title: Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia.
abstract: Apolipoprotein C-III is a major protein constituent of triglyceride rich lipoproteins and HDL. It occurs in plasma in three isoforms differing by their sialic acid content. Apo C-III putatively inhibits lipolysis and the apo E mediated hepatic uptake of remnants from triglyceride rich particles. We identified a heterozygous carrier of an apolipoprotein C-III variant by the presence of additional bands after isoelectric focusing (IEF) of VLDL. Structural analysis of the variant protein by HPLC, time-of-flight secondary ion mass spectrometry, and automated gas phase sequencing revealed a lysine to glutamic acid replacement in position 58. The underlying A to G exchange was verified by direct sequencing subsequent to amplification by polymerase chain reaction of exon 4 of the apo C-III gene. Family studies revealed vertical transmission of this defect. The two variant carriers exhibited plasma concentrations of HDL cholesterol and apo A-I above the 95th percentiles of sex matched controls whereas the unaffected father and sister showed normal values. The plasma concentrations of apo C-III in the two variant carriers were decreased by 30-40% compared with those of the two unaffected family members and to random controls. Using two-dimensional immunoelectrophoresis as well as IEF and subsequent scanning densitometry, we found that the low serum concentration of apo C-III was a consequence of diminished concentrations of the variant apo C-III isoproteins in both VLDL (15% of normal) and HDL (25% of normal). Apo C-III(Lys58----Glu) heterozygotes possessed unusual HDL as demonstrated by nondenaturing gradient gel electrophoresis. They consisted mainly of HDL2b and contained a proportion of atypically large particles, enriched in apo E, with a Stokes diameter of 13-18 nm and resembling HDLc. In conclusion, heterozygosity for a structural apo C-III variant--apo C-III(Lys58----Glu)--was identified in two hyperalphalipoproteinemic subjects characterized by the presence of low plasma apo C-III concentrations and atypically large HDL.
authors.affiliation: Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität Münster, Federal Republic of Germany.
authors.forename: A
authors.initials: A
authors.lastname: von Eckardstein
authors.forename: H
authors.initials: H
authors.lastname: Holz
authors.forename: M
authors.initials: M
authors.lastname: Sandkamp
authors.forename: W
authors.initials: W
authors.lastname: Weng
authors.forename: H
authors.initials: H
authors.lastname: Funke
authors.forename: G
authors.initials: G
authors.lastname: Assmann
mesh_terms: D000328:Adult; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification*; D001483:Base Sequence; D002499:Centrifugation, Density Gradient; D004586:Electrophoresis; D005260:Female; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D014280:Triglycerides / Q000097:blood
chemical_list: D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides