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

Abstract

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.

Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity.

“…Lipid analyses were performed from blood drawn from fasting individuals as described previously (25,26) with the exception that serum levels of HDL cholesterol and triglyceride were determined after precipitation of LDL and VLDL with MgCI2 and dextran sulfate, and levels of LDL cholesterol and triglyceride were calculated as the levels in total serum minus that in VLDL plus HDL. When appropriate, serum levels of total cholesterol and LDL cholesterol were adjusted for age (to 25 yr) and gender by nonlinear regression analysis using data in the Lipid Research Clinics Population Studies Data Book (27 taining lipoprotein-deficient serum (10%) and lovastatin (1 sg/ml; Merck & Co., West Point, PA).…”

“…The method described by Hixon and Vernier (42) was followed to ascertain the apoE genotypes. When possible, phenotypes were determined by isoelectric focusing of apoVLDL as previously described (26,43 (nucleotides 10469-10990) on a strand-separating gel showed an abnormal pattern in the case of one patient (Fig. 1, lane 2).…”

A functional polymorphism of apolipoprotein C1 detected by mass spectrometry

“…Hyperlipidemia may result from increased inhibition of β‐VLDL binding to the receptor and reduced clearance of VLDLs from the circulation. Variants of ApoC2 and ApoC3 have been linked to metabolic disease [16–18]. This study reports the first case of a structural variant of ApoC1 as well as some protein properties that suggest the functional significance of this residue change.…”

Apolipoprotein function in health and disease: insights from natural mutations

“…All identified carriers are heterozygotes for the presence of the mutant, which displays normal LPL activating capacity and in vivo metabolism [92]. Another rare apoC-II mutant, designated apoC-II SanFrancisco and characterized by the Glu-38!Lys substitution, has been identified in three unrelated hyperlipidaemic patients [95]. The mutant is functionally normal and is present in plasma bound to lipoproteins.…”