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. 1994 Aug;94(2):516–520. doi: 10.1172/JCI117363

Identification of mutations in the putative ATP-binding domain of the adrenoleukodystrophy gene.

P Fanen 1, S Guidoux 1, C O Sarde 1, J L Mandel 1, M Goossens 1, P Aubourg 1
PMCID: PMC296124  PMID: 8040304

Abstract

The recently identified adrenoleukodystrophy (ALD) gene is predicted to encode a peroxisomal protein of 745 amino acids that includes one domain for ATP-binding, termed nucleotide-binding fold (NBF). To determine whether mutations occur in the putative NBF of ALD protein, we analyzed by denaturing gradient gel electrophoresis (DGGE) exon 6 and 8 that encode most part of this domain in 50 ALD patients. Four amino acid substitutions, three frameshift mutations leading to premature termination signal, and a splicing mutation were identified. These amino acid substitutions occurred at residues highly conserved in other ATP-binding cassette (ABC) proteins. In addition, a nonsense mutation was detected in exon 4.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amselem S., Sobrier M. L., Duquesnoy P., Rappaport R., Postel-Vinay M. C., Gourmelen M., Dallapiccola B., Goossens M. Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism. J Clin Invest. 1991 Mar;87(3):1098–1102. doi: 10.1172/JCI115071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson M. P., Rich D. P., Gregory R. J., Smith A. E., Welsh M. J. Generation of cAMP-activated chloride currents by expression of CFTR. Science. 1991 Feb 8;251(4994):679–682. doi: 10.1126/science.1704151. [DOI] [PubMed] [Google Scholar]
  3. Attree O., Vidaud D., Vidaud M., Amselem S., Lavergne J. M., Goossens M. Mutations in the catalytic domain of human coagulation factor IX: rapid characterization by direct genomic sequencing of DNA fragments displaying an altered melting behavior. Genomics. 1989 Apr;4(3):266–272. doi: 10.1016/0888-7543(89)90330-3. [DOI] [PubMed] [Google Scholar]
  4. Aubourg P. R., Sack G. H., Jr, Meyers D. A., Lease J. J., Moser H. W. Linkage of adrenoleukodystrophy to a polymorphic DNA probe. Ann Neurol. 1987 Apr;21(4):349–352. doi: 10.1002/ana.410210406. [DOI] [PubMed] [Google Scholar]
  5. Azzaria M., Schurr E., Gros P. Discrete mutations introduced in the predicted nucleotide-binding sites of the mdr1 gene abolish its ability to confer multidrug resistance. Mol Cell Biol. 1989 Dec;9(12):5289–5297. doi: 10.1128/mcb.9.12.5289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bahram S., Arnold D., Bresnahan M., Strominger J. L., Spies T. Two putative subunits of a peptide pump encoded in the human major histocompatibility complex class II region. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10094–10098. doi: 10.1073/pnas.88.22.10094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cartier N., Sarde C. O., Douar A. M., Mosser J., Mandel J. L., Aubourg P. Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy. Hum Mol Genet. 1993 Nov;2(11):1949–1951. doi: 10.1093/hmg/2.11.1949. [DOI] [PubMed] [Google Scholar]
  8. Chen C. J., Chin J. E., Ueda K., Clark D. P., Pastan I., Gottesman M. M., Roninson I. B. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986 Nov 7;47(3):381–389. doi: 10.1016/0092-8674(86)90595-7. [DOI] [PubMed] [Google Scholar]
  9. Drumm M. L., Wilkinson D. J., Smit L. S., Worrell R. T., Strong T. V., Frizzell R. A., Dawson D. C., Collins F. S. Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes. Science. 1991 Dec 20;254(5039):1797–1799. doi: 10.1126/science.1722350. [DOI] [PubMed] [Google Scholar]
  10. Gill D. R., Hyde S. C., Higgins C. F., Valverde M. A., Mintenig G. M., Sepúlveda F. V. Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Cell. 1992 Oct 2;71(1):23–32. doi: 10.1016/0092-8674(92)90263-c. [DOI] [PubMed] [Google Scholar]
  11. Gregory R. J., Rich D. P., Cheng S. H., Souza D. W., Paul S., Manavalan P., Anderson M. P., Welsh M. J., Smith A. E. Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2. Mol Cell Biol. 1991 Aug;11(8):3886–3893. doi: 10.1128/mcb.11.8.3886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gyllensten U. B., Erlich H. A. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7652–7656. doi: 10.1073/pnas.85.20.7652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gärtner J., Moser H., Valle D. Mutations in the 70K peroxisomal membrane protein gene in Zellweger syndrome. Nat Genet. 1992 Apr;1(1):16–23. doi: 10.1038/ng0492-16. [DOI] [PubMed] [Google Scholar]
  14. Higgins C. F. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. doi: 10.1146/annurev.cb.08.110192.000435. [DOI] [PubMed] [Google Scholar]
  15. Hyde S. C., Emsley P., Hartshorn M. J., Mimmack M. M., Gileadi U., Pearce S. R., Gallagher M. P., Gill D. R., Hubbard R. E., Higgins C. F. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature. 1990 Jul 26;346(6282):362–365. doi: 10.1038/346362a0. [DOI] [PubMed] [Google Scholar]
  16. Kamijo K., Taketani S., Yokota S., Osumi T., Hashimoto T. The 70-kDa peroxisomal membrane protein is a member of the Mdr (P-glycoprotein)-related ATP-binding protein superfamily. J Biol Chem. 1990 Mar 15;265(8):4534–4540. [PubMed] [Google Scholar]
  17. Lerman L. S., Silverstein K. Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:482–501. doi: 10.1016/0076-6879(87)55032-7. [DOI] [PubMed] [Google Scholar]
  18. Mimura C. S., Holbrook S. R., Ames G. F. Structural model of the nucleotide-binding conserved component of periplasmic permeases. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):84–88. doi: 10.1073/pnas.88.1.84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mosser J., Douar A. M., Sarde C. O., Kioschis P., Feil R., Moser H., Poustka A. M., Mandel J. L., Aubourg P. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature. 1993 Feb 25;361(6414):726–730. doi: 10.1038/361726a0. [DOI] [PubMed] [Google Scholar]
  20. Myers R. M., Maniatis T., Lerman L. S. Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:501–527. doi: 10.1016/0076-6879(87)55033-9. [DOI] [PubMed] [Google Scholar]
  21. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  22. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sheffield V. C., Cox D. R., Lerman L. S., Myers R. M. Attachment of a 40-base-pair G + C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes. Proc Natl Acad Sci U S A. 1989 Jan;86(1):232–236. doi: 10.1073/pnas.86.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Trowsdale J., Hanson I., Mockridge I., Beck S., Townsend A., Kelly A. Sequences encoded in the class II region of the MHC related to the 'ABC' superfamily of transporters. Nature. 1990 Dec 20;348(6303):741–744. doi: 10.1038/348741a0. [DOI] [PubMed] [Google Scholar]
  25. Youssoufian H., Kazazian H. H., Jr, Phillips D. G., Aronis S., Tsiftis G., Brown V. A., Antonarakis S. E. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. 1986 Nov 27-Dec 3Nature. 324(6095):380–382. doi: 10.1038/324380a0. [DOI] [PubMed] [Google Scholar]

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