A novel nonsense apolipoprotein A-I mutation (apoA-I(E136X)) causes low HDL cholesterol in French Canadians.
Dastani Z,
Dangoisse C,
Boucher B,
Desbiens K,
Krimbou L,
Dufour R,
Hegele RA,
Pajukanta P,
Engert JC,
Genest J,
Marcil M.
Division of Cardiology, McGill University Health Center, Royal Victoria Hospital, 687 Pine Avenue West, Montréal, Qué., Canada H3A 1A1.
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.
PMID: 16023124 [PubMed - indexed for MEDLINE]