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Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters

Abstract

ADRENOLEUKODYSTROPHY (ALD) is an X-linked disease affecting 1/20,000 males either as cerebral ALD in childhood or as adrenomyeloneuropathy (AMN) in adults1. Childhood ALD is the more severe form, with onset of neurological symptoms between 5–12 years of age. Central nervous system demyelination progresses rapidly and death occurs within a few years. AMN is a milder form of the disease with onset at 15–30 years of age and a more progressive course. Adrenal insufficiency (Addison's disease) may remain the only clinical manifestation of ALD. The principal biochemical abnormality of ALD is the accumulation of very-long-chain fatty acids (VLCFA) because of impaired β-oxidation in peroxisomes1,2. The normal oxidation of VLCFA-CoA in patients' fibroblasts3–5 suggested that the gene coding for the VLCFA-CoA synthetase could be a candidate gene for ALD. Here we use positional cloning to identify a gene partially deleted in 6 of 85 independent patients with ALD. In familial cases, the deletions segregated with the disease. An identical deletion was detected in two brothers presenting with different clinical ALD phenotypes. Candidate exons were identified by computer analysis of genomic sequences6 and used to isolate complementary DNAs by exon connection7 and screening of cDNA libraries. The deduced protein sequence shows significant sequence identity to a peroxisomal membrane protein of Mr 70K that is involved in peroxisome biogenesis and belongs to the ‘ATP-binding cassette’ superfamily of transporters.

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References

  1. 1

    Moser, H. w. & Moser, A. in The Metabolic Basis of Inherited Disease (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle. D.) 1511–1532 (McGraw-Hill, New York, 1989).

    Google Scholar 

  2. 2

    Singh, I., Moser, A. E., Goldfischer, S. & Moser, H. W. Proc. natn. Acad. Sci. U.S.A. 81, 4203–4207 (1984).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Hashmi, M., Stanley, W. & Singh, I. FEBS Lett. 196, 247–250 (1986).

    Article  Google Scholar 

  4. 4

    Lazo, O. et al. Proc. natn. Acad. Sci. U.S.A. 85, 7647–7651 (1988).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Wanders, R. J. A. et al. J. inher. metab. Dis. 11, 173–177 (1988).

    CAS  Article  Google Scholar 

  6. 6

    Uberbacher, E. C. & Mural, R. Proc. natn. Acad. Sci. U.S.A. 88, 11261–11265 (1992).

    ADS  Article  Google Scholar 

  7. 7

    Fearon, E. R. et al. Science 247, 49–56 (1990).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Migeon, B. R. et al. Proc. natn. Acad. Sci. U.S.A. 78, 5066–5070 (1981).

    ADS  CAS  Article  Google Scholar 

  9. 9

    Boué, J. et al. Hum. Genet 69, 272–274 (1985).

    Article  Google Scholar 

  10. 10

    Aubourg, P., Sack, G. H., Meyers, D. A., Lease, J. J. & Moser, H. W. Ann. Neurol. 21, 349–352 (1987)

    CAS  Article  Google Scholar 

  11. 11

    Nathans, J., Thomas, D. & Hogness, D. Science 232, 193–202 (1986).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Sack, G. H., Raven, B. & Moser, H. W. Am. J. hum. Genet. 44, 794–798 (1989).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Aubourg, P., Sack, G. H. & Moser, H. W. Am. J. hum. Genet. 42, 408–413 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Aubourg, P. et al. Am. J. hum. Genet. 46, 459–469 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Feil, R. et al. Am. J. hum. Genet. 49, 1361–1371 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Kioschis, P. et al. Cytogenet. Cell Genet. 58, 2070 (1991).

    Google Scholar 

  17. 17

    Kamijo, K., Taketani, S., Yokota, S., Osumi, T. & Hashimoto, T. J. biol. Chem. 265, 4534–4540 (1990).

    CAS  PubMed  Google Scholar 

  18. 18

    Kamijo, K., Kamijo, T., Ueno, I., Osumi, T. & Hashimoto, T. Biochim. biophys. Acta 1129, 323–327 (1992).

    CAS  Article  Google Scholar 

  19. 19

    Xiao, J. H. Davidson, I., Matthes, H., Garnier, J. M., & Chambon, P. Cell 65, 551–568 (1991).

    CAS  Article  Google Scholar 

  20. 20

    Kozak, M. Nucleic Acids Res. 15, 8125–8148 (1987).

    CAS  Article  Google Scholar 

  21. 21

    Gärtner, J., Moser, H. & Valle, D. Nature Genet. 1, 16–23 (1992).

    Article  Google Scholar 

  22. 22

    Walker, J. E., Saraste, M., Runswick, M. J. & Gay, N. J. EMBO J 8, 945–951 (1982).

    Article  Google Scholar 

  23. 23

    Suzuki, H. et al. J. biol. Chem. 265, 8681–8685 (1990).

    CAS  PubMed  Google Scholar 

  24. 24

    Roninson, I. B. Molecular and Cellular Biology of Multidrug Resistance in Tumor cells (Plenum, New York, 1991).

    Google Scholar 

  25. 25

    Riordan, J. R. et al. Science 245, 1066–1080 (1989).

    ADS  CAS  Article  Google Scholar 

  26. 26

    Trowsdale, J. et al. Nature 348, 741–744 (1990).

    ADS  CAS  Article  Google Scholar 

  27. 27

    Bahram, S., Arnold, D., Bresnahan, M., Strominger, J. L. & Spies, T. Proc natn. Acad. Sci. U.S.A. 88, 10094–10098 (1991).

    ADS  CAS  Article  Google Scholar 

  28. 28

    Cutting, G. R. et al. Nature 346, 366–369 (1990).

    ADS  CAS  Article  Google Scholar 

  29. 29

    Higgins, C. F. et al. J. bioenerg. Biomembr. 22, 571–593 (1990).

    CAS  Article  Google Scholar 

  30. 30

    Shimozawa, N. et al. Science 255, 1132–1134 (1992).

    ADS  CAS  Article  Google Scholar 

  31. 31

    Erdmann, R. et al. Cell 64, 499–510 (1991).

    CAS  Article  Google Scholar 

  32. 32

    Höhfeld, J., Veenhuis, M. & Kunau, W. H. J. cell Biol. 114, 1167–1178 (1992).

    Article  Google Scholar 

  33. 33

    Imanaka, T., Small, G. M. & Lazarow, P. B. J. cell Biol. 105, 2915–2922 (1987).

    CAS  Article  Google Scholar 

  34. 34

    Singh, I., Lazo, O., Dhaunsi, G. S. & Contreras, M. J. biol. Chem. 267, 13306–13313 (1992).

    CAS  PubMed  Google Scholar 

  35. 35

    Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Press, New York, 1989).

    Google Scholar 

  36. 36

    Lipman, D. J. & Pearson, W. R. Science 227, 1435–1441 (1985).

    ADS  CAS  Article  Google Scholar 

  37. 37

    Gilson, E., Nikaido, H. & Hofnung, M. Nucleic Acids Res. 10, 7449–7458 (1982).

    CAS  Article  Google Scholar 

  38. 38

    Moser, H. W. et al. J. inher. metab. Dis. 15, 645–664 (1992).

    CAS  Article  Google Scholar 

  39. 39

    Lazarow, P. B. & Moser, H. W. in The Metabolic Basis of Inherited Diseases (eds Scriver, C. R., Beaudet, A. L., Sly, W. S. & Valle, D.) 1479–1509 (McGraw-Hill, New York 1989).

    Google Scholar 

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Mosser, J., Douar, AM., Sarde, CO. et al. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature 361, 726–730 (1993). https://doi.org/10.1038/361726a0

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