Alternative titles; symbols
HGNC Approved Gene Symbol: APTX
SNOMEDCT: 715366004;
Cytogenetic location: 9p21.1 Genomic coordinates (GRCh38) : 9:32,972,616-33,025,120 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p21.1 | Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia | 208920 | Autosomal recessive | 3 |
The APTX gene encodes aprataxin, a member of the histidine triad (HIT) superfamily, members of which have nucleotide-binding and diadenosine polyphosphate hydrolase activities (Date et al., 2001).
By positional cloning, Date et al. (2001) and Moreira et al. (2001) identified a novel gene encoding a member of the histidine triad superfamily, which had previously been identified as FLJ20157 (GenBank AK000164), as the causative gene in ataxia-oculomotor apraxia syndrome (EAOH; 208920). Date et al. (2001) called the gene product aprataxin, with the gene symbol APTX. Although many HIT proteins had been identified (e.g., FHIT, 601153; HINT, 601314), aprataxin was the first to be linked to a distinct phenotype.
Moreira et al. (2001) identified 2 major mRNA species of APTX resulting from alternative splicing of exon 3: a short form of 168 amino acids and the first ATG codon in exon 3, and a long form with an additional 115 nucleotides of the 5-prime portion of exon 3, resulting in the addition of another 174 amino acids (for a total of 342 amino acids) and the first codon ATG codon in exon 1. The calculated molecular mass of the long form is 39.1 kD (Sano et al., 2004). Moreira et al. (2001) and Date et al. (2001) numbered mutations according to both the long and short forms of the transcript. Moreira et al. (2001) demonstrated by RT-PCR that the APTX gene is ubiquitously expressed. The long transcript is the major form found in human cell lines, with the shorter frameshifted form present in lower amounts; liver tissue has equal amounts of the 2 transcripts. By Northern blot analysis, Date et al. (2001) demonstrated ubiquitous expression of the 2.2-kb long form and limited expression of the 1.35-kb short form. Moreira et al. (2001) noted that the long form of aprataxin is predicted to have a nuclear localization, based on the presence of a nuclear localization signal and a putative DNA-binding site.
By quantitative RT-PCR, Sano et al. (2004) confirmed that the long form of aprataxin is the dominant tissue isoform in brain, heart, lung, kidney, liver, and trachea. They also confirmed nuclear localization of the long form.
Date et al. (2001) showed by homology search that both forms of aprataxin have a highly conserved HIT motif (His-X-His-X-His-X-X, where X is a hydrophobic amino acid), an essential motif for HIT proteins. HIT proteins have been classified into 2 branches: the fragile HIT protein family found only in animals and fungi, and the ancient HIT nucleotide-binding protein (HINT) family that has representatives in all cellular life. Phylogenetic tree analysis showed that aprataxin is the third member of the HIT protein superfamily. The mutations found in patients with early-onset ataxia with oculomotor apraxia and hypoalbuminemia involved highly conserved amino acids.
The APTX gene maps to chromosome 9p13.3 (Date et al., 2001; Moreira et al., 2001).
Sano et al. (2004) demonstrated in vitro that the long form of aprataxin, but not the short form, interacts with the C-terminal domain of the XRCC1 (194360) gene, suggesting that the N-terminal region of aprataxin is essential for the interaction. Sano et al. (2004) noted that the N terminus of the long form of aprataxin is homologous with the polynucleotide kinase 3-prime phosphatase gene (PNKP; 605610). Whitehouse et al. (2001) reported that XRCC1 interacts with PNKP in addition to its interactions with DNA polymerase-beta (POLB; 174760) and DNA ligase III (LIG3; 600940), forming a multiprotein complex that repairs single-strand breaks, typical of those induced by reactive oxygen species and ionizing radiation. Sano et al. (2004) suggested that aprataxin may be involved in this repair complex, and that accumulation of damaged DNA underlies the pathophysiologic mechanisms of EAOH.
Gueven et al. (2004) demonstrated that aprataxin is a nuclear protein, present in both the nucleoplasm and the nucleolus. Mutations in the APTX gene destabilized the aprataxin protein, and fusion constructs of enhanced green fluorescent protein and aprataxin, representing deletions of putative functional domains, generated highly unstable products. Cells from EAOH patients were characterized by enhanced sensitivity to agents that caused single-strand breaks in DNA, but there was no evidence for a gross defect in single-strand break repair. Sensitivity to hydrogen peroxide and the resulting genome instability were corrected by transfection with full-length aprataxin cDNA. Aprataxin interacted with the repair proteins XRCC1, PARP1 (173870), and p53 (191170) and colocalized with XRCC1 along charged particle tracks on chromatin. The authors concluded that aprataxin may influence the cellular response to genotoxic stress interacting with a number of proteins involved in DNA repair.
Clements et al. (2004) reported that cell lines derived from patients with ataxia-oculomotor apraxia-1 (AOA1; 208920) exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM (607585) following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of ataxia telangiectasia. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionizing radiation, hydrogen peroxide, and methyl methanesulfonate. Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4 (194363). Aprataxin possesses a divergent forkhead-associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase (PNKP; 605610), and appears to mediate the interactions with CK2 (see 115440)-phosphorylated XRCC1 and XRCC4 through this domain. Clements et al. (2004) concluded that aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.
Luo et al. (2004) provided biochemical data to demonstrate that 2 preformed XRCC1 protein complexes exist in cycling HeLa cells. One complex contains known enzymes that are important for single-stranded break repair, including DNA ligase III (LIG3), PNKP, and polymerase-beta (174760); the other is a novel complex that contains LIG3 and aprataxin. Luo et al. (2004) characterized the new XRCC1 complex. XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on ser518, thr519, and thr523 largely determines aprataxin binding to XRCC1 through its FHA domain. 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. Thus, Luo et al. (2004) concluded that aprataxin plays a role to maintain the steady-state protein level of XRCC1. Luo et al. (2004) concluded that collectively, their data provide insights into the single-strand break repair molecular machinery in the cell and point to involvement of aprataxin in this process, thus linking single-stranded break repair to the neurologic disease AOA1.
Aprataxin associates with DNA repair proteins XRCC1 and XRCC4, which are partners of DNA ligase III and ligase IV (601837), respectively, suggestive of a role in DNA repair. 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. Using purified aprataxin protein and extracts derived from either APTX-defective chicken DT40 cells or Aptx -/- mouse primary neural cells, Ahel et al. (2006) showed that aprataxin resolves abortive DNA ligation intermediates. Specifically, aprataxin catalyzes the nucleophilic release of adenylate groups covalently linked to 5-prime-phosphate termini at single-strand nicks and gaps, resulting in the production of 5-prime-phosphate termini that can be efficiently rejoined. Ahel et al. (2006) suggested that neurologic disorders associated with APTX mutations may be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events.
Hirano et al. (2007) demonstrated that XRCC1 and APTX accumulated to laser-induced single-strand DNA breaks and UV-induced cyclobutane pyrimidine dimers within minutes of irradiation in HeLa and Chinese hamster ovary cells. Recruitment of APTX was dependent on the presence of XRCC1. APTX mutant proteins accumulated in DNA lesions but showed impaired stability, most likely due to activation of the ubiquitin-proteasomal pathway. Fibroblasts isolated from patients with EAOH showed increased sensitivity to reactive oxygen species and decreased repair of single-strand DNA breaks compared to controls, which could be partially rescued by antioxidant treatment. Accumulated oxidative DNA damage was confirmed in EAOH cerebellar cells. The findings indicated that loss of APTX function results in impaired repair of single-strand DNA breaks and that increased reactive oxygen species contribute to the disease.
Aprataxin has been shown to interact with PARP1, a key player in the detection of DNA single-strand breaks. Harris et al. (2009) reported reduced expression of PARP1, apurinic endonuclease-1 (APEX1; 107748) and OGG1 (601982) in AOA1 cells and demonstrated a requirement for PARP1 in the recruitment of aprataxin to sites of DNA single-strand breaks. Mouse embryonic fibroblasts (MEFs) derived from Parp1-knockout mice showed reduced levels of aprataxin and reduced DNA-adenylate hydrolysis; however, inhibition of PARP1 activity did not affect aprataxin activity in vitro. Rather, aprataxin failed to relocalize to sites of DNA single-strand breaks in Parp1-null MEFs compared to wildtype cells, and inhibition of PARP1 activity resulted in delayed recruitment of aprataxin to DNA breaks. There were elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between aprataxin, PARP1, APE1 and OGG1 in the DNA damage response. Harris et al. (2009) proposed both direct and indirect modulating functions for aprataxin on base excision repair.
Tumbale et al. (2014) examined the importance of APTX to RNase-H2-dependent excision repair (RER) of a lesion that is very frequently introduced into DNA, a ribonucleotide. Tumbale et al. (2014) showed that ligases generate adenylated 5-prime ends containing a ribose characteristic of RNase H2 incision. APTX efficiently repairs adenylated RNA-DNA, and acting in an RNA-DNA damage response, promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RER. Structure-function studies of human APTX-RNA-DNA-AMP-zinc complexes define a mechanism for detecting and reversing adenylation at RNA-DNA junctions. This involves A-form RNA binding, proper protein folding, and conformational changes, all of which are affected by heritable APTX mutations in ataxia with oculomotor apraxia-1 (208920). Tumbale et al. (2014) concluded that accumulation of adenylated RNA-DNA may contribute to neurologic disease.
Garcia-Diaz et al. (2015) found that most, but not all, cell lines derived from AOA1 patient fibroblasts showed coenzyme Q10 (CoQ10) deficiency due to reduced mRNA and protein expression of PDSS1 (607429), the first committed enzyme of CoQ10 biosynthesis. Low PDSS1 was caused by reduced activity of a transcriptional regulatory pathway that included APE1, NRF1 (600879), and NRF2 (see 600609). Knockdown of APTX or APE1 in HeLa cells recapitulated CoQ10 deficiency and other mitochondrial abnormalities, and these abnormalities were reversed by upregulation of NRF2. Garcia-Diaz et al. (2015) concluded that mitochondrial dysfunction in APTX-depleted cells is not due to involvement of APTX in mtDNA repair, but rather to a role for APTX in transcriptional regulation of mitochondrial function.
Date et al. (2001) and Moreira et al. (2001) identified mutations in the APTX gene as the cause of ataxia-oculomotor apraxia-1 (AOA1; 208920). Date et al. (2001) observed that an insertion or deletion mutation resulted in a severe phenotype with childhood onset, whereas missense mutations resulted in a mild phenotype with relatively late age at onset; in their pedigree 2637 with compound heterozygosity for val89-to-gly (V89G; 606350.0004) and pro32-to-leu (P32L; 606350.0002), the age at onset was 25 years.
Castellotti et al. (2011) identified recessive APTX mutations in 13 (6.4%) of 204 Italian probands with progressive cerebellar ataxia. The most common mutation was W279X (606350.0006), which was found in homozygous state in 7 patients and in compound heterozygosity with another pathogenic APTX mutation in 1 patient. Three additional novel mutations were identified. The patients had a homogeneous phenotype consistent with AOA1. Western blot analysis of patient lymphocytes showed severely decreased levels of APTX protein, consistent with loss of function as a disease mechanism. There were no genotype/phenotype correlations.
Date et al. (2001) found that affected individuals in 3 pedigrees with EAOH (208920) carried a homozygous insertion of a T after nucleotide 167 (167delT; nucleotide number starting at the first ATG codon of the short form), which results in a frameshift with a premature stop. Affected individuals in these 3 families were homozygous; in 3 other pedigrees affected members had this mutation in heterozygous state in combination with a different mutation. Among their patients, Moreira et al. (2001) found that the Japanese founding haplotypes were associated with the same mutation, which they called 689insT according to the gene's long transcript.
The second most common mutation found by Date et al. (2001) in families with EAOH (208920) was a C-to-T transition resulting in a pro32-to-leu amino acid change. This mutation removes a proline residue that is highly conserved among all the subfamilies of HIT proteins. Moreira et al. (2001) designated this mutation PRO206LEU according to the APTX gene's long transcript.
In one pedigree, Date et al. (2001) observed that members with EAOH (208920) were homozygous for a 318delT single-nucleotide deletion resulting in a frameshift with a premature stop. In 3 pedigrees, the 167insT (606350.0001), P32L (606350.0002), and 318delT mutations were present in compound heterozygous state.
In a family with EAOH (208920), Date et al. (2001) observed that affected members had a val89-to-gly (V89G) missense mutation involving one of the highly conserved hydrophobic amino acids of the histidine triad. As the HIT motif forms part of the phosphate binding loop, the V89G mutation probably affects the phosphate-binding activity.
In a Japanese brother and sister with EAOH (208920) born of consanguineous parents, Shimazaki et al. (2002) identified a homozygous missense mutation in the aprataxin gene, an 80A-G transition which resulted in a his27-to-arg substitution.
In patients with EAOH (208920) from 5 Portuguese families, Moreira et al. (2001) identified an 837G-A transition in exon 6 of the APTX gene, resulting in a trp279-to-ter (W279X) mutation, in association with a founding haplotype.
In an Italian patient with classic EAOH, Tranchant et al. (2003) identified homozygosity for the W279X mutation. Two French sibs were found to have compound heterozygosity for the W279X mutation and a missense mutation. Their phenotype was mild, with later onset of ataxia, no hypoalbuminemia, and no oculomotor apraxia. The authors noted the phenotypic variability and suggested that the missense mutation in the French sibs likely produced a semifunctional protein.
Quinzii et al. (2005) identified a homozygous W279X mutation in 3 sibs originally reported by Musumeci et al. (2001) as having familial cerebellar ataxia with muscle coenzyme Q10 (CoQ10) deficiency (see, e.g., COQ10D1, 607426). All 3 patients responded well to CoQ10 supplementation. An affected cousin was heterozygous for the W279X mutation, but the authors suspected he had another mutation. Thirteen additional patients with coenzyme Q deficiency did not have APTX mutations. Quinzii et al. (2006) noted that CoQ10 deficiency has been associated with 3 major clinical phenotypes and remarked that the finding of mutation in the APTX gene in these sibs supports the hypothesis that the ataxic form of CoQ10 deficiency is a genetically heterogeneous entity in which deficiency of CoQ10 can be secondary.
Le Ber et al. (2007) found decreased muscle CoQ10 in 5 of 6 patients with AOA1. Three patients who were homozygous for the W279X mutation had the lowest values. The CoQ10 deficiency did not correlate with disease duration, severity, or other blood parameters, and mitochondrial morphology and respiratory function were normal.
Castellotti et al. (2011) identified recessive APTX mutations in 13 (6.4%) of 204 Italian probands with progressive cerebellar ataxia. The most common mutation was W279X, which was found in homozygous state in 7 patients and in compound heterozygosity with another pathogenic APTX mutation in 1 patient.
In 2 affected members of a Tunisian family with EAOH (208920), Amouri et al. (2004) identified a deletion of all 7 exons of the APTX gene. The patients showed typical clinical features of the disorder despite absence of the gene.
In affected members of 2 unrelated Tunisian families with EAOH (208920), Amouri et al. (2004) identified a G-to-A transition at the acceptor splice site of exon 7 of the APTX gene, presumably leading to skipping of exon 7. The findings demonstrated that truncation of the terminal zinc finger domain is sufficient to cause the full clinical phenotype.
In a patient with adult-onset ataxia with oculomotor apraxia (208920), Criscuolo et al. (2005) identified a homozygous 6668T-C transition in exon 5 of the APTX gene, resulting in a leu223-to-pro (L223P) substitution. The patient had onset at age 40 years of gait ataxia and dysarthria, but had normal ocular movements and normal serum albumin. The L223P mutation occurs in the middle of an alpha-helix domain and was predicted to cause some destabilization of protein folding.
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