Mendoza-Barberá, ElenaJulve, JosepNilsson, Stefan K.Lookene, AivarMartín Campos, Jesús M.Roig, RosaLechuga Sancho, Alfonso M.Sloan, John H.Fuentes Prior, PabloBlanco Vaca, Francisco2024-05-072024-05-072013-01-100022-2275https://hdl.handle.net/2445/210981<p>During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del, p.Leu253Pro, and p.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in severe hypertriglyceridemia remain poorly understood, and the functional impairment/s induced by these specific mutations was not obvious. Therefore, we performed a thorough structural and functional analysis that included follow-up of patients and their closest relatives, measurement of apoA-V serum concentrations, and sequencing of the APOA5 gene in 200 nonhyperlipidemic controls. Further, we cloned, overexpressed, and purified both wild-type and mutant apoA-V variants and characterized their capacity to activate LPL. The interactions of recombinant wild-type and mutated apoA-V variants with liposomes of different composition, heparin, LRP1, sortilin, and SorLA/LR11 were also analyzed. Finally, to explore the possible structural consequences of these mutations, we developed a three-dimensional model of full-length, lipid-free human apoA-V. A complex, wide array of impairments was found in each of the three mutants, suggesting that the specific residues affected are critical structural determinants for apoA-V function in lipoprotein metabolism and, therefore, that these APOA5 mutations are a direct cause of hypertriglyceridemia.</p>13 p.application/pdfeng(c) American Society for Biochemistry and Molecular Biology, 2013Expressió gènicaMalalties cardiovascularsTriglicèridsGene expressionCardiovascular diseasesTriglyceridesinfo:eu-repo/semantics/article7226072024-05-07info:eu-repo/semantics/openAccess