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The molecular mechanisms of inherited hypercholesterolemia

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From Molecule to Men

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Abstract

Both observational and intervention studies have proven that hypercholesterolemia is a major risk factor for cardiovascular disease. Genetic factors are significant determinants of cholesterol and LDL cholesterol. Among the sources of genetic variation are monogenetic disorders resulting in severe clinical phenotypes and genetic polymorphisms affecting the metabolism of plasma lipoproteins. The best characterized monogenetic disorders of lipoprotein metabolism are familial hypercholesterolemia and familial defective apo B-100. In familial hypercholesterolemia (FH), the primary defect is a mutation in the gene encoding the LDL receptor. More than 300 mutant allels distorting receptor function are known to date. This genetic heterogeneity has to be accounted in the diagnosis of familial hypercholesterolemia at the molecular level. Familial defective apo B-100 has for a long time been considered to result from one point mutation changing codon 3500 from arginine to glutamine. Recent work, however, shows that this disorder is heterogeneous at the genetic level as well and that approaches to diagnose familial defective apo B-100 by probing for the arg3500→gln substitution will fail to detect other, more rare variants of apo B-100 also associated with decreased binding of LDL to LDL receptors. The most extensively studied genetic polymorphism affecting LDL cholesterol is the polymorphism of apolipoprotein E. Three common alleles exist at the apo E gene locus, namely apo E2, apo E3, and apo E4. Apo E3 represents the wild type allele. Compared to apo E3 homozygotes, carriers of one or two alleles of apo E4 have slightly higher LDL cholesterol concentrations whereas carriers of apo E2 tend to have lower LDL cholesterol. A small proportion of apo E2 homozygotes, however, develope type III hyperlipoproteinemia, a highly atherogenic form disorder of lipoprotein metabolism characterized by the accumulation of remnant particles derived from the incomplete catabolism of triglyceride-rich lipoproteins. In very rare cases, type III hyperlipoproteinemia may be transmitted in an autosomal dominant fashion. The common feature of mutations underlying this form of type III hyperlipoproteinemia appears to be that they severly impair the interaction of apo E with heparin sulfate proteoglycans rather than with lipoprotein receptors.

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  1. Division of Clinical Chemistry, Department of Medicine, Albert Ludwigs-University, Hugstetter Straße 55, 79106, Freiburg im Breisgau, Germany

    Priv.-Doz. Dr. med. Winfried März, M. S. Nauck, M. M. Hoffmann & H. Wieland

  2. Gustav Embden Center of Biological Chemistry, University Hospital, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

    E. Fisher

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  1. Abt. Kardiologie und Angiologie, Universität Freiburg — Med. Klinik III, Hugstetter Straße 55, 79106, Freiburg, Germany

    M. Zehender  & H. Just  & 

  2. Medizinische Klinik und Poliklinik, Innere Medizin C, Albert-Schweitzer-Straße 33, 48149, Münster, Germany

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März, W., Nauck, M.S., Fisher, E., Hoffmann, M.M., Wieland, H. (2000). The molecular mechanisms of inherited hypercholesterolemia. In: Zehender, M., Just, H., Breithardt, G. (eds) From Molecule to Men. Steinkopff, Heidelberg. https://doi.org/10.1007/978-3-642-57724-6_13

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