Mapping a gene for combined hyperlipidaemia in a mutant mouse strain


Familial combined hyperlipidaemia (FCHL) is a common, multifactorial disorder associated with elevated levels of plasma triglyceride, cholesterol, or both1–3. A characteristic feature is increased secretion of very low density lipoproteins (VLDL) and apolipoprotein B (apoB; refs 3,4). Although FCHL is the most common cause of premature coronary artery disease (CAD), accounting for over 10% of cases, its aetiology remains largely unknown3–6. One powerful approach to the dissection of complex genetic traits involves the use of animal models7. We have identified a mouse strain, HcB-19/Dem (HcB-19), which exhibits hypertriglyceridaemia, hypercholesterolaemia and elevated levels of plasma apoB. Like FCHL patients, HcB-19 mice also exhibit increased secretion of triglyceride-rich lipoproteins, and their hyperlipidaemia becomes progressively more severe with age. It is likely that the hyperlipidaemia results from a mutation of a novel gene that arose during development of strain HcB-19. We mapped the hyperlipidaemia gene (Hyplip 1) to the distal portion of mouse chromosome 3. This region is syntenic to human chromosome 1q21–q23, which has recently been shown to harbour a gene associated with FCHL in families from a Finnish isolate (see accompanying manuscript by Pajukanta et al., ref. 8).

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  1. 1

    Goldstein, J.L., Schrott, H.G., Hazzard, W.R., Bierman, E.L. & Motulsky, A.G. Hyperlipidemia in coronary heart disease II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J. Clin. Invest. 52, 1544–1568 (1973).

  2. 2

    Brunzell, J.D. et al. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J. Lipid Res. 24, 147–155 (1983).

  3. 3

    Kwiterovich, P.O. Genetics and molecular biology of familial combined hyperlipidemia. Curr. Opin. Lipidol. 4, 133–143 (1993).

  4. 4

    Venjatesan, S., Cullen, P., Pacy, P., Halliday, D. & Scott, S. Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. Arterioscler. Thromb. Vasc. 13, 110–118 (1993).

  5. 5

    Aitman, T.J. et al. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arterioscler. Thromb. Vasc. Biol. 17, 748–754 (1997).

  6. 6

    Pajvkanta, P. et al. No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families. Arterioscler. Thromb. Vasc. Biol. 17, 841–850 (1997).

  7. 7

    Silver, L.M. Mouse Genetics Concepts and Applications. 195–263 (Oxford Press, New York, 1995).

  8. 8

    Pajukanta, P. et al. Linkage of combined hyperlipidemia to chromosome 1q21–q23. Nature Genet. 18, 367–371 (1998).

  9. 9

    Demant, P. & Hart, A.A.M. Recombinant congenic strains: a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics 24, 416–422 (1986).

  10. 10

    Groot, P.C. et al. The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J. 6, 2826–2835 (1992).

  11. 11

    Collin, G.B., Asada, Y., Varnum, D.S. & Nadeau, J.H. DNA pooling as a quick method of finding candidate linkages in multigenic trait analysis: an example involving susceptibility to germ cell tumors. Mamm. Genome 7, 68–70 (1996).

  12. 12

    Falconer, D.S. Introduction to Quantitative Genetics. (Longman, London, 1991).

  13. 13

    Welch, C.L. et al. Genetic regulation of cholesterol homeostasis: chromosomal organization of candidate genes. J. Lipid. Res. 37, 1406–1421 (1997).

  14. 14

    McGarry, J.D., Woeltje, K.F., Kuwajima, M. & Foster, D.W. Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabet Metab. Rev. 5, 271–284 (1989).

  15. 15

    Valera, A. et al. Overexpression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in transgenic mice causes hepatic hyperketogenesis. J. Biol. Chem. 269, 6267–6270 (1994).

  16. 16

    Hedrick, C.C., Castellani, L.W., Warden, C.H., Puppione, D.L. & Lusis, A.J. Influence of mouse apolipoprotein A-II on plasma lipoproteins in transgenic mice. J. Biol. Chem. 269, 20676–20682 (1993).

  17. 17

    Doolittle, M.H., Wong, H., Davis, R.C. & Schotz, M.C. Synthesis of hepatic lipase in liver and extrahepatic tissues. J. Lipid Res. 28, 1326–1333 (1993).

  18. 18

    Khan, B.V., Fungwe, T.V., Wilcox, H.G. & Heimberg, M. Cholesterol is required for the secretion of the very low density lipoprotein: in vivo studies. Biochim. Biophys. Acta 1044, 297–304 (1990).

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Correspondence to Aldons J. Lusis.

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