title: 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.
abstract: 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.
authors.affiliation: Gustav Embden-Centre of Biological Chemistry, Johann Wolfgang Goethe-University, Theodor Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Fisher
authors.forename: H
authors.initials: H
authors.lastname: Scharnagl
authors.forename: M M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: K
authors.initials: K
authors.lastname: Kusterer
authors.forename: D
authors.initials: D
authors.lastname: Wittmann
authors.forename: H
authors.initials: H
authors.lastname: Wieland
authors.forename: W
authors.initials: W
authors.lastname: Gross
authors.forename: W
authors.initials: W
authors.lastname: März
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000378:metabolism*; D004586:Electrophoresis / Q000379:methods; D005260:Female; D006239:Haplotypes; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D018110:Receptors, Lipoprotein / Q000235:genetics* / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D018110:Receptors, Lipoprotein; C072413:apolipoprotein B receptor