Human Genetics

, Volume 79, Issue 4, pp 352–356 | Cite as

The apolipoprotein(a) gene resides on human chromosome 6q26–27, in close proximity to the homologous gene for plasminogen

  • Susan Lynn Frank
  • Ivana Klisak
  • Robert S. Sparkes
  • T. Mohandas
  • James E. Tomlinson
  • John W. McLean
  • Richard M. Lawn
  • Aldons J. Lusis
Original Investigations

Summary

Apolipoprotein(a) [apo(a)], the glycoprotein associated with the lipoprotein(a) [Lp(a)] subfraction of plasma lipoproteins, has been shown to exhibit heritable molecular weight isoforms ranging from 400–700 kDa. Increased serum concentrations of Lp(a) correlate positively with the risk of atherosclerosis. Variations in Lp(a) plasma levels among individuals are inherited as a codominant quantitative trait. As part of an effect to define the basis of these variations and further clarify the expression of the protein, we have determined the chromosomal location of the human apo(a) gene. Blot hybridization analysis of DNA from a panel of mouse-human somatic cell hybrids with an apo(a) cDNA probe revealed a complex pattern of bands, all of which segregated with chromosome 6. In situ hybridization yielded a single peak of grain density located on chromosome 6q26–27. Apo(a) cDNA sequences exhibit striking homology to those of the plasma protease plasminogen, and, therefore, we have reexamined the chromosome assignment of the plasminogen gene. We conclude that both the apo(a) and plasminogen genes reside on human chromosome 6q22–27, consistent with a gene duplication mechanism for their evolutionary origin. The results are of significance for the genetic control of apo(a) expression and genetic influences predisposing to atherosclerosis.

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References

  1. Armstrong VW, Walli AK, Seidel D (1985) Isolation characterization and uptake in human fibroblasts of an apo(a)-free lipoprotein obtained on reduction of lipoprotein (a). J Lipid Res 26: 1314–1323Google Scholar
  2. Armstrong VW, Cremer P, Eberle E, Manke A, Schulze F, Wieland H, Kreuzer H, Seidel D (1986) The association between serum Lp(a) concentrations and angiographically assessed coronary atherosclerosis. Atherosclerosis 62:249–257Google Scholar
  3. Berg K (1983) Genetics of coronary disease. In: Steinberg AG, Beary AG, Motulsky AR, Childs B (eds) Progress in medical genetics. Saunders, Philadelphia, pp 35–90Google Scholar
  4. Cannizzaro CA, Emanuel BS (1984) An improved method for G banding chromosomes after in situ hybridization. Cytogenet Cell Genet 38:308–309Google Scholar
  5. Castellino FJ (1981) Recent advances in the chemistry of fibrinolytic system. Chem Rev 81:431–446Google Scholar
  6. Dahlen G, Guyton JR, Attar M, Farmer JA, Kautz JA, Gotto AM (1986) Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation 74:758–765Google Scholar
  7. Eaton DL, Fless GM, Kohr WJ, McLean JW, Xu Q, Miller CG, Lawn RM, Scanu AM (1987) Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. Proc Natl Acad Sci USA 84:3224–3228Google Scholar
  8. Feinberg AP, Vogelstein B (1983) A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 132:6–13Google Scholar
  9. Fless GM, Rolih CA, Scanu AM (1984) Heterogeneity of human plasma lipoprotein(a). Isolation and characterization of the lipoprotein subspecies and their apoproteins. J Biol Chem 259: 11470–11478Google Scholar
  10. Forsgren M, Raden B, Israelsson M, Larsson K, Heden LO (1987) Molecular cloning and characterization of a full length cDNA clone for human plasminogen. FEBS Lett 213:254–260Google Scholar
  11. Gaubatz JW, Heidman C, Gotto AM Jr, Morrisett JD, Dahlen GH (1983) Human plasma lipoprotein(a). Structural properties. J Biol Chem 258:4582–4589Google Scholar
  12. Gaubatz JW, Chari MV, Nava ML, Guyton JR, Morrisett JD (1987) Isolation and characterization of the two major apoproteins in human lipoprotein(a). J Lipid Res 28:69–79Google Scholar
  13. Harper ME, Saunders GS (1981) Localization of single copy DNA sequences on G-banded chromosomes by in situ hybridization. Chromosoma 83:431–439Google Scholar
  14. Harvie NR, Schultz JS (1970) Studies of Lp-lipoprotein as a quantitative genetic trait. Proc Natl Acad Sci USA 66:99–103Google Scholar
  15. Hassted SJ, Wilson DE, Edwards CQ, Cannon WN, Carmelli D, Williams RR (1983) The genetics of quantitative plasma Lp(a): analysis of a large pedigree. Am J Med Genet 16:179–188Google Scholar
  16. Kostner GM, Avogaro P, Cazzolato G, Marth E, Bittolo-Bon G, Quinci GB (1981) Lipoprotein Lp(a) and the risk for myocardial infarction. Atherosclerosis 38:51–61Google Scholar
  17. McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM (1987) cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 330: 132–137Google Scholar
  18. Mohandas T, Heinzmann C, Sparkes RS, Wasmuth J, Edwards P, Lusis AJ (1986) Assignment of human 3-hydroxy-3-methylglutaryl coenzyme A reductase gene to q13–q23 region of chromosome 5. Somatic Cell Mol Genet 12:89–94Google Scholar
  19. Murray JC, Buetow KH, Donovan M, Hornuny S, Motulsky AG, Disteche C, Dyer K, Swisshelm K, Anderson J, Giblett E, Sadler E, Eddy R, Shows TB (1987) Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26–6q27. Am J Hum Genet 40:338–350Google Scholar
  20. Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL (1986) Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA 256:2540–2544Google Scholar
  21. Sing CF, Schultz JS, Shreffler DC (1974) The genetics of the LP antigen. II. A family study and proposed models of genetic control. Ann Hum Genet 38:47–56Google Scholar
  22. Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517Google Scholar
  23. Utermann G, Weber W (1983) Protein composition of Lp(a) lipoprotein from human plasma. FEBS Lett 154:357–361Google Scholar
  24. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C (1987) Lp(a) glycoprotein phenotypes: inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 80: 458–465Google Scholar
  25. Weitkamp LR, Guttormsen SA, Schultz JS (1988) Linkage between the loci for the Lp(a) lipoprotein (LP) and plasminogen (PLG). Hum Genet 89:80–82Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • Susan Lynn Frank
    • 1
  • Ivana Klisak
    • 2
  • Robert S. Sparkes
    • 2
  • T. Mohandas
    • 3
  • James E. Tomlinson
    • 4
  • John W. McLean
    • 4
  • Richard M. Lawn
    • 4
  • Aldons J. Lusis
    • 1
    • 2
  1. 1.Department of MicrobiologyUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Medicine, School of MedicineUniversity of CaliforniaLos AngelesUSA
  3. 3.Division of Medical GeneticsHarbor-UCLA Medical CenterTorranceUSA
  4. 4.Department of Cardiovascular ResearchGenentech, Inc.South San FranciscoUSA

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