Apolipoprotein E-1Harrisburg: a new variant of apolipoprotein E dominantly associated with type III hyperlipoproteinemia.
Apolipoprotein E (apoE) is important in the modulation of the catabolism of chylomicron and very low density lipoprotein (VLDL) remnants. ApoE has three major genetically determined isoproteins in plasma, designated apoE-2, apoE-3 and apoE-4, with homozygosity for the allele coding for apoE-2 being associated with dysbetalipoproteinemia or type III hyperlipoproteinemia (HLP). We describe a new variant of apoE, apoE-1Harrisburg, which is, in contrast to apoE-2, dominantly associated with type III HLP. Five of twelve members of the affected kindred are heterozygous for the mutant form of apoE, and four of the five have type III HLP, while the fifth member has dysbetalipoproteinemia on diet therapy. Neuraminidase digestion, which removes charged sialic acid residues, did not alter the electrophoretic position of the apoE-1Harrisburg isoprotein, indicating that the altered charge of apoE-1Harrisburg was not due to sialic acid addition to the apolipoprotein. Cysteamine modification, which adds a positively charged group to cysteine, resulted in a shift of apoE-1Harrisburg from the E-1 to the E-2 isoform position, indicating that there is one cysteine in apoE-1Harrisburg as is the case for apoE-3. These results are consistent with apoE-1Harrisburg originating in the allele for apoE-3 with the mutation leading to a negative two-unit charge shift. The definitive identification of a kindred with an apoE variant, apoE-1Harrisburg, dominantly associated with dysbetalipoproteinemia and type III HLP provides a unique opportunity to gain important insights into the structure-function requirements of the E apolipoprotein as well as the mechanisms by which apoE modulates lipoprotein metabolism.
Mann
W A
WA
Molecular Disease Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892.
Gregg
R E
RE
Sprecher
D L
DL
Brewer
H B
HB
D000293:Adolescent; D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000097:blood* / Q000235:genetics / Q000302:isolation & purification; D015180:Electrophoresis, Gel, Two-Dimensional; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000097:blood* / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000097:blood / Q000302:isolation & purification; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype
D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; C061571:apolipoprotein E1 (Harrisburg)