Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis

Abstract

NEURONAL ceroid lipofuscinoses (NCL) represent a group of common progressive encephalopathies of children which have a global incidence of 1 in 12,500 (ref. 1). These severe brain diseases are divided into three autosomal recessive subtypes, assigned to different chromosomal loci2á¤-4. The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years5, and characteristic storage bodies are found in brain and other tissues at autopsy6. The molecular pathogenesis underlying the selective loss of neurons of neocortical origin has remained unknown. Here we report the identification, by positional candidate methods, of defects in the palmitoyl-protein thioesterase gene in all 42 Finnish INCL patients and several non-Finnish patients. The most common mutation results in intracellular accumulation of the polypeptide and undetectable enzyme activity in the brain of patients.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Rider, J. A. & Rider, D. L. Am. J. med. Genet. (Suppl.) 5, 21–26 (1988).

    CAS  Article  Google Scholar 

  2. 2

    Gardiner, M. et al. Genomics 8, 387–390 (1990).

    CAS  Article  Google Scholar 

  3. 3

    Järvelä, I. et al. Genomics 9, 170–173 (1991).

    Article  Google Scholar 

  4. 4

    Williams, R. et al. Am. J. hum. Genet. 53, 931–935 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Santavuori, P., Haltia, M. & Rapola, J. J. dev. Med. Child Neurol. 16, 644–653 (1974).

    CAS  Article  Google Scholar 

  6. 6

    Rapola, J. & Haltia, M. Brain 96, 833–840 (1973).

    CAS  Article  Google Scholar 

  7. 7

    Collins, F. Nature Genet. 1, 3–7 (1992).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Hellsten, E. et al. Genomics 16, 720–725 (1993).

    CAS  Article  Google Scholar 

  9. 9

    Mäkelä, T. P. et al. Hum. molec. Genet. 1, 217 (1992).

    Article  Google Scholar 

  10. 10

    Hellsten, E. et al. Genomics 25, 404–412 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Nau, M. M. et al. Nature 318, 69–73 (1985).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Mäkelä, T. P., Saksela, K., Evan, G. & Alitalo, K. EMBO J. 10, 1331–1335 (1991).

    Article  Google Scholar 

  13. 13

    Perälä, M., Hänninen, M., Hästbackov, J., Elima, K. & Vuorio, E. FEBS Lett. 319, 177–180 (1993).

    Article  Google Scholar 

  14. 14

    Camp, L. A., Verkruyse, L. A., Afendis, S. J., Slaughter, C. A. & Hofmann, S. L. J. biol. Chem. 269, 23212–23219 (1994).

    CAS  PubMed  Google Scholar 

  15. 15

    Derewenda, Z. S. & Sharp, A. M. Trends biochem. Sci. 18, 20–25 (1993).

    CAS  Article  Google Scholar 

  16. 16

    Witkowski, A., Witkowska, H. E. & Smith, S. J. biol. Chem. 269, 379–383 (1994).

    CAS  PubMed  Google Scholar 

  17. 17

    Seabra, M. C., Brown, M. S. & Goldstein, J. L. Science 259, 377–381 (1993).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Syvänen, A.-C., Sajantila, A. & Lukka, M. Am. J. hum. Genet. 52, 46–59 (1993).

    PubMed  PubMed Central  Google Scholar 

  19. 19

    Heiskanen, M. et al. BioTechnology 17, 928–929 (1994).

    CAS  Google Scholar 

  20. 20

    Ioannou, P. A. et al. Nature Genet. 6, 84–89 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Syvänen, A.-C., Aalto-Setälä, K., Kontula, K. & Söderlund, H. FEBS Lett. 258, 71–74 (1989).

    Article  Google Scholar 

  22. 22

    Camp, L. A. & Hofmann, S. L. J. biol. Chem. 268, 22566–22574 (1993).

    CAS  PubMed  Google Scholar 

  23. 23

    Erlanson, C. Scand. J. Gastroenter. 5, 333–336 (1970).

    CAS  Google Scholar 

  24. 24

    Stacey, A. & Schnieke, A. Nucleic Acids Res. 18, 2829 (1990).

    CAS  Article  Google Scholar 

  25. 25

    Taylor, J. W., Ott, J. & Eckstein, F. Nucleic Acids Res. 13, 8764–8765 (1985).

    Google Scholar 

  26. 26

    Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    ADS  CAS  Article  Google Scholar 

  27. 27

    Felgner, P. L. et al. Proc. natn. Acad. Sci. U.S.A. 84, 7413–7417 (1987).

    ADS  CAS  Article  Google Scholar 

  28. 28

    Proia, R. L., D'azzo, A. & Neufeld, E. F. J. biol. Chem. 259, 3350–3354 (1984).

    CAS  PubMed  Google Scholar 

  29. 29

    Laemmli, U. K. Nature 227, 680–685 (1970).

    ADS  CAS  Article  Google Scholar 

  30. 30

    Riikonen, A. et al. DNA Cell Biol. 13, 257–264 (1994).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vesa, J., Hellsten, E., Verkruyse, L. et al. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Nature 376, 584–587 (1995). https://doi.org/10.1038/376584a0

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing