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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Nov;92(5):2386–2393. doi: 10.1172/JCI116844

Involvement of the tyrosinase gene in the deposition of cardiac lipofuscin in mice. Association with aortic fatty streak development.

J H Qiao 1, C L Welch 1, P Z Xie 1, M C Fishbein 1, A J Lusis 1
PMCID: PMC288421  PMID: 8227355

Abstract

Lipofuscin pigment, a terminal oxidation product, accumulates within cells during the normal aging process and under certain pathological conditions. We have analyzed a genetic cross between two inbred mouse strains, BALB/cJ and a subline of C57BL/6J, which differ in lipofuscin deposition. A comparison of the segregation pattern of cardiac lipofuscin with the albino locus (c) on mouse chromosome 7 revealed complete concordance. Analysis of spontaneous mutants of the tyrosinase gene, encoded by the albino locus, confirmed that the tyrosinase gene itself controls lipofuscin formation. Genetic analysis of other strains indicated that one or more additional genes cab contribute to the inheritance of lipofuscin. We also present evidence for an association between cardiac lipofuscin deposition and aortic fatty streak development in the mouse.

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Selected References

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  1. Ahmed F., Shire J. G. Lysosomal mutations inhibit lipofuscinosis of the spleen in C57BL mice. J Hered. 1985 Jul-Aug;76(4):311–312. doi: 10.1093/oxfordjournals.jhered.a110101. [DOI] [PubMed] [Google Scholar]
  2. Armstrong D. A. Oxidized LDL ceroid, and prostaglandin metabolism in human atherosclerosis. Med Hypotheses. 1992 Jul;38(3):244–248. doi: 10.1016/0306-9877(92)90103-j. [DOI] [PubMed] [Google Scholar]
  3. Ball R. Y., Bindman J. P., Carpenter K. L., Mitchinson M. J. Oxidized low density lipoprotein induces ceroid accumulation by murine peritoneal macrophages in vitro. Atherosclerosis. 1986 May;60(2):173–181. doi: 10.1016/0021-9150(86)90009-2. [DOI] [PubMed] [Google Scholar]
  4. Ball R. Y., Carpenter K. L., Mitchinson M. J. What is the significance of ceroid in human atherosclerosis? Arch Pathol Lab Med. 1987 Dec;111(12):1134–1140. [PubMed] [Google Scholar]
  5. Barton D. E., Kwon B. S., Francke U. Human tyrosinase gene, mapped to chromosome 11 (q14----q21), defines second region of homology with mouse chromosome 7. Genomics. 1988 Jul;3(1):17–24. doi: 10.1016/0888-7543(88)90153-x. [DOI] [PubMed] [Google Scholar]
  6. Blackett A. D., Hall D. A. Tissue vitamin E levels and lipofuscin accumulation with age in the mouse. J Gerontol. 1981 Sep;36(5):529–533. doi: 10.1093/geronj/36.5.529. [DOI] [PubMed] [Google Scholar]
  7. Crichton D. N., Busuttil A., Price W. H. Splenic lipofuscinosis in mice. J Pathol. 1978 Oct;126(2):113–120. doi: 10.1002/path.1711260210. [DOI] [PubMed] [Google Scholar]
  8. Crichton D. N., Busuttil A., Ross A. An ultrastructural study of murine splenic lipofuscinosis. J Ultrastruct Res. 1980 Aug;72(2):130–140. doi: 10.1016/s0022-5320(80)90051-9. [DOI] [PubMed] [Google Scholar]
  9. Crichton D. N., Shire J. G. Genetic basis of susceptibility to splenic lipofuscinosis in mice. Genet Res. 1982 Jun;39(3):275–285. doi: 10.1017/s0016672300020954. [DOI] [PubMed] [Google Scholar]
  10. Granholm N. H., Japs R. A., Kappenman K. E. Differentiation of hairbulb pigment cell melanosomes in compound agouti and albino locus mouse mutants (Ay, a, c2J; C57BL/6J). Pigment Cell Res. 1990 Jan-Feb;3(1):16–27. doi: 10.1111/j.1600-0749.1990.tb00257.x. [DOI] [PubMed] [Google Scholar]
  11. Halaban R., Moellmann G. White mutants in mice shedding light on humans. J Invest Dermatol. 1993 Feb;100(2 Suppl):176S–185S. [PubMed] [Google Scholar]
  12. Hearing V. J., Tsukamoto K. Enzymatic control of pigmentation in mammals. FASEB J. 1991 Nov;5(14):2902–2909. [PubMed] [Google Scholar]
  13. Jain S. K., Levine S. N., Duett J., Hollier B. Reduced vitamin E and increased lipofuscin products in erythrocytes of diabetic rats. Diabetes. 1991 Oct;40(10):1241–1244. doi: 10.2337/diab.40.10.1241. [DOI] [PubMed] [Google Scholar]
  14. Jiménez M., Tsukamoto K., Hearing V. J. Tyrosinases from two different loci are expressed by normal and by transformed melanocytes. J Biol Chem. 1991 Jan 15;266(2):1147–1156. [PubMed] [Google Scholar]
  15. Katz M. L., Drea C. M., Eldred G. E., Hess H. H., Robison W. G., Jr Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium. Exp Eye Res. 1986 Oct;43(4):561–573. doi: 10.1016/s0014-4835(86)80023-9. [DOI] [PubMed] [Google Scholar]
  16. Kaya M., Edward D. P., Tessler H., Hendricks R. L. Augmentation of intraocular inflammation by melanin. Invest Ophthalmol Vis Sci. 1992 Mar;33(3):522–531. [PubMed] [Google Scholar]
  17. Koga S., Nakano M., Tero-Kubota S. Generation of superoxide during the enzymatic action of tyrosinase. Arch Biochem Biophys. 1992 Feb 1;292(2):570–575. doi: 10.1016/0003-9861(92)90032-r. [DOI] [PubMed] [Google Scholar]
  18. Koobs D. H., Schultz R. L., Jutzy R. V. The origin of lipofuscin and possible consequences to the myocardium. Arch Pathol Lab Med. 1978 Feb;102(2):66–68. [PubMed] [Google Scholar]
  19. Lander E. S., Botstein D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics. 1989 Jan;121(1):185–199. doi: 10.1093/genetics/121.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lowings P., Yavuzer U., Goding C. R. Positive and negative elements regulate a melanocyte-specific promoter. Mol Cell Biol. 1992 Aug;12(8):3653–3662. doi: 10.1128/mcb.12.8.3653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marzabadi M. R., Sohal R. S., Brunk U. T. Effect of ferric iron and desferrioxamine on lipofuscin accumulation in cultured rat heart myocytes. Mech Ageing Dev. 1988 Dec;46(1-3):145–157. doi: 10.1016/0047-6374(88)90122-4. [DOI] [PubMed] [Google Scholar]
  22. Mehrabian M., Demer L. L., Lusis A. J. Differential accumulation of intimal monocyte-macrophages relative to lipoproteins and lipofuscin corresponds to hemodynamic forces on cardiac valves in mice. Arterioscler Thromb. 1991 Jul-Aug;11(4):947–957. doi: 10.1161/01.atv.11.4.947. [DOI] [PubMed] [Google Scholar]
  23. Paigen B., Mitchell D., Reue K., Morrow A., Lusis A. J., LeBoeuf R. C. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3763–3767. doi: 10.1073/pnas.84.11.3763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Paigen B., Morrow A., Holmes P. A., Mitchell D., Williams R. A. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987 Dec;68(3):231–240. doi: 10.1016/0021-9150(87)90202-4. [DOI] [PubMed] [Google Scholar]
  25. Porter S., Mintz B. Multiple alternatively spliced transcripts of the mouse tyrosinase-encoding gene. Gene. 1991 Jan 15;97(2):277–282. doi: 10.1016/0378-1119(91)90063-h. [DOI] [PubMed] [Google Scholar]
  26. Qiao J. H., Castellani L. W., Fishbein M. C., Lusis A. J. Immune-complex-mediated vasculitis increases coronary artery lipid accumulation in autoimmune-prone MRL mice. Arterioscler Thromb. 1993 Jun;13(6):932–943. doi: 10.1161/01.atv.13.6.932. [DOI] [PubMed] [Google Scholar]
  27. Reddy K., Fletcher B., Tappel A., Tappel A. Measurement and spectral characteristics of fluorescent pigments in tissues of rats as a function of dietary polyunsaturated fats and vitamin E. J Nutr. 1973 Jun;103(6):908–915. doi: 10.1093/jn/103.6.908. [DOI] [PubMed] [Google Scholar]
  28. Ruppert S., Müller G., Kwon B., Schütz G. Multiple transcripts of the mouse tyrosinase gene are generated by alternative splicing. EMBO J. 1988 Sep;7(9):2715–2722. doi: 10.1002/j.1460-2075.1988.tb03125.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. STREHLER B. L., MARK D. D., MILDVAN A. S. GEE MV: Rate and magnitude of age pigment accumulation in the human myocardium. J Gerontol. 1959 Oct;14:430–439. doi: 10.1093/geronj/14.4.430. [DOI] [PubMed] [Google Scholar]
  30. Schraermeyer U., Stieve H. Peroxidase and tyrosinase are present in secondary lysosomes that degrade photosensory membranes of the crayfish photoreceptor: possible role in pigment granule formation. Pigment Cell Res. 1991 Oct;4(4):163–171. doi: 10.1111/j.1600-0749.1991.tb00434.x. [DOI] [PubMed] [Google Scholar]
  31. Shibahara S., Tomita Y., Sakakura T., Nager C., Chaudhuri B., Müller R. Cloning and expression of cDNA encoding mouse tyrosinase. Nucleic Acids Res. 1986 Mar 25;14(6):2413–2427. doi: 10.1093/nar/14.6.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sohal R. S., Marzabadi M. R., Galaris D., Brunk U. T. Effect of ambient oxygen concentration on lipofuscin accumulation in cultured rat heart myocytes--a novel in vitro model of lipofuscinogenesis. Free Radic Biol Med. 1989;6(1):23–30. doi: 10.1016/0891-5849(89)90155-x. [DOI] [PubMed] [Google Scholar]
  33. Tanaka S., Yamamoto H., Takeuchi S., Takeuchi T. Melanization in albino mice transformed by introducing cloned mouse tyrosinase gene. Development. 1990 Feb;108(2):223–227. doi: 10.1242/dev.108.2.223. [DOI] [PubMed] [Google Scholar]
  34. Townsend D., Witkop C. J., Jr, Mattson J. Tyrosinase subcellular distribution and kinetic parameters in wild type and C-locus mutant C57BL/6J mice. J Exp Zool. 1981 Apr;216(1):113–119. doi: 10.1002/jez.1402160112. [DOI] [PubMed] [Google Scholar]
  35. Winder A. J. Expression of a mouse tyrosinase cDNA in 3T3 Swiss mouse fibroblasts. Biochem Biophys Res Commun. 1991 Jul 31;178(2):739–745. doi: 10.1016/0006-291x(91)90170-c. [DOI] [PubMed] [Google Scholar]
  36. Witztum J. L., Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. doi: 10.1172/JCI115499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wood J. M., Schallreuter K. U. Studies on the reactions between human tyrosinase, superoxide anion, hydrogen peroxide and thiols. Biochim Biophys Acta. 1991 Aug 6;1074(3):378–385. doi: 10.1016/0304-4165(91)90088-x. [DOI] [PubMed] [Google Scholar]
  38. Yokoyama T., Silversides D. W., Waymire K. G., Kwon B. S., Takeuchi T., Overbeek P. A. Conserved cysteine to serine mutation in tyrosinase is responsible for the classical albino mutation in laboratory mice. Nucleic Acids Res. 1990 Dec 25;18(24):7293–7298. doi: 10.1093/nar/18.24.7293. [DOI] [PMC free article] [PubMed] [Google Scholar]

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