Exome Sequencing,<i>ANGPTL3</i>Mutations, and Familial Combined Hypolipidemia

TLDR

ANGPTL3 is known to inhibit lipoprotein lipase and endothelial lipase, thereby raising plasma triglyceride and HDL cholesterol levels in rodents. We performed exome sequencing on two family members with combined hypolipidemia characterized by extremely low LDL cholesterol and high HDL cholesterol and triglyceride levels. Both participants carried compound heterozygous nonsense mutations in ANGPTL3, underscoring the gene’s role in human LDL cholesterol metabolism and demonstrating the utility of exome sequencing for uncovering novel genetic causes of inherited disorders. Funding was provided by the National Human Genome Research Institute and other agencies.

Abstract

We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).