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Fisher, E; Scharnagl, H; Hoffmann, MM; Kusterer, K; Wittmann, D; Wieland, H; Gross, W; März, W.
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.
CLIN CHEM 1999 45: 1026-1038. [OPEN ACCESS]
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Leading authors Med Uni Graz: März Winfried
Co-authors Med Uni Graz: Scharnagl Hubert
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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.
Find related publications in this database (using NLM MeSH Indexing): Adolescent -; Adult -; Aged -; Aged, 80 and over -; Amino Acid Substitution -; Apolipoproteins B - genetics; Child - genetics; Child, Preschool - genetics; Electrophoresis - methods; Female - methods; Haplotypes - methods; Humans - methods; Hypercholesterolemia, Familial - genetics; Lipoproteins, LDL Cholesterol - metabolism; Male - metabolism; Middle Aged - metabolism; Mutation - metabolism; Pedigree - metabolism; Receptors, Lipoprotein - genetics; Research Support, Non-U.S. Gov't - genetics