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Human lysozyme gene mutations cause hereditary systemic amyloidosis

Nature volume 362, pages 553557 (08 April 1993) | Download Citation

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Abstract

HEREDITARY non-neuropathic systemic amyloidosis (Ostertag-type)1 is a rare autosomal dominant disease in which amyloid deposition in the viscera is usually fatal by the fifth decade. In some families it is caused by mutations in the apolipoprotein AI gene2,3 but in two unrelated English families under our care the amyloid deposits did not contain apoAI, despite a report that this may have been the case in one of them4. Lysozyme is a ubiquitous bacteriolytic enzyme present in external secretions5 and in poly-morphs and macrophages, but its physiological role is not always clear6. Here we report that in these two families, lysozyme is the amyloid fibril protein. Affected individuals are heterozygous for point mutations in the lysozyme gene that cause substitution of highly conserved residues, namely threonine for isoleucine at position 56 in one family, and histidine for aspartic acid at residue 67 in the other. Amyloid fibrils from one individual were composed of the full-length Thr-56 variant lysozyme molecule. To our knowledge, this is the first report of naturally occurring variants of human lysozyme and of lysozyme-associated disease. As the structures of human7 and hen egg-white lysozyme8 are known to atomic resolution and their folding and structure–function relationships have been exhaustively analysed, our observations should provide a powerful model for understanding amyloidogenesis.

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References

  1. 1.

    Zentralbl. Aug. Path. 56, 253–254 (1932).

  2. 2.

    , , & in Amyloid and Amyloidosis 1990 (eds Natvig, J. B. et al.) 385–388 (Kluwer Academic, Dordrecht, 1991).

  3. 3.

    et al. Proc. natn. Acad. Sci. U.S.A. 89, 7389–7393 (1992).

  4. 4.

    , , & Q. Jl Med. 81, 945–956 (1991).

  5. 5.

    Roy. Soc. Proc. B93, 306–317 (1922).

  6. 6.

    & Molec. cell. Biochem. 63, 165–189 (1984).

  7. 7.

    & J. molec. Biol. 152, 737–762 (1981).

  8. 8.

    et al. Nature 206, 757–761 (1965).

  9. 9.

    & Histopathology 20, 41–46 (1992).

  10. 10.

    & Arch. Ophthalmol. 110, 882–885 (1992).

  11. 11.

    , , , & in The Enzymes (ed. Boyer, P. D.) 665–868 (Academic, New York, 1972).

  12. 12.

    , , & Nucleic Acids Res. 16, 869–781 (1988).

  13. 13.

    et al. in Lysozyme (eds Osserman, E. F., Canfield, R. E. & Beychok, S.) 251–267 (Academic, New York, 1974).

  14. 14.

    et al. Nature 280, 563–586 (1979).

  15. 15.

    , & J. biol. Chem. 267, 10842–10849 (1992).

  16. 16.

    et al. J. comp. Chem. 4, 187–217 (1983).

  17. 17.

    , , , & Biochemistry 26, 3754–3758 (1987).

  18. 18.

    , , & Biochemistry 31, 725–732 (1992).

  19. 19.

    in Immunological Diseases 4th edn Vol. 1 (eds Samter, M., Talmage, D. W., Frank, M. M., Austen, K. F. & Claman, H. N.) 631–674 (Little Brown, Boston, 1988).

  20. 20.

    , , , & Q. Jl Med. 51, 25–32 (1982).

  21. 21.

    , & New Engl. J. Med 323, 508–513 (1990).

  22. 22.

    , & J. Histochem. Cytochem, 10, 355–364 (1962).

  23. 23.

    , , , & J. clin. Invest. 47, 924–933 (1968).

  24. 24.

    Immunocytochemistry 2nd edn (Wiley, New York, 1979).

  25. 25.

    , & Protein Sci. 1, 1215–1224 (1992).

  26. 26.

    , & Biochem. J. 262, 659–663 (1989).

  27. 27.

    & Parasit. Today 3, 220–222 (1987).

  28. 28.

    et al. Atherosclerosis 89, 137–141 (1991).

  29. 29.

    , , , & Eur. J. Biochem. 182, 507–516 (1989).

  30. 30.

    et al. Science 239, 487–491 (1988).

  31. 31.

    , , & Nucleic Acids Res. 18, 4028 (1990).

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Author information

Affiliations

  1. Immunological Medicine Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK

    • M. B. Pepys
    • , P. N. Hawkins
    • , D. R. Booth
    • , D. M. Vigushin
    •  & G. A. Tennent
  2. MRC Lipoprotein Team, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 ONN, UK

    • A. K. Soutar
  3. Ludwig Institute for Cancer Research, University College and Middlesex School of Medicine, London W1P 8BT, UK

    • N. Totty
    • , O. Nguyen
    •  & J. J. Hsuan
  4. Laboratory of Molecular Biophysics, University of Oxford, Oxford CX1 3QU, UK

    • C. C. F. Blake
    •  & C. J. Terry
  5. Department of Renal Medicine, Southmead General Hospital, Bristol BS10 5NB, UK

    • T. G. Feest
  6. Wordsley Hospital, Stourbridge CY8 5QX, UK

    • A. M. Zalin

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https://doi.org/10.1038/362553a0

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