A novel nonsense apolipoprotein A-I mutation (apoA-IE136X) 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 stong 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 ≥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.