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Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
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2013 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 54, no 3, 649-661 p.Article in journal (Refereed) Published
Abstract [en]

During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del,p.Leu253Pro,andp.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.-Mendoza-Barbera, E., J. Julve, S. K. Nilsson, A. Lookene, J. M. Martin-Campos, R. Roig, A. M. Lechuga-Sancho, J. J. Sloan, P. Fuentes-Prior, and F. Blanco-Vaca. Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia. 

Place, publisher, year, edition, pages
2013. Vol. 54, no 3, 649-661 p.
Keyword [en]
apoA-V, familial hyperchylomicronemia, homology modeling, molecular bases of disease, LRP1, sortilin, SorLA/LR11, triglyceride metabolism, type V hyperlipidemia
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-67385DOI: 10.1194/jlr.M031195ISI: 000314877000009OAI: diva2:615898
Available from: 2013-04-12 Created: 2013-03-18 Last updated: 2013-04-12Bibliographically approved

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