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Apolipoprotein E Mutants, Hyperlipidemia and Arteriosclerosis

  • Gerd Utermann

Abstract

A genetic polymorphism of apolipoprotein E was first described in 1977 and it was shown at that time that one phenotype in this genetic system is associated with primary dysbetalipoproteinemiaJ It is now well established that genetic apo E polymorphism is under the control of 3 common alleles (∑2, ∑3, ∑4) at the apo E structural gene locus, that specify for isoforms E2, E3, and E4 and have frequencies of 0.077 (∑2), 0.773 (∑3) and 0.150 (∑4) in the German population.2,3 Apo E2 and apo E4 differ from the parent apo E3 isoform by single cysteine for arginine interchanges at one of two positions in the primary structure: apo E2 (Arg158 → Cys) and apo E4 (Cys-112 → Arg).4,5 Examination of a DNA sequence that included the known apo E polymorphic sites showed that the mutant apo E phenotypes can be explained on the basis of a single base substitution in the first position of each of the respective codons.6

Keywords

Single Base Substitution Human Apolipoprotein Slow Mobility Mixed Hyperlipidemia Lysine Analogue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    G. Utermann, M. Hees, and A. Steinmetz, Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinemia in man, Nature 269: 604 – 607 (1977).PubMedCrossRefGoogle Scholar
  2. 2.
    V. I. Zannis, P. W. Just, and J. L. Breslow, Human apolipoprotein E isoprotein subclasses are genetically determined, Am. J. Hum. Genet. 33: 11 – 24 (1981).PubMedGoogle Scholar
  3. 3.
    G. Utermann, A. Steinmetz, and W. Weber, Genetic control of human apolipoprotein E polymorphism: Comparison of one- and two-dimensional techniques of isoprotein analysis, Hum. Genet. 60: 344 – 351 (1982).PubMedCrossRefGoogle Scholar
  4. 4.
    K. H. Weisgraber, S. C. Rail, Jr., and R. W. Mahley, Human E apolipoprotein heterogeneity: cysteine-arginine inter-changes in the aminoacid sequence of the apo E isoforms, J. Biol. Chem. 256: 9077 – 9081 (1981).PubMedGoogle Scholar
  5. 5.
    S. C. Rail, Jr., K. H. Weisgraber, and R. W. Mahley, Human apolipoprotein E: The complete amino acid sequence, J. Biol. Chem. 257: 4171 – 4178 (1982).Google Scholar
  6. 6.
    J. L. Breslow, J. McPherson, A. L. Nussbaum, H. W. Williams, R. Lofquist-Kahl, S. K. Karathanasis, and V. I. Zannis, Identification and DNA sequence of a human apolipoprotein E cDNA clone, J. Biol. Chem. 257: 14639 – 14641 (1982).PubMedGoogle Scholar
  7. 7.
    S. C. Rail, Jr., K. H. Weisgraber, T. L. Innerarity, and R. W. Mahley, Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects, Proc. Natl. Acad. Sci., U.S.A., 79: 4696 - 4700 (1982).CrossRefGoogle Scholar
  8. 8.
    S. C. Rail, Jr., K. H. Weisgraber, T. L. Innerarity, and R. Mahley, Structure and function of apolipoprotein E: Exis-tence of multiple E2 alleles in type III hyperlipoproteinemia, in: “Proceedings from the International Symposium on Latent Dysbetalipoproteinemias and Atherosclerosis,” J. L. de Gennes and R. Paoletti, ed., Raven Press, New York, In Press (1983).Google Scholar
  9. 9.
    L. M. Havekes, J. A. Gevers Leuven, E. van Corven, E. de Wit, and J. J. Emeis, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinemia patient, Eur. J. Clin. Invest., In Press (1983).Google Scholar
  10. 10.
    W. J. Schneider, P. T. Kovanen, M. S. Brown, J. L. Goldstein, G. Utermannn, W. Weber, R. J. Havel, L. Kotite, J. P. Kane, T. L. Innerarity, and R. W. Mahley, Familial dysbetalipoproteinemia: Abnormal binding of mutant apolipoprotein E to LDL receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows, J. Clin. Invest. 68: 1075 – 1085 (1981).PubMedCrossRefGoogle Scholar
  11. 11.
    K. H. Weisgraber, T. L. Innerarity, and R. W. Mahley, Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site, J. Biol. Chem. 257: 2518 – 2521 (1982).PubMedGoogle Scholar
  12. 12.
    R. J. Havel, Y. S. Chao, E. E. Windier, L. Kotite, and S. Guo, Isoprotein specifity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia, Proc. Natl. Acad. Sci. USA 77: 4349 – 4353 (1980).PubMedCrossRefGoogle Scholar
  13. 13.
    R. E. Gregg, L. A. Zech, E. J. Schaefer, and H. B. Brewer, Jr., Type III hyperlipoproteinemia: Defective metabolism of an abnormal apolipoprotein E, Science 211: 584 – 586 (1981).PubMedCrossRefGoogle Scholar
  14. 14.
    G. Utermann, K. H. Vogelberg, A. Steinmetz, W. Schoenborn, N. Pruin, M. Jaeschke, M. Hees, and H. Canzler, Polymorphism of apolipoprotein E. II. Genetics of hyperlipoproteinemia type III, Clin. Genet. 15: 37 – 62 (1977).CrossRefGoogle Scholar
  15. 15.
    G. Utermann, N. Pruin, and A. Steinmetz, Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man, Clin. Genet. 15: 63 – 72 (1979).PubMedCrossRefGoogle Scholar
  16. 16.
    W. R. Hazzard, G. R. Warnick, G. Utermann, and J. J. Albers, Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: Relationship to dysbetalipoproteinemia and hyperlipidemia, Metabolism 30: 79 – 88 (1981).PubMedCrossRefGoogle Scholar
  17. 17.
    S. C. Rall, K. H. Weisgraber, T. L. Innerarity, R. W. Mahley, and G. Assmann, Identical structural and receptor binding defects in apolipoprotein E2 in hypo-, normo-, hypercholesterolemia dysbetalipoproteinemia, J. Clin. Invest. 71: 1023 – 1031 (1983).PubMedCrossRefGoogle Scholar
  18. 18.
    M. R. Wardell, P. A. Suckling, and E. D. Janus, Genetic variation in human apolipoprotein E., J. Lipid Res. 23: 1174 – 1182 (1982).PubMedGoogle Scholar
  19. 19.
    G. Utermann, K. H. Weisgraber, W. Weber, and R. W. Mahley, Genetic polymorphism of apoliprotein E: Variable forms of apolipoprotein E2 distinguished on sodium dodecyl sulfate- polyacrylamide electrophoresis, manuscript submitted (1983).Google Scholar
  20. 20.
    G. Utermann, Apolipoprotein E: Role in lipoprotein metabolism and pathophysiology of hyperlipoproteinemia type III, La Ricerca in Clinica e in Laboratorio 12: 23 – 33 (1982).PubMedGoogle Scholar
  21. 21.
    G. Utermann, Coronary heart disease, in: “Principles and Practice of Medical Genetics,”A. E. H. Emery and D. L. Rimoin, eds., Churchill Livingstone Publ., Edinburgh, N.Y. (1983).Google Scholar
  22. 22.
    G. Utermann, M. Jaeschke, and J. Menzel, Familial hyperlipoproteinemia type III. Deficiency of a specific apolipoprotein (Apo E-III) in the very low-density lipoproteins, FEBS- Letters 56: 352 – 355 (1975).PubMedCrossRefGoogle Scholar
  23. 23.
    G. Utermann, H. Canzler, M. Hees, M. Jaeschke, G. Muehlfellner, W. Schoenborn, K. H. Vogelberg, Studies on the metabolic defect in Broad-disease (hyperlipoproteinemia type III), Clin. Genet. 12: 139 – 154 (1977).PubMedCrossRefGoogle Scholar
  24. 24.
    A. Pagnan, R. J. Havel, P. Kane, and L. Kotite, Characterization of human very low-density lipoproteins containing two electro- phoretic populations: double pre-beta lipoproteinemia and primary dysbetalipoproteinemia, J. Lipid Res. 18: 613 – 622 (1977).PubMedGoogle Scholar
  25. 25.
    J. L. Breslow, V. I. Zannis, T. R. San Giacomo, J. L. H. C. Thirs, T. Tracy, and C. J. Glueck, Studies of familial type III hyperlipoproteinemia using as a genetic marker the apo E phenotype E-2/2, J. Lipid Res. 23: 1224 – 1235 (1982).PubMedGoogle Scholar
  26. 26.
    G. R. Warnick, C. Mayfield, J. J. Albers, and W. R. Hazzard, Gel isoelectric focusing method for specific diagnosis of familial hyperlipoproteinemia type III, Clin. Chem. 25: 279 – 284 (1979).PubMedGoogle Scholar
  27. 27.
    W. S. Weidman, B. Suarez, J. M. Falko, J. L. Witzum, J. Kolar, M. Roben, and G. Schonfeld, Type III hyperlipoproteinemia: Development of a VLDL apo E gel isoelectric focusing technique and application in family studies, J. Lab. Clin. Med. 13: 549 – 569 (1979).Google Scholar
  28. 28.
    G. Ghiselli, R. E. Gregg, L. A. Zech, E. J. Schaefer, and H. B. J. Brewer, Phenotype study of apolipoprotein E isoforms in hyperlipoproteinemic patients, Lancet 1: 405 – 407 (1982).CrossRefGoogle Scholar
  29. P. M. Stuyt, A. F. H. Stalenhoef, P. N. M. Demacker, and A. van’t Laar, Hyperlipoproteinemia type V and apolipoprotein E4, Lancet, p. 934 (1982).Google Scholar
  30. 30.
    G. Utermann, H. Kaffarnik, and A. Steinmetz, Apolipoprotein E phenotypes in hyperlipidemia, Hum. Genet., In Press (1983).Google Scholar
  31. 31.
    G. Utermann, A. Hardewig, and F. Zimmer, Apo E phenotypes in patients with myocardial infarction, Hum. Genet., In Press (1983).Google Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Gerd Utermann
    • 1
  1. 1.Institut fuer Humangenetik und Genetische Poliklinik der Philipps-UnversitaetMarburgFederal Republic of Germany

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