A NOVEL APOLIPOPROTEIN C-III VARIANT, APOC-III(GLN38-]LYS), ASSOCIATED WITH MODERATE HYPERTRIGLYCERIDEMIA IN A LARGE KINDRED OF MEXICAN ORIGIN

Apolipoprotein C-III (apoC-III) is a major protein component of very l ow density lipoproteins (VLDL), chylomicrons, and a minor component of high density lipoproteins (HDL). Studies of naturally occurring human variants of apoC-III will help in adding to our understanding of the physiological function of this apolipoprotein. Using isoelectric focus ing (IEF) of VLDL fractions we screened over 2500 lipid clinic patient s and have identified an individual with a novel apoC-III variant. DNA sequencing revealed the variant to be a Lys for Gln exchange at amino acid residue 38 due to an A for C substitution in exon 3. This was co nfirmed by NH2-terminal protein sequence analysis. The mutant Lys38 va riant was present in VLDL at about the same level as the normal form a lthough the total amount of apoC-III was increased by 34%. The proband , a 16-year-old boy of Mexican origin, had a plasma level of total tri glycerides above the 95th percentile for his age. Family studies revea led a further 16 individuals who were heterozygous for this apoC-III(G ln38 --> Lys) variant Compared to 21 unaffected relatives, the 17 hete rozygous subjects had a statistically significant 32% elevation of the ir plasma levels of triglycerides when adjusted for age, sex, body mas s index, and lifestyle. Other lipid and lipoprotein values were unaffe cted. The presence of an additional positive charge at residue 38 sugg ests that this residue is involved in the function of apoC-III. The el evation of plasma levels of triglycerides supports the view that apoC- III is involved in the regulation of the catabolism of triglyceride-ri ch lipoproteins.