Untersuchung der in vivo Kinetik von ApoB3543 (ApoB-Marburg) mittels stabiler Isotopentechnik

Hypercholesterolemia, especially high LDL-cholesterol is a major risk factor for coronary heart disease (CHD). LDL plays a central role in genesis of the arteriosclerosis. Apolipoprotein B-100 (apoB) is the major structural protein of LDL an serves as a ligand to the LDL-receptor. Binding defects of apoB to the LDL-receptor (familiar defective apoB, FDB) and LDL-receptor defects are the most common cause of monogenetic hypercholesterolemia. So far a total of four distinct mutations of the apoB gene were reported, namely Arg3500Gln, Arg3532Cys, Arg3500Trp, R3480W). The present study was performed to identify potentially new apoB mutations and to screen for known mutations in 853 patients. All of them underwent a diagnostic heart catherisation. We utilized denaturing gradient gel electrophoresis (DGGE) based mutations screening of the codon 3546-3553 region in exon 26 of the apoB gene. The region is known to be crucial for the structural confirmation of the apoB binding site to the LDL receptor. In addition stable isotope kinetic studies were performed to illuminate the in vivo effects on lipoprotein metabolism. We found in four patients a single nucleotide substitution at position 10836 in codon 3543 in the apoB gene. LDL receptor defects were excluded. We found only one patient with the FDB mutation Arg3500Gln. The frequency of this new mutation in the general population is presently unclear. In our study the His3543Tyr mutation is four times more frequent compared to FDB. In all known FDB mutations a positively charged amino avid is converted into polar uncharged. This lost of a positive loading is crucial for a defective binding to the LDL receptor. The apoB Marburg mutation shows with a moderate hypercholesterolemia like Arg3532Cys a similar clinic to FDB. The in vivo kinetics of the new mutation are comparable to classic FDB. We conclude that the His3543Tyr mutation is a clinical relevant mutation with similar effects of the lipoprotein metabolism like FDB. Therefore this mutation must be considered a frequent cause of hyperlipidemia in man.