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), designated apoC-IISF, was identified in three unrelated hyperlipidemic patients. 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 203 mg/dl) and the third, an African-American male (TC 345 mg/dl, TG 1000 mg/dl). Each subject was found to be heterozygous for a G to A substitution in the codon for residue 38, resulting in a Lys for Glu exchange. This accounts for the increased pl value of 5.3. The third patient, in addition to apoC-IISF, had apoC-II2, another charge variant. This was determined by DNA sequencing, confirming the Gln for Lys change at residue 55 previously predicted by analysis of peptide fragments in this laboratory. Similar Michaelis constants of activation and activation energies were observed when the ability of apoC-IISF to activate lipoprotein lipase was compared to normal apoC-II. This indicates that major changes in charge around residue 38 lack effect on the activation properties. The variant may be altered in some other property, such as lipid binding, but since the distribution of apoC-IISF revealed no simple co-inheritance with lipid levels, it is unclear to what extent it plays a role in the observed hyperlipidemia. The presence of other factors acting together with the variant may predispose to elevated lipid levels.