Familial dysbetalipoproteinemia: a genetically heterogenous disease caused by mutations of the ligand apolipoprotein E.
Apolipoprotein E is present on the surface of very-low-density lipoprotein (VLDL) and chylomicron-remnants and is essential for the receptor mediated endocytosis of these particles via hepatic receptors. Several types of mutations of the apoE can cause a deficiency in the clearance of these remnant particles. An accumulation of lipoprotein-remnant particles may occur and familial dysbetalipoproteinemia (FD) develops. Genotyping of the various apoE variants and relation of these mutations with their effect on the lipoprotein-remnant removal have provided more insight in the structure-relationship of apoE ligand-receptor interactions. It is postulated that the apoE2 (Arg158----Cys) mutation is just outside the binding domain and that its deficient binding can be stimulated by exogenous factors. This hypothesis can explain why apoE2/E2 homozygosity can only induce FD under certain circumstances. ApoE mutations that occur in the binding domain, e.g., apoE2 (Lys146----Gln) have a direct effect on the ligand-receptor binding and, in these individuals, FD is inherited in an autosomal dominant way. Finally, apoE3-Leiden has an arginine residue at 112 and has a repeat of seven extra amino acid residues just outside the binding domain. Because of this repeat, conformational changes of the binding domain can ensue. Due to the fact that in apo E3-Leiden the arginine residue is present at 112, apoE3 Leiden is predominantly present on chylomicron and VLDL remnants. In these persons FD is also inherited in an autosomal dominant way.
Vermeer
B J
BJ
Department of Dermatology, University Medical Centre, Leiden, The Netherlands.
Frants
R R
RR
Havekes
L M
LM
D001057:Apolipoproteins E / Q000097:blood / Q000235:genetics; D005784:Gene Amplification; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000235:genetics*; D009154:Mutation; D010641:Phenotype
D001057:Apolipoproteins E