Abstract
Apolipoprotein (apo)A-I is the major protein component of HDL and the cofactor for LCAT. We describe a large Spanish kindred, living in the Mediterranean Island of Mallorca, that presents a dominant form of hypoalphalipoproteinemia. The lipid profile of this family was studied because the proband, a 40-year-old male presenting signs of coronary atherosclerosis, showed severe HDL deficiency. However, none of the other family members had a known history of cardiovascular disease. Sequence analysis of the apoA-I gene in affected members identified a 33-base pair deletion, corresponding to residues 165–175 of the mature protein, eliminating the first 11 amino acids of the internal repeat 7. ApoA-IMALLORCA is associated with HDL-cholesterol deficiency (concentration ranging from 8–48% of the value in non-carriers), and a 2- to 3-fold decrease in plasma concentrations of apoA-I and apoA-II and endogenous LCAT activity, concomitant with a slight decrease in serum cholesterol efflux capability. Impairment of LCAT activity in HDL particles containing only mutated forms of apoA-I would not explain a pattern of dominant inheritance. HDL particles containing wild type apoA-I and at least one mutant apoA-I may also present impaired LCAT activity and/or other alterations leading to defective HDL maturation, a situation that would increase HDL lipid catabolism. We conclude that amino acids 165–175 of apoA-I are critical for normal HDL metabolism, at least in part because of their role in LCAT activation. However, apoA-IMALLORCA is not necessarily associated with clinical signs of atherosclerosis. —Martin-Campos, J. M., J. Julve, J. C. Escola, J.Ordonez-Llanos, J. Gomez, J. Binimelis, F. Gonzalez-Sastre, and F. Blanco-Vaca. ApoA-IMALLORCA impairs LCAT activation and induces dominant familial hypoalphalipoproteinemia. J. Lipid Res. 2002. 43: 115–123.
Highlights
ApolipoproteinA-I is the major protein component of HDL and the cofactor for LCAT
ApoA-I is an important ligand for the binding of HDL to cell receptors such as scavenger receptor class B type I (SR-BI) and cholesterol efflux regulatory protein (CERP) [6, 7]
We describe a novel deletion mutation in the human apoA-I gene that induces dominantly inherited hypoalphalipoproteinemia characterized by HDL-cholesterol deficiency concomitant with a milder decrease in plasma apoA-I and apoA-II concentrations and LCAT activity
Summary
Apolipoprotein (apo)A-I is the major protein component of HDL and the cofactor for LCAT. ApoA-I is an important ligand for the binding of HDL to cell receptors such as scavenger receptor class B type I (SR-BI) and cholesterol efflux regulatory protein (CERP) [6, 7]. These characteristics contribute to the ability of HDL to induce reverse cholesterol transport and, potentially to the protective effect of HDL against atherothrombotic cardiovascular disease. The 22 mer repeats could form tandem antiparallel helices that are perpendicular to the plane of the phospholipid bilayer (the picket-fence model), at least in the discoidal HDL particles [14, 15] These amphipathic ␣-helices act as protein detergents that stabilize the structure of lipoprotein particles [15]. Deletion of repeat 6 (residues 143 –164) or repeat 7 (residues 165–186) resulted in a 98–99% reduction in LCAT activation compared with wild-type apoA-I [18], demonstrating the important role of these domains in LCAT action
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