Normolipemic dysbetalipoproteinemia and hyperlipoproteinemia type III in subjects homozygous for a rare genetic apolipoprotein E variant (apoE1).

: A family with three heterozygote and two homozygote carriers of the rare apolipoprotein E1 isoform was detected by isoelectric focusing. One of the homozygous patients had type III hyperlipidemia, while the other showed normolipemic dysbetalipoproteinemia. Restriction fragment length analysis as well as allele specific oligonucleotides were used to identify the structural alterations forming the abnormal epsilon 1 genotype. Comparison with the most common epsilon 3 allele showed that two base exchanges A for G in codon 127 and T for G in codon 158 (Asp for Gly and Cys for Arg, respectively) are responsible for the amino acid substitution which causes the charge shift observed in isoelectric focusing. The same defects have been described in the only previously characterized apoE1 (Weisgraber et al. 1984. J. Clin. Invest. 73: 1024-1033). In addition to the study by Weisgraber and coworkers, who reported on a heterozygous patient, we here describe the metabolic and clinical consequences of a homozygosity for this rare allele. Changes in lipoprotein metabolism, as well as in clinical phenotypes, were exactly identical to those seen in patients homozygous for the epsilon 2 allele, which has in common with the epsilon 1 allele the mutation in codon 158, but lacks the substitution in codon 127. In addition, lipoprotein profiles of the epsilon 3/epsilon 1 heterozygotes were indistinguishable from those of epsilon 3/epsilon 2 heterozygotes. Therefore, we conclude that the additional mutation in codon 127 that characterizes the epsilon 1 allele is of no functional importance in vivo.