title: The replacement of arginine by cysteine at residue 151 in apolipoprotein A-I produces a phenotype similar to that of apolipoprotein A-IMilano.
abstract: Rare nonsynonymous mutations in the apolipoprotein A-I (apo A-I) gene are associated with low HDL-cholesterol levels. Despite the inverse correlation of high density lipoprotein (HDL)-cholesterol levels with the risk of coronary heart disease (CHD) in the population, reduced circulating concentrations of HDL do not necessarily predispose to premature CHD. One apo A-I defect was even reported to cause longevity. We describe a French patient who presented with very low serum HDL-cholesterol levels (10 mg/dl). Sequence analysis of the apo A-I gene identified a heterozygous mutation in the apo A-I gene which causes a cysteine for arginine replacement at residue 151. Family members with the mutation displayed 50% lower levels of plasma HDL-cholesterol and of apo A-I than unaffected members. Plasma activity of lecithin:cholesterol acyl transferase (LCAT) was significantly lower in apo A-I(R151C) heterozygotes than in controls. Furthermore, we found that as for apo A-IMilano (R173C), apo A-I(R151C) forms heterodimers with apo A-II. Moreover, HDL particles were abnormal in both lipid composition and size distribution. Despite these quantitative and qualitative differences in HDL, neither the history of the family over three generations nor the examination of the patient, gave any indication of premature occurrence of atherosclerosis or CHD. We conclude that apo A-I(R151C) causes a phenocopy of apo A-IMilano (R173C), an apo A-I variant which is assumed to cause longevity and which is considered as a potentially anti-atherogenic agent.
authors.affiliation: Service d'Endocrinologie-Métabolisme, Hôpital Pitié Salpétrière, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Bruckert
authors.forename: A
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: H
authors.initials: H
authors.lastname: Funke
authors.forename: I
authors.initials: I
authors.lastname: Beucler
authors.forename: H
authors.initials: H
authors.lastname: Wiebusch
authors.forename: G
authors.initials: G
authors.lastname: Turpin
authors.forename: G
authors.initials: G
authors.lastname: Assmann
mesh_terms: D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D002648:Child; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D003327:Coronary Disease / Q000097:blood / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D004586:Electrophoresis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D017354:Point Mutation; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D013631:Tangier Disease / Q000097:blood / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008074:Lipoproteins; D001120:Arginine; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D003545:Cysteine