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Gene Review

APTX  -  aprataxin

Homo sapiens

Synonyms: AOA, AOA1, AXA1, Aprataxin, EAOH, ...
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Disease relevance of APTX


Psychiatry related information on APTX


High impact information on APTX

  • The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal [5].
  • AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol [5].
  • Consequent DNA damage, beyond the limited capacity of DNA repair proteins, i.e., APTX and ligase I, may participate in triggering cell death [6].
  • BSO decreased nuclear APTX and ligase I levels in I482Sf and normal control fibroblasts, but increased SSBs only in I482Sf [6].
  • ALADIN(I482S) affected a karyopherin-alpha/beta-mediated import pathway and decreased nuclear accumulations of aprataxin (APTX), a repair protein for DNA single-strand breaks (SSBs), and of DNA ligase I in I482Sf [6].

Chemical compound and disease context of APTX


Biological context of APTX

  • The gene mutated in AOA1, APTX, is predicted to code for a protein called aprataxin that contains domains of homology with proteins involved in DNA damage signalling and repair [10].
  • It is not, however, known whether aprataxin has a direct or indirect role in DNA repair, or what the physiological substrate of aprataxin might be [1].
  • Sensitivity to hydrogen peroxide and the resulting genome instability are corrected by transfection with full-length aprataxin cDNA [10].
  • We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T [11].
  • The molecular genetic analysis demonstrated the APTX mutation W279X at locus 9p13.3 (ataxia with oculomotor apraxia 1 disease), and psychologic studies showed mild cognitive impairment [12].

Anatomical context of APTX

  • In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS) [11].
  • An acute loss of aprataxin by small interfering RNA renders HeLa cells sensitive to methyl methanesulfonate treatment by a mechanism of shortened half-life of XRCC1 [13].
  • METHODS: The clinical features, laboratory findings, sural nerve biopsy results, and brain MRI or CT findings for these patients were evaluated, and molecular analysis was performed, which involved sequencing of the aprataxin gene directly or use of the subcloning method [14].
  • The transaminase inhibitor AOA inhibited both aspartate efflux from the mitochondria and respiration [15].

Associations of APTX with chemical compounds

  • Specifically, aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5'-phosphate termini at single-strand nicks and gaps, resulting in the production of 5'-phosphate termini that can be efficiently rejoined [1].
  • Disease-associated mutations in Aprataxin target a histidine triad domain that is similar to Hint, a universally conserved AMP-lysine hydrolase, or truncate the protein NH2-terminal to a zinc finger [16].
  • The activity of S-adenosylmethionine decarboxylase (AdoMetDC) was greatly increased in cells treated with AOAP [17].
  • Treatment of Ehrlich ascites-tumour cells with 1-amino-oxy-3-aminopropane (AOAP), a potent inhibitor of ornithine decarboxylase, resulted in a marked decrease in cellular contents of putrescine and spermidine, concomitant with an arrest of cell growth [17].
  • Inhibitors of either ethylene biosynthesis (AOA) or action (NBD) increased the basal level of VR-ACS1 mRNA [18].
  • These results pinpoint APTX as the first protein to adopt canonical histidine triad-type reaction chemistry for the repair of DNA [19].
  • A good correlation was observed between irinotecan sensitivity and the expression of aprataxin (APTX), a histidine triad domain superfamily protein involved in DNA repair [20].

Physical interactions of APTX

  • The FHA domain of aprataxin interacts with the C-terminal region of XRCC1 [21].
  • Moreover, we found that poly (ADP-ribose) polymerase-1 (PARP-1) is also co-immunoprecipitated with APTX [21].

Other interactions of APTX

  • We demonstrated that the 20 N-terminal amino acids of the FHA domain of APTX are important for its interaction with the C-terminal region (residues 492-574) of XRCC1 [21].
  • These findings suggest that APTX, together with XRCC1 and PARP-1, plays an essential role in SSBR [21].
  • Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4 [11].
  • Nucleolar localization of aprataxin is dependent on interaction with nucleolin and on active ribosomal DNA transcription [22].
  • Aprataxin, a Hint branch hydrolase, is mutated in ataxia-oculomotor apraxia syndrome [23].

Analytical, diagnostic and therapeutic context of APTX

  • These data indicate that neurological disorders associated with APTX mutations may be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events [1].
  • Circulating AOA detected by an ELISA may represent a practical and suitable marker for diagnosis of POF [24].
  • At the close of 1994, the AOA News reported that at least 14 companies were preparing to market equipment for excimer laser photorefractive keratectomy (PRK) [25].
  • AOA (15e) was the most potent among these derivatives, which resulted in 60% suppression of tumor volume at a dose of 20 mg/kg (Q2D x 9), intravenous injection on day 26 in nude mice bearing human breast carcinoma MX-1 xenografts [26].
  • The majority of the O.D.s responding felt that new equipment and techniques, contact lenses, and vision training should be given first priority as research areas, and felt that 5% or more of their AOA dues should be devoted to research [27].


  1. The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates. Ahel, I., Rass, U., El-Khamisy, S.F., Katyal, S., Clements, P.M., McKinnon, P.J., Caldecott, K.W., West, S.C. Nature (2006) [Pubmed]
  2. Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype. Criscuolo, C., Mancini, P., Saccà, F., De Michele, G., Monticelli, A., Santoro, L., Scarano, V., Banfi, S., Filla, A. Neurology (2004) [Pubmed]
  3. Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein. Sano, Y., Date, H., Igarashi, S., Onodera, O., Oyake, M., Takahashi, T., Hayashi, S., Morimatsu, M., Takahashi, H., Makifuchi, T., Fukuhara, N., Tsuji, S. Ann. Neurol. (2004) [Pubmed]
  4. Aprataxin mutations are a rare cause of early onset ataxia in Germany. Habeck, M., Zühlke, C., Bentele, K.H., Unkelbach, S., Kress, W., Bürk, K., Schwinger, E., Hellenbroich, Y. J. Neurol. (2004) [Pubmed]
  5. The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Moreira, M.C., Barbot, C., Tachi, N., Kozuka, N., Uchida, E., Gibson, T., Mendonça, P., Costa, M., Barros, J., Yanagisawa, T., Watanabe, M., Ikeda, Y., Aoki, M., Nagata, T., Coutinho, P., Sequeiros, J., Koenig, M. Nat. Genet. (2001) [Pubmed]
  6. ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome. Hirano, M., Furiya, Y., Asai, H., Yasui, A., Ueno, S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Quinzii, C.M., Kattah, A.G., Naini, A., Akman, H.O., Mootha, V.K., DiMauro, S., Hirano, M. Neurology (2005) [Pubmed]
  8. Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent after radiotherapy. A Phase II study. Brandes, A.A., Tosoni, A., Vastola, F., Pasetto, L.M., Coria, B., Danieli, D., Iuzzolino, P., Gardiman, M., Talacchi, A., Ermani, M. Cancer (2004) [Pubmed]
  9. Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Le Ber, I., Dubourg, O., Benoist, J.F., Jardel, C., Mochel, F., Koenig, M., Brice, A., Lombès, A., Dürr, A. Neurology (2007) [Pubmed]
  10. Aprataxin, a novel protein that protects against genotoxic stress. Gueven, N., Becherel, O.J., Kijas, A.W., Chen, P., Howe, O., Rudolph, J.H., Gatti, R., Date, H., Onodera, O., Taucher-Scholz, G., Lavin, M.F. Hum. Mol. Genet. (2004) [Pubmed]
  11. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. Clements, P.M., Breslin, C., Deeks, E.D., Byrd, P.J., Ju, L., Bieganowski, P., Brenner, C., Moreira, M.C., Taylor, A.M., Caldecott, K.W. DNA Repair (Amst.) (2004) [Pubmed]
  12. Familial cognitive impairment with ataxia with oculomotor apraxia. Mahajnah, M., Basel-Vanagaite, L., Inbar, D., Kornreich, L., Weitz, R., Straussberg, R. J. Child Neurol. (2005) [Pubmed]
  13. A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment. Luo, H., Chan, D.W., Yang, T., Rodriguez, M., Chen, B.P., Leng, M., Mu, J.J., Chen, D., Songyang, Z., Wang, Y., Qin, J. Mol. Cell. Biol. (2004) [Pubmed]
  14. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations. Shimazaki, H., Takiyama, Y., Sakoe, K., Ikeguchi, K., Niijima, K., Kaneko, J., Namekawa, M., Ogawa, T., Date, H., Tsuji, S., Nakano, I., Nishizawa, M. Neurology (2002) [Pubmed]
  15. Oxidation of glutamine in HeLa cells: role and control of truncated TCA cycles in tumour mitochondria. Piva, T.J., McEvoy-Bowe, E. J. Cell. Biochem. (1998) [Pubmed]
  16. Disease-associated mutations inactivate AMP-lysine hydrolase activity of Aprataxin. Seidle, H.F., Bieganowski, P., Brenner, C. J. Biol. Chem. (2005) [Pubmed]
  17. Feedback regulation of S-adenosylmethionine decarboxylase synthesis. Persson, L., Khomutov, A.R., Khomutov, R.M. Biochem. J. (1989) [Pubmed]
  18. VR-ACS6 is an auxin-inducible 1-aminocyclopropane-1-carboxylate synthase gene in mungbean (Vigna radiata). Yoon, I.S., Mori, H., Kim, J.H., Kang, B.G., Imaseki, H. Plant Cell Physiol. (1997) [Pubmed]
  19. Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin. Rass, U., Ahel, I., West, S.C. J. Biol. Chem. (2008) [Pubmed]
  20. Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. Dopeso, H., Mateo-Lozano, S., Elez, E., Landolfi, S., Ramos Pascual, F.J., Hernández-Losa, J., Mazzolini, R., Rodrigues, P., Bazzocco, S., Carreras, M.J., Espín, E., Armengol, M., Wilson, A.J., Mariadason, J.M., Ramon Y Cajal, S., Tabernero, J., Schwartz, S., Arango, D. Clin. Cancer Res. (2010) [Pubmed]
  21. The FHA domain of aprataxin interacts with the C-terminal region of XRCC1. Date, H., Igarashi, S., Sano, Y., Takahashi, T., Takahashi, T., Takano, H., Tsuji, S., Nishizawa, M., Onodera, O. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  22. Nucleolar localization of aprataxin is dependent on interaction with nucleolin and on active ribosomal DNA transcription. Becherel, O.J., Gueven, N., Birrell, G.W., Schreiber, V., Suraweera, A., Jakob, B., Taucher-Scholz, G., Lavin, M.F. Hum. Mol. Genet. (2006) [Pubmed]
  23. Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Brenner, C. Biochemistry (2002) [Pubmed]
  24. Prevalence, specificity and significance of ovarian antibodies during spontaneous premature ovarian failure. Fénichel, P., Sosset, C., Barbarino-Monnier, P., Gobert, B., Hiéronimus, S., Béné, M.C., Harter, M. Hum. Reprod. (1997) [Pubmed]
  25. How predictable are the results of excimer laser photorefractive keratectomy? A review. Grosvenor, T. Optometry and vision science : official publication of the American Academy of Optometry. (1995) [Pubmed]
  26. Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives. Bacherikov, V.A., Chang, J.Y., Lin, Y.W., Chen, C.H., Pan, W.Y., Dong, H., Lee, R.Z., Chou, T.C., Su, T.L. Bioorg. Med. Chem. (2005) [Pubmed]
  27. Research on research. Carter, J., Wheeler, G., Yolton, R. Journal of the American Optometric Association. (1978) [Pubmed]
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