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Clinical Chemistry 45: 1026-1038, 1999;
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(Clinical Chemistry. 1999;45:1026-1038.)
© 1999 American Association for Clinical Chemistry, Inc.

Articles

Mutations in the Apolipoprotein (apo) B-100 Receptor-binding region: Detection of apo B-100 (Arg3500->Trp) Associated with Two New Haplotypes and Evidence That apo B-100 (Glu3405->Gln) Diminishes Receptor-mediated Uptake of LDL

Eva Fisher1, Hubert Scharnagl3, Michael M. Hoffmann3, Klaus Kusterer2, Daniela Wittmann1, Heinrich Wieland3, Werner Gross1 and Winfried März3,a

1 Gustav Embden-Centre of Biological Chemistry and
2 Department of Internal Medicine, Johann Wolfgang Goethe-University, Theodor Stern-Kai 7, 60590 Frankfurt am Main, Germany.

3 Division of Clinical Chemistry, Department of Medicine, Albert Ludwigs-University, Hugstetter Strasse 55, 79098 Freiburg, Germany.
a Author for correspondence. Fax 49-761-270-3444; e-mail maerz{at}mzl200.ukl.uni-freiburg.de

Background: Ligand-defective apolipoprotein (apo) B-100 is a major cause of hypercholesterolemia. For many years, apo B-100 (Arg3500->Gln) has been the only mutation known to cause ligand-defective apo B-100.

Methods: Using temperature gradient gel electrophoresis, we screened 297 unrelated individuals with LDL-cholesterol >1.55 g/L and triglycerides <2.0 g/L for sequence variants of the putative LDL receptor-binding domain of apo B-100.

Results: We found apo B-100 (Arg3500->Gln) in 21 individuals (7.1%). When extrapolated to the general population, this corresponds to the highest prevalence of apo B-100 (Arg3500->Gln) reported to date. Furthermore, we identified three unrelated carriers (1%) of a silent substitution (CTG->CTA) affecting the codon for leucine3350, four carriers (1.3%) of apo B-100 (Glu3405->Gln), and two subjects (0.7%) with apo B-100 (Arg3500->Trp). apo B-100 (Arg3500->Trp) was assigned to two different, previously unknown haplotypes. The binding, uptake, and degradation of apo B-100 (Arg3500->Trp) was lower than that of normal LDL, but higher than with apo B-100 (Arg3500->Gln), implying that the substitution of Trp3500 for Arg may cause less severe reduction of binding than the substitution of Gln. LDL from individuals heterozygous for apo B-100 (Glu3405->Gln) bound to LDL receptors at the same rate as normal LDL, but was taken up and degraded at significantly reduced rates, suggesting that domains of apo B-100 involved in binding and uptake do not completely overlap.

Conclusions: In Germany, apo B-100 (Arg3500->Gln) may be more frequent than previously assumed. Both apo B-100 (Arg3500->Trp) and apo B-100 (Glu3405->Gln) may contribute to the phenotype of ligand-defective LDL. These variants will be missed if screening is confined to apo B-100 (Arg3500->Gln) only.© 1999 American Association for Clinical Chemistry




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