Apolipoprotein E1 Baden (Arg 180→Cys) : A new apolipoprotein E variant associated with hypertriglyceridemia

Abstract

Apolipoprotein (apo) E mediates the removal of chylomicron and very low density lipoprotein remnants from plasma. It is polymorphic in sequence and the products of the three common alleles ( ϵ2, ϵ3, ϵ4) differ from one another in their binding to lipoprotein receptors. ApoE2 is defective in binding and homozygosity for apoE2 is associated with type III hyperlipoproteinemia (HLP). Other rare isoforms of apoE have been found to be associated either with dominant type III HLP or with the development of hypertriglyceridemia. We identified a 42 year-old hypertriglyceridemic woman with an apoE phenotype 3/1. Restriction isotyping using AflIII /HaeII resulted in an apparent apoE genotype 3/2, suggesting that the mutation occurred in an ϵ2 allele. DNA sequence analysis revealed a C→T point mutation at the first position of the codon for amino acid residue 180 of the mature apoE. This predicted a change Arg 180→Cys. The mutation altered a recognition site for the endonuclease HaeII, which allowed us rapidly to screen for this mutation. In relatives of the proband, apoE1 Baden was consistently associated with hypertriglyceridemia. Similar to other apoE variants linked to hypertriglyeridemia, the Arg 180→Cys mutation is located within the lipid binding domain of apoE. We therefore suggest that apoE1 Baden may cause hypertrigylceridemia, possibly by inhibiting the hydrolysis of triglycerides associated with very low density lipoproteins.