Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia

APOE Leiden and APOE5 have been reported to be associated with elevated triglycerides.

“APOE Leiden (a partial duplication of 21 nucleotides coding for seven amino acids) associated with type III hyperlipoproteinemia [5] and APOE5 (Val 135_Arg142dup) heterozygote [6] have been reported to be associated with elevated triglycerides”

No case involving the duplication of an amino acid residue in APOE has been known to be involved in renal lesions.

“no case involving the duplication of an amino acid residue in APOE has been known to be involved in renal lesions.”

ApoE Leiden is a rare variant of human apolipoprotein E.

“ApoE Leiden, one of the most thoroughly studied of the rare apoE variants (6, 11, 12)”

In heterozygotes, apoE Leiden is present in higher concentrations in total plasma than the other apoE allele product.

“In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product.”

ApoE Leiden is characterized by defective receptor binding.

“In in vitro assays, apoE Leiden is defective in its affinity for the low density lipoprotein (LDL) receptor (6, 11, 14)”

In heterozygotes, apoE Leiden is present in higher concentrations in VLDL than the other apoE allele product.

“In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product.”

Certain other apoE variants are associated with a dominant mode of inheritance, i.e., heterozygosity is sufficient for expression of type III hlp.

“In contrast, certain other apoE variants are associated with a dominant mode of inheritance (5-10), i.e., heterozygosity for these apoE variants is sufficient for the expression of type III hlp.”

In in vitro assays, apoE Leiden is defective in its affinity for the LDL receptor, having about 25% of normal apoE3 binding affinity.

“In in vitro assays, apoE Leiden is defective in its affinity for the low density lipoprotein (LDL) receptor (6, 11, 14), having about 25% of normal apoE3 binding affinity.”

Subjects heterozygous for the apoE Leiden mutation show a predominance of the variant apoE over the wild-type protein in total plasma, but especially in the VLDL fraction (4:1 ratio or higher).

“Interestingly, subjects heterozygous for the apoE Leiden mutation show a predominance of the variant apoE over the wild-type protein in total plasma, but especially in the VLDL fraction (4:1 ratio or higher) (6, 11, 12)”

ApoE Leiden is considerably more active in receptor binding than apoE2, which exhibits less than 2% of normal apoE3 binding.

“ApoE Leiden is considerably more active in receptor binding than apoE2 (6, 14), which exhibits less than 2% of normal apoE3 binding.”

Apolipoprotein E3-Leiden is a variant of apoE that is associated with dominant expression of type III hyperlipoproteinemia and is defective in binding to the low density lipoprotein receptor.

“Apolipoprotein (apo) E3-Leiden is a variant of apoE that is associated with dominant expression of type III hyperlipoproteinemia and that is defective in binding to the low density lipoprotein receptor.”

The total isolated apoE consisted of at least 90% of the variant apoE3-Leiden isoform.

“Because the total isolated apoE consisted of at least 90% of the variant apoE3Leiden isoform (2), it was used directly, without further purification, for receptor binding analysis in an in vitro assay (21).”

Three other apoE variants display an absolute correlation between the presence of only one allele for the variant and the occurrence of type III hyperlipoproteinemia, indicating that these mutants are associated with dominant, rather than recessive, expression of this disorder.

“In contrast to apoE2(158 Arg→Cys), three other apoE variants display an absolute correlation between the presence of only one allele for the variant and the occurrence of type III hyperlipoproteinemia, indicating that these mutants are associated with dominant, rather than recessive, expression of this disorder (2, 10, 11).”

The first example of dominant expression was established in two generations of the apoE3-Leiden (V.) kindred; six of eight family members examined are heterozygous for this variant and express type III disease, and the two unaffected family members are homozygous for normal apoE3.

“The first example was established in two generations of the apoE3-Leiden (V.) kindred (2). Six of eight family members examined are heterozygous for this variant and express type III disease (2). The two unaffected family members are homozygous for normal apoE3.”

Apolipoprotein E3-Leiden, after being purified and recombined with egg phosphatidylcholine, was defective in binding to LDL receptors on both cultured human fibroblasts and HeLa cells.

“Apolipoprotein E3-Leiden, after being purified and recombined with egg phosphatidylcholine, also was defective in binding to LDL receptors on both cultured human fibroblasts and HeLa cells (1, 2).”

Upon isoelectric focusing, apoE3-Leiden focused in the E3 position.

“Upon isoelectric focusing, apoE3-Leiden focused in the E3 position (Fig. 2), in agreement with previous reports (1, 2).”

Four individuals had xanthomas, including palmar xanthomas, which have been described only in type III hyperlipoproteinemia.

“In addition, four individuals had xanthomas, including palmar xanthomas (2), which have been described only in type III hyperlipoproteinemia (4).”

ApoE3-Leiden·DMPC complexes were defective in binding to LDL receptors on human fibroblasts.

“As shown in Fig. 6, the apoE3-Leiden·dimyristoylphosphatidylcholine (DMPC) complexes were defective in binding to the LDL receptors on human fibroblasts, in agreement with the findings of Havekes and co-workers (1, 2), who used apoE3-Leiden·egg phosphatidylcholine complexes.”

The apoE3-Leiden mutant constituted the vast majority of the total apoE in affected subjects.

“In addition, the apoE3-Leiden mutant constituted the vast majority of the total apoE in affected subjects (2), indicating that it is either produced at a greater rate than the normal isoform or is catabolized at a much slower rate.”

The apoE3-Leiden mutant is either produced at a greater rate than the normal isoform or is catabolized at a much slower rate.

“In addition, the apoE3-Leiden mutant constituted the vast majority of the total apoE in affected subjects (2), indicating that it is either produced at a greater rate than the normal isoform or is catabolized at a much slower rate.”

The minor band that shifted to the E4 position after cysteamine treatment contained 1.3 mol of cysteine (determined as cysteic acid)/mol of protein, confirming that the second allelic product expressed in the propositus is normal apoE3.

“Amino acid analysis of this material showed that it contained 1.3 mol of cysteine (determined as cysteic acid)/ mol of protein, confirming that the second allelic product expressed in the propositus is normal apoE3 (2).”

Havekes et al. reported that apoE3-Leiden has a retarded mobility, migrating between normal apoE3 and apoE2(158 Arg→Cys), in another gel system in which apoE2(158 Arg→Cys) has a retarded mobility.

“In another gel system in which apoE2(158 Arg→Cys) has a retarded mobility (22), Havekes et al. (2) have reported that apoE3-Leiden also has a retarded mobility, migrating between normal apoE3 and apoE2(158 Arg→Cys).”

All six individuals possessing the mutant apoE3-Leiden isoform had β-VLDL and elevated plasma concentrations of cholesterol, triglycerides, and apoE.

“All six individuals possessing the mutant apoE3-Leiden isoform had β-VLDL and elevated plasma concentrations of cholesterol, triglycerides, and apoE (2).”

DNA sequence analysis has confirmed the presence of a 21-base pair duplication that corresponds to amino acids 121-127 (or 120-126).

“DNA sequence analysis has confirmed the presence of a 21-base pair duplication that corresponds to amino acids 121-127 (or 120-126).2”

The affected subjects are heterozygous for apoE3-Leiden and all express type III hyperlipoproteinemia.

“Although the affected subjects are heterozygous for apoE3Leiden, they all express type III hyperlipoproteinemia (2), indicating that this lipid disorder is transmitted in a dominant fashion in this family.”

Type III hyperlipoproteinemia is transmitted in a dominant fashion in this family.

“Although the affected subjects are heterozygous for apoE3Leiden, they all express type III hyperlipoproteinemia (2), indicating that this lipid disorder is transmitted in a dominant fashion in this family.”