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http://hdl.handle.net/2445/210981
Title: | Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia |
Author: | Mendoza Barberá, Elena de Julve, Josep Nilsson, Stefan K. Lookene, Aivar Martín Campos, Jesús M. Roig, Rosa Lechuga Sancho, Alfonso M. Sloan, John H. Fuentes Prior, Pablo Blanco Vaca, Francisco |
Keywords: | Expressió gènica Malalties cardiovasculars Triglicèrids Gene expression Cardiovascular diseases Triglycerides |
Issue Date: | 10-Jan-2013 |
Publisher: | American Society for Biochemistry and Molecular Biology |
Abstract: | <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> |
Note: | Reproducció del document publicat a: https://doi.org/10.1194/jlr.M031195 |
It is part of: | Journal of Lipid Research, 2013, vol. 54, num.3, p. 649-661 |
URI: | http://hdl.handle.net/2445/210981 |
Related resource: | https://doi.org/10.1194/jlr.M031195 |
ISSN: | 0022-2275 |
Appears in Collections: | Articles publicats en revistes (Biologia, Sanitat i Medi Ambient) |
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