THE REPLACEMENT OF ARGININE BY CYSTEINE AT RESIDUE-151 IN APOLIPOPROTEIN-A-I PRODUCES A PHENOTYPE SIMILAR TO THAT OF APOLIPOPROTEIN A-I-MILANO

Rare nonsynonymous mutations in the apolipoprotein A-I (ape A-I) gene are associated with low HDL-cholesterol levels. Despite the inverse co rrelation of high density lipoprotein (HDL)-cholesterol levels with th e risk of coronary heart disease (CHD) in the population, reduced circ ulating concentrations of HDL do not necessarily predispose to prematu re CHD. One apo A-I defect was even reported to cause longevity. We de scribe a French patient who presented with very low serum HDL-choleste rol levels (10 mg/dl). Sequence analysis of the apo A-I gene identifie d a heterozygous mutation in the apo A-I gene which causes a cysteine for arginine replacement at residue 151. Family members with the mutat ion displayed 50% lower levels of plasma HDL-cholesterol and of apo A- I than unaffected members. Plasma activity of lecithin:cholesterol acy l transferase (LCAT) was significantly lower in apo A-I(R151C) heteroz ygotes than in controls. Furthermore, we found that as for apo A-I-Mil ano (R173C), apo A-I(R151C) forms heterodimers with apo A-II. Moreover , HDL particles were abnormal in both lipid composition and size distr ibution. Despite these quantitative and qualitative differences in HDL , neither the history of the family over three generations nor the exa mination of the patient, gave any indication of premature occurrence o f atherosclerosis or CHD. We conclude that apo A-I(R151C) causes a phe nocopy of apo A-I-Milano (R173C), an apo A-I variant which is assumed to cause longevity and which is considered as a potentially anti-ather ogenic agent. Copyright (C) 1997 Elsevier Science Ireland Ltd.