Recent developments in the genetics of LDL deficiency

Inherited diseases of lipoprotein metabolism may give rise to marked hypocholesterolemia with low or absent levels of LDL, depending on the gene involved and mode of inheritance of the condition, together with the severity of the mutation or mutations present. In this review, we discuss the recent developments in the genetics of LDL deficiency.

Carriers of a single loss-of-function variant in ANGPTL3 have reduced LDL-cholesterol and triglyceride concentrations, whereas homozygotes have markedly reduced LDL-cholesterol, triglyceride and HDL-cholesterol concentrations, a recessive form of hypocholesterolemia designated as familial combined hypolipidemia.

The identification of loss-of-function ANGPTL3 mutations as a cause of familial combined hypolipidemia suggests a new mechanism for the regulation of LDL metabolism in humans, thereby making ANGPTL3 an attractive protein to target for therapeutics.