoprotein cholesterol (0.97±0.16 and 0.56±0.20 mmol/L, 
respectively) in whom no mutations of known candidate genes for monogenic 
hypobetalipoproteinemia and hypoalphalipoproteinemia had been detected. These 
subjects were found to be homozygous or compound heterozygous for ANGPTL3 
loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) associated with 
the absence of ANGPTL3 in plasma. They had reduced plasma levels of 
triglyceride-containing lipoproteins and of HDL particles that contained only 
apolipoprotein A-I and pre-β-high-density lipoprotein. In addition, their 
apolipoprotein B-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 and moderately reduced low-density lipoprotein cholesterol 
(2.52±0.38 mmol/L) but normal plasma high-density lipoprotein cholesterol.
CONCLUSIONS: Complete ANGPTL3 deficiency caused by loss-of-function mutations of 
ANGPTL3 is associated with a recessive hypolipidemia characterized by a 
reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, 
changes in subclasses of high-density lipoprotein, and reduced cholesterol 
efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a 
moderate reduction of low-density lipoprotein.