Disease relevance of APTX

• Ataxia oculomotor apraxia-1 (AOA1) is a neurological disorder caused by mutations in the gene (APTX) encoding aprataxin [1].
• Consistent with this, APTX-defective cell lines are sensitive to agents that cause single-strand breaks and exhibit an increased incidence of induced chromosomal aberrations [1].
• The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates [1].
• Three patients with AOA1 were identified in an APTX mutation screening on 28 Southern Italian patients with progressive ataxia and peripheral neuropathy [2].
• Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is an autosomal recessive neurodegenerative disorder characterized by early-onset ataxia, ocular motor apraxia, and hypoalbuminemia [3].

Psychiatry related information on APTX

• Aprataxin (APTX) mutations are the cause of ataxia with ocular motor apraxia type 1(AOA1), an autosomal recessive disorder linked to chromosome 9p13.AOA1 seems to be one of the most frequent causes of recessive ataxia in Japan and Portugal [4].

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

• Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation [7].
• BACKGROUND: To the authors' knowledge, there is a scarcity of accurate data regarding the feasibility of standard chemotherapy with procarbazine, lomustine, and vincristine (PCV) in a homogeneous series of patients with primary anaplastic oligodendroglioma (AO) and oligoastrocytoma (AOA) that was recurrent after surgery and standard radiotherapy [8].
• APTX gene mutations responsible for ataxia-oculomotor apraxia 1 (AOA1) were identified in a family previously reported with ataxia and coenzyme Q10 (CoQ10) deficiency [9].

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].

References