Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin

Nature Genetics volume 29, pages 189–193 (2001)Cite this article

Abstract

The newly recognized ataxia–ocular apraxia 1 (AOA1; MIM 208920)1,2,3,4 is the most frequent cause of autosomal recessive ataxia in Japan2,4,5,6,7,8,9 and is second only to Friedreich ataxia in Portugal10. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy3,5,9 and the later decrease of serum albumin levels and elevation of total cholesterol2,4,5,9. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3′- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR)11 following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex12. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Haplotype analysis in Portuguese (AOA-P1, -P4, -P5, -P7 and -P11) and Japanese (AOA-J1, -J2 and -J3) families.
Figure 2: Physical map of the AOA1 region on 9p13.3 and genomic organization of APTX.
Figure 3: AOA1 mutations. Electrophorogram of patient (top panel) and control (lower panel) sequences.
Figure 4: Expression of mouse and human APTX.
Figure 5: ClustalX sequence alignments for the PANT and HIT domains of human aprataxin.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Aicardi, J. et al. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann. Neurol. 24, 497–502 (1988).

    Article  CAS  Google Scholar 

  2. Uekawa, K., Yuasa, T., Kawasaki, S., Makibuchi, T. & Ideta, T. A hereditary ataxia associated with hypoalbuminemia and hyperlipidemia—a variant form of Friedreich's disease or a new clinical entity? Clin. Neurol. 32, 1067–1074 (1992).

    CAS  Google Scholar 

  3. Barbot, C. et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch. Neurol. 58, 201–205 (2001).

    Article  CAS  Google Scholar 

  4. Moreira, M.C. et al. Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am. J. Hum. Genet. 68, 501–508 (2001).

    Article  CAS  Google Scholar 

  5. Fukuhara, N., Nakajima, T., Sakajiri, K., Matsubara, N. & Fujita, M. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): a new disease. J. Neurol. Sci. 133, 140–151 (1995).

    Article  CAS  Google Scholar 

  6. Hanihara, T., Kubota, H., Amano, N., Iwamoto, H. & Iwabuchi, K. Siblings of early onset cerebellar ataxia with hypoalbuminemia. Rinsho Shinkeigaku (Clin. Neurol.) 35, 83–86 (1995).

    CAS  Google Scholar 

  7. Kubota, H. et al. Familial early onset cerebellar ataxia with hypoalbuminemia. No To Shinkei 47, 289–294 (1995).

    CAS  Google Scholar 

  8. Sekijima, Y. et al. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): clinical and neuropathological features of a Japanese family. J. Neurol. Sci. 158, 30–37 (1998).

    Article  CAS  Google Scholar 

  9. Tachi, N., Kozuka, N., Ohya, K., Chiba, S. & Sasaki, K. Hereditary cerebellar ataxia with peripheral neuropathy and mental retardation. Eur. Neurol. 43, 82–87 (2000).

    Article  CAS  Google Scholar 

  10. Moreira, M.C., Miranda, C., Barbot, C., Coutinho, P. & Sequeiros, J. Recessive ataxias in Portugal. Arq. Med. 13, 39–45 (1999).

    Google Scholar 

  11. Whitehouse, C.J. et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104, 107–117 (2001).

    Article  CAS  Google Scholar 

  12. McLennan, A.G. Dinucleoside polyphosphates—friend or foe? Pharmacol. Ther. 87, 73–89 (2000).

    CAS  Google Scholar 

  13. Date, H. et al. Early onset ataxia with ocular–motor apraxia and hypoalbuminemia is caused by mutations in a new HIT-superfamily gene. Nature Genet. 29, 184–188 (2001).

    Article  CAS  Google Scholar 

  14. Jilani, A. et al. Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3′-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. J. Biol. Chem. 274, 24176–24186 (1999).

    Article  CAS  Google Scholar 

  15. Karimi-Busheri, F. et al. Molecular characterization of a human DNA kinase. J. Biol. Chem. 274, 24187–24194 (1999).

    Article  CAS  Google Scholar 

  16. Brenner, C., Bieganowski, P., Pace, H.C. & Huebner, K. The histidine triad superfamily of nucleotide-binding proteins. J. Cell. Physiol. 181, 179–187 (1999).

    Article  CAS  Google Scholar 

  17. Yoshihara, K. & Tanaka, Y. ADP-ribosylation of diadenosine 5′,5″-P1,P4-tetraphosphate by poly(ADP-ribose) polymerase in vitro. J. Biol. Chem. 256, 6756–6761 (1981).

    CAS  Google Scholar 

  18. Caldecott, K.W., Aoufouchi, S., Johnson, P. & Shall, S. XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular 'nick-sensor' in vitro. Nucleic Acids. Res. 24, 4387–4394 (1996).

    Article  CAS  Google Scholar 

  19. Mackey, Z.B. et al. DNA ligase III is recruited to DNA strand breaks by a zinc finger motif homologous to that of poly(ADP-ribose) polymerase. Identification of two functionally distinct DNA binding regions within DNA ligase III. J. Biol. Chem. 274, 21679–21687 (1999).

    Article  CAS  Google Scholar 

  20. Gibson, T.J., Postma, J.P.M., Brown, R.S. & Argos, P. A model for the tertiary structure of the 28 residue DNA-binding motif ('zinc finger') common to many eukaryotic transcriptional regulatory proteins. Protein Engng. 2, 209–218 (1988).

    Article  CAS  Google Scholar 

  21. Gatti, R.A. et al. Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 70, 99–117 (1991).

    Article  CAS  Google Scholar 

  22. Hawley, R.S. & Friend, S.H. Strange bedfellows in even stranger places: the role of ATM in meiotic cells, lymphocytes, tumors, and its functional links to p53. Genes Dev. 10, 2383–2388 (1996).

    Article  CAS  Google Scholar 

  23. Durocher, D. & Jackson, S.P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr. Opin. Cell Biol. 13, 225–231 (2001).

    Article  CAS  Google Scholar 

  24. Kastan, M.B. & Lim, D.S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000).

    Article  CAS  Google Scholar 

  25. Shiloh, Y. ATM and ATR: networking cellular responses to DNA damage. Curr. Opin. Genet. Dev. 11, 71–77 (2001)

    Article  CAS  Google Scholar 

  26. Schultz, J., Copley, R.R., Doerks, T., Ponting, C.P. & Bork, P. SMART: a Web-based tool for the study of genetically mobile domains. Nucleic Acids Res. 28, 231–234 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to express our gratitude to all patients and families for their collaboration, as well as to R. Chorão, C. Ferreira, I. Fineza, K. Dias, J.P. Monteiro, K. Sasaki, M. Shizuka-Ikeda, C. Alves, L. Pereira and A. Amorim. We are indebted to J.-L. Mandel for his enthusiastic support and fruitful discussions; to D. Simon, H. Puccio and A. Buj-Bello for their support and their sharing of biological material; and to D. Sommer-Stephan, S. Vicaire, E. Troesch, F. Ruffenach, I. Colas and T. Matamá for excellent technical help. Family characterization and DNA sampling were supported by a grant from the Comissão de Fomento da Investigação em Cuidados de Saúde, Portuguese Ministry of Health (no. 207/99) and grants from Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science and Technology) and from the Portuguese Ministry of Health (projects PRAXIS/PSAU/P/SAU/84/96, POCTI 34535/99, POCTI 32643/99 and PECS/C/SAU/219/95). Genetic studies were supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpitaux Universitaires de Strasbourg, and the Human Frontier Science Program (to M.K. and T.B.). M.C.M. has graduate fellowship PRAXIS XXI/BD/18169/98 from the Fundação para a Ciência e a Tecnologia—Portugal.

Author information

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis-Pasteur, Illkirch, C.U. de Strasbourg, France

    Maria-Céu Moreira & Michel Koenig

  2. UnIGENe-IBMC and ICBAS, Universidade do Porto, Porto, Portugal

    Maria-Céu Moreira, Clara Barbot, Paula Coutinho & Jorge Sequeiros

  3. Department of Neurology, Hospital Maria Pia, Porto, Portugal

    Clara Barbot

  4. School of Health Sciences, Sapporo Medical University, Japan

    Nobutada Tachi, Naoki Kozuka & Eiji Uchida

  5. European Molecular Biology Laboratory, Heidelberg, Germany

    Toby Gibson

  6. Department of Hematology, Hospital do Divino Espírito Santo, S. Miguel, Açores, Portugal

    Pedro Mendonça

  7. Department of Neurology, Hospital Pedro Hispâno, Matosinhos, Portugal

    Manuela Costa

  8. Department of Neurology, Hospital Geral de Sto. António, Porto, Portugal

    José Barros

  9. Department of Neurology, Isesaki Fukushima Hospital, Isesaki, Japan

    Takayuki Yanagisawa

  10. Department of Neurology, Gunma University School of Medicine, Maebashi, Japan

    Mitsunori Watanabe & Yoshio Ikeda

  11. Department of Neurology, Tohoku University School of Medicine, Sendai, Japan

    Masashi Aoki & Tetsuya Nagata

  12. Division of Neurology, Hospital de S. Sebastião, Santa Maria da Feira, Portugal

    Paula Coutinho

Authors
  1. Maria-Céu Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clara Barbot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobutada Tachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoki Kozuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eiji Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toby Gibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pedro Mendonça
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuela Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. José Barros
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Takayuki Yanagisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mitsunori Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshio Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masashi Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tetsuya Nagata
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Paula Coutinho
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jorge Sequeiros
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michel Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Koenig.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moreira, MC., Barbot, C., Tachi, N. et al. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet 29, 189–193 (2001). https://doi.org/10.1038/ng1001-189

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1001-189

This article is cited by

Search

Advanced search

Quick links

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