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.