Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia

Abstract

Hypertriglyceridemia is common in humans and is a well-established cardiovascular risk factor independent of HDL cholesterol ( 1 ). Hypertriglyceridemia is present in hyperlipidemia types I, IIb, III, IV, and V, all of which (with the exception of type I hyperlipidemia, also known as familial hyperchylomicronemia) are currently considered complex diseases with a strong polygenic component ( 2, 3 ). While LPL and APOC2 gene mutations have been known for decades to be a cause of familial hyperchylomicronemia ( 4-6 ), mutations in the APOA5 or glycosylphosphatidylinositol-anchored HDL-binding protein 1 ( GPIHBP1 ) genes have been found more recently to explain some cases of this disease in which no LPL or APOC2 mutations were found ( 7-9 ). APOA5 variants have also been linked to the polygenic hyperlipidemia types IIb, III, IV, and V as well as to cardiovascular disease risk ( 3,(10)(11)(12)(13)(14).ApoA-V was fi rst identifi ed and characterized as a liver preprotein of 366 amino acid residues that is secreted 08-1147 (to F.B.-V.), 11-01076 (to F.B.-V.), 10-00277 (to J.J.), and SAF2010-15668 (to P.F.-P.) This work was funded by Instituto de Salud Carlos III (ISCIII) Grants

Postprandial lipemia as a cardiometabolic risk factor

“…Gene variations in this locus can alter postprandial lipemia: carriers of the rare allele of Thr347Ser have a lower postprandial increase of TG levels associated with TRL remnants 72 , while data for the Gln360His variant are so far inconsistent 73,74 . ApoA-V favors lipoprotein lipase-mediated triglyceride hydrolysis and hepatic clearance of lipoprotein remnant particles; mutations in the APOA5 gene are associated with severe hypertriglyceridemia 75 . Two APOA5 SNPs (À1131T 4C…”

Sortilin and lipoprotein metabolism

“…Tveten et al sequenced the SORT1 gene in more than 800 hypercholesterolemic individuals and found no pathological mutations and concluded that SORT1 mutations are unlikely to cause autosomal dominant hypercholesterolemia [16]. Interestingly, Mendoza-Barberá identified three novel mutations in ApoAV in three individuals with unexplained hypertriglyceridemia, and in vitro functional studies show that these mutants are impaired in their ability to interact with sortilin [47]. Finally, the role of sortilin in the blood vessel wall is emerging as an important factor in atherosclerotic disease.…”

Clinical and Biochemical Features of Different Molecular Etiologies of Familial Chylomicronemia

“…[1][2][3][4][5][6] Clearance is largely mediated through the hydrolyzing action of lipoprotein lipase gene (LPL), located on the endothelial surface of adipose and muscle tissue. 7 The phenotype of FCS includes at least one physical manifestation of chylomicronemia, which include eruptive xanthoma, lipemia retinalis, pancreatitis, or hepatosplenomegaly. 5,6 Although severe hypertriglyceridemia (TG .…”