ApoA-I(MALLORCA) impairs LCAT activation and induces dominant familial hypoalphalipoproteinemia.
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-I(MALLORCA) 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-I(MALLORCA) is not necessarily associated with clinical signs of atherosclerosis.
Martín-Campos
Jesús M
JM
Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau, C/Antoni M Claret 167, 08025 Barcelona, Spain.
Julve
Josep
J
Escolà
Joan Carles
JC
Ordóñez-Llanos
Jordi
J
Gómez
Joaquin
J
Binimelis
Jaume
J
González-Sastre
Francesc
F
Blanco-Vaca
Francisco
F
D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000172:deficiency* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*; D013030:Spain / Q000208:ethnology; D013631:Tangier Disease / Q000201:enzymology / Q000235:genetics*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase