Molecular cloning and characteristics of a new apolipoprotein C-II mutant identified in three unrelated individuals with hypercholesterolemia and hypertriglyceridemia

A new rare mutant form of apolipoprotein C-II (apoC-II), designatedapoC-II_SF, was identified in three unrelated hyperlipidemicpatients. The first was a Caucasian male with a total cholesterol(TC) of 313 mg/dl and total triglyceride (TG) of 282 mg/dl,the second an African-American female (TC 345 mg/dl, TG 203mg/dl) and the third, an African—American male (TC 345mg/dl, TG 1000 mg/dl). Each subject was found to be heterozygousfor a G to A substitution in the codon for residue 38, resultingin a Lys for Glu exchange. This accounts for the increased plvalue of 5.3. The third patient, in addition to apoC-II_SF, hadapoC-II₂, another charge variant. This was determined by DNAsequencing, confirming the Gln for Lys change at residue 55previously predicted by analysis of peptide fragments in thislaboratory. Similar Michaelis constants of activation and activationenergies were observed when the ability of apoC-II_SF to activatelipoprotein lipase was compared to normal apoC-II. This indicatesthat major changes in charge around residue 38 lack effect onthe activation properties. The variant may be altered in someother property, such as lipid binding, but since the distributionof apoC-II_SF revealed no simple co-inheritance with lipid levels,it is unclear to what extent it plays a role in the observedhyperlipidemia. The presence of other factors acting togetherwith the variant may predispose to elevated lipid levels.