Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
Por:
Mendoza-Barbera, E, Julve, J, Nilsson, SK, Lookene, A, Martin-Campos, JM, Roig, R, Lechuga-Sancho, AM, Sloan, JH, Fuentes-Prior, P, Blanco-Vaca, F
Publicada:
1 mar 2013
Resumen:
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. J. Lipid Res. 2013. 54: 649-661.
Filiaciones:
Mendoza-Barbera, E:
Inst Biomed Res IIB St Pau, Barcelona 08025, Spain
Julve, J:
Inst Biomed Res IIB St Pau, Barcelona 08025, Spain
CIBER Diabet & Enfermedades Metab Asociadas, Barcelona 08017, Spain
Nilsson, SK:
Umea Univ, Dept Med Biosci Physiol Chem, SE-90187 Umea, Sweden
Lookene, A:
Tallinn Univ Technol, Dept Chem, EE-12618 Tallinn, Estonia
Martin-Campos, JM:
Inst Biomed Res IIB St Pau, Barcelona 08025, Spain
Roig, R:
Inst Biomed Res IIB St Pau, Barcelona 08025, Spain
Lechuga-Sancho, AM:
Hosp Univ Puerta Mar, Unidad Endocrinol Pediat, Cadiz 11009, Spain
Sloan, JH:
Eli Lilly & Co, Indianapolis, IN 46285 USA
Fuentes-Prior, P:
Inst Biomed Res IIB St Pau, Barcelona 08025, Spain
Blanco-Vaca, F:
Inst Biomed Res IIB St Pau, Barcelona 08025, Spain
CIBER Diabet & Enfermedades Metab Asociadas, Barcelona 08017, Spain
Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, E-08193 Barcelona, Spain
Green Published, Hybrid Gold
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