A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians.
The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency was examined in a group of 54 unrelated French Canadian subjects. The lecithin:cholesterol acyl transferase (LCAT) and apolipoprotein (apo) A-I gene were analyzed in all probands by direct DNA sequencing. While no LCAT mutation was detected, a novel nonsense apoA-I mutation (E136X) was found in 3/54 probands. Genetic analysis of two kindreds showed a strong co-segregation of the apoA-I locus with the low HDL-C trait. The E136X mutation was detected in families by MaeI restriction digestion. E136X carriers (n=17) had marked HDL-C deficiency; among the nine carriers > or = 35 years old, five men had developed premature coronary artery disease (CAD). A peptide of apparent molecular weight of 14 kDa was identified in fresh plasma, the HDL fractions and lipoprotein deficient plasma from the three probands but not in normal controls (n=3), suggesting that the mutant apoA-I peptide is secreted and binds lipids. The mutation was not observed in an additional 210 chromosomes from unrelated subjects of French Canadian descent, < 60 years of age, with CAD and low HDL-C levels. We conclude that apoA-I (E136X) is a cause of HDL-C deficiency in the French Canadian population and is associated with premature CAD.
Dastani
Zari
Z
Division of Cardiology, McGill University Health Center, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Qué., Canada H3A 1A1.
Dangoisse
Carole
C
Boucher
Betsie
B
Desbiens
Katia
K
Krimbou
Larbi
L
Dufour
Robert
R
Hegele
Robert A
RA
Pajukanta
Päivi
P
Engert
James C
JC
Genest
Jacques
J
Marcil
Michel
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D002648:Child; D008076:Cholesterol, HDL / Q000097:blood / Q000172:deficiency*; D018389:Codon, Nonsense; D003327:Coronary Disease / Q000097:blood / Q000208:ethnology / Q000235:genetics; D004247:DNA / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005602:France / Q000208:ethnology; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D013631:Tangier Disease / Q000097:blood / Q000208:ethnology / Q000235:genetics*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D018389:Codon, Nonsense; D004247:DNA