APTX

Summary

APTX (aprataxin, HGNC:15984) is a protein-coding gene on chromosome 9p21.1, encoding Aprataxin (Q7Z2E3). DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair.

This gene encodes a member of the histidine triad (HIT) superfamily. The encoded protein may play a role in single-stranded DNA repair through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity. Mutations in this gene have been associated with ataxia-ocular apraxia. Alternatively spliced transcript variants have been identified for this gene.

Source: NCBI Gene 54840 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 346 total — 23 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes
• MANE Select transcript: NM_001195248

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15984
Approved symbol	APTX
Name	aprataxin
Location	9p21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20157, AOA, AOA1, EAOH, EOAHA
Ensembl gene	ENSG00000137074
Ensembl biotype	protein_coding
OMIM	606350
Entrez	54840

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 22 protein_coding, 21 nonsense_mediated_decay, 15 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000309615, ENST00000379813, ENST00000379817, ENST00000379819, ENST00000379825, ENST00000397172, ENST00000436040, ENST00000460940, ENST00000460945, ENST00000463596, ENST00000464632, ENST00000465003, ENST00000467331, ENST00000468275, ENST00000472896, ENST00000473270, ENST00000474658, ENST00000476858, ENST00000477119, ENST00000478279, ENST00000479656, ENST00000480031, ENST00000482687, ENST00000483148, ENST00000485479, ENST00000486724, ENST00000489583, ENST00000494649, ENST00000494973, ENST00000495360, ENST00000496030, ENST00000671774, ENST00000671912, ENST00000672152, ENST00000672244, ENST00000672281, ENST00000672286, ENST00000672438, ENST00000672476, ENST00000672493, ENST00000672519, ENST00000672535, ENST00000672553, ENST00000672615, ENST00000672846, ENST00000673114, ENST00000673171, ENST00000673181, ENST00000673211, ENST00000673248, ENST00000673333, ENST00000673360, ENST00000673416, ENST00000673485, ENST00000673487, ENST00000673598, ENST00000868582, ENST00000868583, ENST00000868584, ENST00000868585, ENST00000916450, ENST00000969748, ENST00000969749

RefSeq mRNA: 23 — MANE Select: NM_001195248 NM_001195248, NM_001195249, NM_001195250, NM_001195251, NM_001195252, NM_001195254, NM_001368995, NM_001368996, NM_001368997, NM_001368998, NM_001368999, NM_001369000, NM_001369001, NM_001369002, NM_001369003, NM_001369004, NM_001369005, NM_001369006, NM_001370669, NM_001370670, NM_001370673, NM_175069, NM_175073

CCDS: CCDS47956, CCDS47957, CCDS6532, CCDS75827, CCDS94395

Canonical transcript exons

ENST00000379817 — 8 exons

Exon	Start	End
ENSE00003505806	32974458	32974561
ENSE00003569468	32988083	32988129
ENSE00003651564	32989759	32989895
ENSE00003654857	32985971	32986030
ENSE00003662443	32987544	32987846
ENSE00003682722	32972616	32973652
ENSE00003688936	33001567	33001628
ENSE00003789480	32984631	32984857

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 92.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.7728 / max 310.2371, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100403	13.4768	1799
100406	6.3275	1688
100405	1.6757	918
100404	0.2928	104

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	92.39	gold quality
islet of Langerhans	UBERON:0000006	91.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.93	gold quality
skin of leg	UBERON:0001511	90.85	gold quality
right adrenal gland	UBERON:0001233	90.75	gold quality
right adrenal gland cortex	UBERON:0035827	90.75	gold quality
skin of abdomen	UBERON:0001416	90.63	gold quality
lower esophagus mucosa	UBERON:0035834	90.55	gold quality
stromal cell of endometrium	CL:0002255	90.54	gold quality
left adrenal gland	UBERON:0001234	90.53	gold quality
right uterine tube	UBERON:0001302	90.48	gold quality
adrenal gland	UBERON:0002369	90.23	gold quality
mucosa of transverse colon	UBERON:0004991	90.22	gold quality
left adrenal gland cortex	UBERON:0035825	90.19	gold quality
adrenal cortex	UBERON:0001235	89.97	gold quality
right lobe of liver	UBERON:0001114	89.96	gold quality
ventricular zone	UBERON:0003053	89.79	gold quality
left testis	UBERON:0004533	89.54	gold quality
esophagus mucosa	UBERON:0002469	89.49	gold quality
adrenal tissue	UBERON:0018303	89.48	gold quality
right testis	UBERON:0004534	89.40	gold quality
zone of skin	UBERON:0000014	89.21	gold quality
body of pancreas	UBERON:0001150	88.97	gold quality
pancreas	UBERON:0001264	88.85	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.76	gold quality
rectum	UBERON:0001052	88.75	gold quality
esophagus	UBERON:0001043	88.61	gold quality
testis	UBERON:0000473	88.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.45	gold quality
granulocyte	CL:0000094	88.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.40
E-MTAB-6524	no	100.57

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• The clinical and genetic features of three non-Portuguese and non-Japanese patients with aprataxin gene mutations are reported. (PMID:12629250)
• A 14 year old girl presented with severe generalized dystonia, ataxia, ocular motor apraxia, and areflexia. and homozygous for an insertion mutation of aprataxin (APTX), 689 ins T. (PMID:14534929)
• aprataxin influences the cellular response to genotoxic stress. (PMID:15044383)
• This study screened a group of 165 early onset ataxia patients for APTX mutations and detected two non-related patients homozygous for the W293X nonsense mutation. (PMID:15164193)
• Two novel mutations were identified, the complete deletion of the gene, which seems to not correlate with an increased severity of the disease, and a splice mutation on the acceptor splice site of exon 7 (875-1G>A (IVS7-1 G>A). (PMID:15365154)
• Aprataxin is 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. (PMID:15380105)
• determined the domains of APTX and XRCC1 required for their interaction; findings suggest that APTX, together with XRCC1 and PARP-1, plays an essential role in single-strand DNA break repair (PMID:15555565)
• A novel homozygous missense mutation (H201Q) was found in one Italian patient. (PMID:15596775)
• Aprataxin was shown to be involved directly in the DNA single-strand-break repair machinery. (PMID:15719174)
• the essential function of Aprataxin is reversal of nucleotidylylated protein modifications; all three domains contribute to formation of a stable enzyme, and the in vitro behavior of cloned APTX alleles can score disease-associated mutations (PMID:15790557)
• Aprataxin has a role in the cellular response to DNA damage (PMID:16547001)
• cross-dependence between aprataxin and nucleolin in the nucleolus (PMID:16777843)
• 2 patients whose clinical features resembled those of multiple system atrophy of the cerebellar subtype (MSA-C) but without ocular motor apraxia and hypoalbuminemia. Each had a different nucleotide transition in the APTX gene. (PMID:17049295)
• Aprataxin is critical for the processing of obstructive DNA termini. (PMID:17240329)
• May have a general proofreading function in DNA repair, removing DNA adenylates as they arise during single-strand break repair, double-strand break repair, and in base excision repair. (PMID:17276982)
• All of the disease-associated apprataxin mutants had extremely shorter half-lives than the WT. We further found that these mutants were targeted for rapid proteasome-mediated degradation (PMID:17485165)
• Aprataxin repairs DNA single-strand breaks with a unique substrate specificity toward damaged 3’-ends including 3’-phosphoglycolate and 3’-phosphate ends, and that disease-associated mutant forms of aprataxin lack this activity. (PMID:17519253)
• Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism. (PMID:17572444)
• We report a patient with homozygous deletion of APTX, who presented with behavioural changes (social withdrawal), and subsequent rapid progression of neurological symptoms associated with severe cognitive decline. (PMID:18202221)
• APTX is the first protein to adopt canonical histidine triad-type reaction chemistry for the repair of DNA (PMID:18836178)
• that short-patch single-strand break repair (SSBR) in AOA1 cell extracts bypasses the point of aprataxin action at oxidative breaks and stalls at the final step of DNA ligation, resulting in the accumulation of adenylated DNA nicks (PMID:19103743)
• Protein kinase C gamma, a causative for spinocerebellar ataxia, negatively regulates nuclear import of aprataxin. (PMID:19561170)
• Data demonstrate the presence of 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, PARP-1, APE-1 and OGG1 in the DNA damage response. (PMID:19643912)
• searched for aprataxin mutations in Greek patients with sporadic cerebellar ataxia where GAA expansion in frataxin gene has been excluded; no detectable point mutation or deletion was found in the aprataxin gene of all the patients (PMID:19953284)
• Data show that the RASGRP1/APTX gene expression ratio was higher in the responder while the AKAP13 expression was higher in the non-responders. (PMID:19960345)
• High aprataxin levels are associated with low irinotecan response in colorectal cancer. (PMID:20371676)
• Loss of HNT3 in rad27Delta cells, which are deficient in long-patch base excision repair (LP-BER), resulted in synergistic sensitivity to H(2)O(2) and methylmethane sulfonate. (PMID:20399152)
• Aprataxin is required for the normal repair rate of DNA single-strand breaks induced by genotoxic agents. (PMID:21412945)
• The clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. (PMID:21465257)
• The patients with early onset ataxia with ocular motor apraxia and hypoalbuminaemia homozygous for the c.689_690insT mutation(APTX) show a more severe phenotype than those with a p.Pro206Leu or p.Val263Gly mutation. (PMID:21486904)
• Aprataxin localizes to mitochondria and preserves mitochondrial function. (PMID:21502511)
• Data suggest that mutations affecting protein folding, the active site pocket and the pivot motif underlie aprataxin dysfunction in the neurodegenerative disorder ataxia with oculomotor apraxia 1 (AOA1). (PMID:21984210)
• TDP1 and APTX take part in the mitochondrial DNA repair and are apparently being transported from the cell nucleus. (Review) (PMID:24161509)
• Structure-function studies of human APTX-RNA-DNA-AMP-Zn complexes define a mechanism for detecting and reversing adenylation at RNA-DNA junctions (PMID:24362567)
• Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction. [review] (PMID:25637650)
• Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway. (PMID:25976310)
• We describe an ataxia with oculomotor apraxia type 1 patient without a severe phenotype, who has a homozygous deletion of the complete coding region of APTX. (PMID:26285866)
• Mutations in TDP1 and APTX have been linked to Spinocerebellar ataxia with axonal neuropathy (SCAN1) and Ataxia-ocular motor apraxia 1 (AOA1), respectively, while mutations in PNKP are considered to be responsible for Microcephaly with seizures (MCSZ) and Ataxia-ocular motor apraxia 4 (AOA4). (PMID:27470939)
• we demonstrated that miR-424 regulated radiosensitivity by directly targeting aprataxin. (PMID:27769049)
• Whole-exome sequencing on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia resulted in the identification of a homozygous novel stop-gain mutation in the APTX gene (c.739A>T; p.Lys247*) that segregates with the phenotype. (PMID:28652255)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aptx	ENSDARG00000027143
mus_musculus	Aptx	ENSMUSG00000028411
rattus_norvegicus	Aptx	ENSRNOG00000006582
drosophila_melanogaster	Aptx	FBGN0038704

Paralogs (1): HINT3 (ENSG00000111911)

Protein

Protein identifiers

Aprataxin — Q7Z2E3 (reviewed: Q7Z2E3)

Alternative names: Forkhead-associated domain histidine triad-like protein

All UniProt accessions (10): A0A0A0MRW7, A0A5F9ZGW5, A0A5F9ZI51, A0A5K1VW64, A0A5K1VW80, C9J8U3, Q7Z2E3, F8WBD6, F8WBM3, Q6JV79

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair. Resolves abortive DNA ligation intermediates formed either at base excision sites, or when DNA ligases attempt to repair non-ligatable breaks induced by reactive oxygen species. Catalyzes the release of adenylate groups covalently linked to 5’-phosphate termini, resulting in the production of 5’-phosphate termini that can be efficiently rejoined. Also able to hydrolyze adenosine 5’-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity. Likewise, catalyzes the release of 3’-linked guanosine (DNAppG) and inosine (DNAppI) from DNA, but has higher specific activity with 5’-linked adenosine (AppDNA).

Subunit / interactions. Interacts with single-strand break repair proteins XRCC1, XRCC4, ADPRT/PARP1 and p53/TP53. Interacts with NCL. Interacts (via FHA-like domain) with MDC1 (phosphorylated).

Subcellular location. Nucleus. Nucleoplasm. Nucleolus Cytoplasm.

Tissue specificity. Widely expressed; detected in liver, kidney and lymph node (at protein level). Isoform 1 is highly expressed in the cerebral cortex and cerebellum, compared to isoform 2 (at protein level). Widely expressed; detected throughout the brain, in liver, kidney, skeletal muscle, fibroblasts, lymphocytes and pancreas.

Disease relevance. Ataxia-oculomotor apraxia syndrome (AOA) [MIM:208920] An autosomal recessive syndrome characterized by early-onset cerebellar ataxia, oculomotor apraxia, early areflexia and late peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The histidine triad, also called HIT motif, forms part of the binding loop for the alpha-phosphate of purine mononucleotide. The FHA-like domain mediates interaction with NCL; XRCC1 and XRCC4. The HIT domain is required for enzymatic activity. The C2H2-type zinc finger mediates DNA-binding.

Miscellaneous. Major form. Minor form. May be an aberrant isoform present in cancer cell lines. May be an aberrant isoform present in cancer cell lines. May be an aberrant isoform present in cancer cell lines. May be an aberrant isoform present in cancer cell lines. May be an aberrant isoform present in cancer cell lines. May be an aberrant isoform present in cancer cell lines.

Isoforms (13)

UniProt ID	Names	Canonical?
Q7Z2E3-1	1, Long	yes
Q7Z2E3-2	2, Short
Q7Z2E3-3	3
Q7Z2E3-4	4
Q7Z2E3-5	5
Q7Z2E3-6	6
Q7Z2E3-7	7
Q7Z2E3-8	8
Q7Z2E3-9	9
Q7Z2E3-10	10
Q7Z2E3-11	11
Q7Z2E3-12	12, LP2, LP2E5, LP2P3, LP2P3E5
Q7Z2E3-13	13, LE5

RefSeq proteins (23): NP_001182177, NP_001182178, NP_001182179, NP_001182180, NP_001182181, NP_001182183, NP_001355924, NP_001355925, NP_001355926, NP_001355927, NP_001355928, NP_001355929, NP_001355930, NP_001355931, NP_001355932, NP_001355933, NP_001355934, NP_001355935, NP_001357598, NP_001357599, NP_001357602, NP_778239, NP_778243 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR011146	HIT-like	Domain
IPR013087	Znf_C2H2_type	Domain
IPR019808	Histidine_triad_CS	Conserved_site
IPR032566	Znf-C2HE	Domain
IPR036265	HIT-like_sf	Homologous_superfamily
IPR041388	FHA_2	Domain
IPR047289	FHA_APTX	Domain

Pfam: PF11969, PF16278, PF17913

Enzyme classification (BRENDA):

• EC 3.1.11.7 — adenosine-5’-diphospho-5’-[DNA] diphosphatase (BRENDA: 2 organisms, 6 substrates, 0 inhibitors, 2 Km, 2 kcat entries)
• EC 3.6.1.70 — guanosine-5’-diphospho-5’-[DNA] diphosphatase (BRENDA: 3 organisms, 4 substrates, 0 inhibitors, 1 Km, 1 kcat entries)
• EC 3.6.1.71 — adenosine-5’-diphospho-5’-[DNA] diphosphatase (BRENDA: 7 organisms, 40 substrates, 2 inhibitors, 11 Km, 10 kcat entries)
• EC 3.6.1.72 — DNA-3’-diphospho-5’-guanosine diphosphatase (BRENDA: 2 organisms, 4 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADENOSINE-5’-DIPHOSPHO-5’-[DNA]	—	4
ADENOSINE-5’-DIPHOSPHO-5’-[DNA]	—	2
ADENOSINE-5’-DIPHOSPHO-5’-(RIBONUCLEOTIDE)-[DNA]	—	2
P1,P4-BIS(5’-ADENOSYL)TETRAPHOSPHATE	0.018–0.039	2
GPPP-BODIPY	0.0131	1
ADENOSINE 5’-PHOSPHORAMIDATE	0.028	1
ADENOSINE-5’-MONOPHOSPHORAMIDATE	0.837	1
P1,P3-BIS(5’-ADENOSYL)TRIPHOSPHATE	0.021	1

Catalyzed reactions (Rhea), 3 shown:

• a 5’-end adenosine-5’-diphospho-5’-2’-deoxyribonucleoside-DNA + H2O = a 5’-end 5’-phospho-2’-deoxyribonucleoside-DNA + AMP + 2 H(+) (RHEA:52128)
• a 5’-end adenosine-5’-diphospho-5’-ribonucleoside-2’-deoxyribonucleotide-DNA + H2O = a 5’-end 5’-phospho-ribonucleoside-2’-deoxyribonucleotide-DNA + AMP + 2 H(+) (RHEA:52132)
• a 3’-end 2’-deoxyribonucleotide-3’-diphospho-5’-guanosine-DNA + H2O = a 3’-end 2’-deoxyribonucleotide 3’-phosphate-DNA + GMP + 2 H(+) (RHEA:52140)

UniProt features (75 total): strand 18, splice variant 11, helix 11, sequence variant 9, mutagenesis site 5, site 4, region of interest 4, turn 4, domain 2, modified residue 2, short sequence motif 2, chain 1, active site 1, zinc finger region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3KT9	X-RAY DIFFRACTION	1.65
6CVQ	X-RAY DIFFRACTION	1.65
4NDH	X-RAY DIFFRACTION	1.85
6CVR	X-RAY DIFFRACTION	1.88
4NDI	X-RAY DIFFRACTION	1.9
4NDF	X-RAY DIFFRACTION	1.94
6CVP	X-RAY DIFFRACTION	2
6CVS	X-RAY DIFFRACTION	2.11
6CVO	X-RAY DIFFRACTION	2.4
4NDG	X-RAY DIFFRACTION	2.54
6CVT	X-RAY DIFFRACTION	2.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z2E3-F1	81.52	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 274 (tele-amp-histidine intermediate); 188 (interaction with dna substrate); 265 (interaction with dna substrate); 276 (interaction with dna substrate); 291 (interaction with dna substrate)

Post-translational modifications (2): 132, 137

Mutagenesis-validated functional residues (5):

Position	Phenotype
43	impairs interaction with xrcc1 and xrcc4. abolishes localization at sites of dna double-strand breaks. loss of interacti
52	impairs interaction with mdc1 and localization at sites of dna double-strand breaks.
274	abolishes enzyme activity.
333	abolishes dna-binding and enzyme activity; when associated with a-336.
336	abolishes dna-binding and enzyme activity; when associated with a-333.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 212 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, MULLIGHAN_NPM1_SIGNATURE_3_UP, MODULE_255, MODULE_317, KAUFFMANN_DNA_REPAIR_GENES, GOBP_REGULATION_OF_DNA_REPAIR, WEI_MYCN_TARGETS_WITH_E_BOX, GATA3_01, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE, GARY_CD5_TARGETS_DN, GOBP_REGULATION_OF_PROTEIN_STABILITY, GATA1_03, MASSARWEH_RESPONSE_TO_ESTRADIOL

GO Biological Process (4): single strand break repair (GO:0000012), regulation of protein stability (GO:0031647), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (18): chromatin binding (GO:0003682), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), double-stranded RNA binding (GO:0003725), zinc ion binding (GO:0008270), phosphoglycolate phosphatase activity (GO:0008967), mismatched DNA binding (GO:0030983), DNA 5’-adenosine monophosphate hydrolase activity (GO:0033699), polynucleotide 3’-phosphatase activity (GO:0046403), phosphoprotein binding (GO:0051219), DNA-3’-diphospho-5’-guanosine diphosphatase activity (GO:0120108), single-strand break-containing DNA binding (GO:1990165), DNA binding (GO:0003677), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA binding	3
cellular anatomical structure	3
binding	2
phosphatase activity	2
pyrophosphatase activity	2
nuclear lumen	2
DNA repair	1
regulation of biological quality	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
RNA binding	1
transition metal ion binding	1
double-stranded DNA binding	1
protein binding	1
damaged DNA binding	1
nucleic acid binding	1
molecular_function	1
catalytic activity	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APTX	XRCC1	P18887	999
APTX	XRCC4	Q13426	994
APTX	APLF	Q8IW19	993
APTX	LIG3	P49916	960
APTX	SETX	Q7Z333	942
APTX	TDP1	Q9NUW8	912
APTX	COQ2	Q96H96	894
APTX	COQ8A	Q8NI60	885
APTX	APEX1	P27695	875
APTX	OGG1	P78554	856
APTX	FXN	Q16595	840
APTX	PDSS1	Q5T2R2	836
APTX	PAXX	Q9BUH6	834
APTX	CHFR	Q96EP1	831
APTX	COQ9	O75208	828

IntAct

71 interactions, top by confidence:

A	B	Type	Score
LIG4	XRCC4	psi-mi:“MI:0914”(association)	0.970
XRCC1	APTX	psi-mi:“MI:0403”(colocalization)	0.880
XRCC1	APTX	psi-mi:“MI:0915”(physical association)	0.880
APTX	XRCC1	psi-mi:“MI:0915”(physical association)	0.880
APTX	XRCC4	psi-mi:“MI:0915”(physical association)	0.830
APTX	PARP1	psi-mi:“MI:0915”(physical association)	0.770
PARP1	APTX	psi-mi:“MI:0915”(physical association)	0.770
PARP1	TP53	psi-mi:“MI:0914”(association)	0.750
LIG3	XRCC1	psi-mi:“MI:0914”(association)	0.740
TDP1	POLB	psi-mi:“MI:0914”(association)	0.640
PNMA1	APTX	psi-mi:“MI:0915”(physical association)	0.560
POLB	H2AC11	psi-mi:“MI:0914”(association)	0.530
XRCC4	NFKB1	psi-mi:“MI:0914”(association)	0.530
APTX	TP53	psi-mi:“MI:0914”(association)	0.460

BioGRID (110): APTX (Two-hybrid), APTX (Affinity Capture-MS), APTX (Affinity Capture-MS), APTX (Affinity Capture-MS), APTX (Affinity Capture-MS), APTX (Affinity Capture-MS), APTX (Affinity Capture-MS), PNMA1 (Two-hybrid), APTX (Affinity Capture-MS), BAD (Affinity Capture-MS), APTX (Affinity Capture-MS), KIF3A (Affinity Capture-MS), XRCC1 (Affinity Capture-Western), XRCC1 (Two-hybrid), APTX (Affinity Capture-Western)

ESM2 similar proteins: A4II32, A7MCT6, D3ZRW8, G5E872, O35465, O54783, O55229, P50747, P61797, Q14164, Q14318, Q14CH1, Q1JP61, Q3B7U9, Q496Y0, Q497B8, Q52WX2, Q5I0I5, Q7TQC5, Q7YRZ1, Q7YRZ2, Q7Z2E3, Q7Z695, Q80WC9, Q8BNV1, Q8BYN3, Q8CGA0, Q8HXH0, Q8IYL2, Q8IZ69, Q8K4H4, Q8N371, Q8NF37, Q8NI29, Q8QZX0, Q920N2, Q96EN8, Q9BGQ0, Q9CXT6, Q9D2Q2

Diamond homologs: P61797, P61798, P61799, P61800, P61801, P61802, Q558W0, Q7T287, Q7TQC5, Q7YRZ1, Q7YRZ2, Q7Z2E3, Q8K3P7, Q8K4H4, Q8MSG8, Q96T60, Q9BGQ0, Q9CPS6, Q9JLV6, Q9M041, Q28BZ2, Q08702, Q5R9L4, Q9NQE9, O84390, P62958, Q5RF69, Q84VV6, Q9PK09, Q9Z863, O74859, Q5PNN8, O07817, P49773, P62959, P70349, P9WML0, P9WML1, Q2YDJ4, O13911

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKCG	up-regulates	APTX	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nonhomologous End-Joining (NHEJ)	5	26.2×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
base-excision repair	5	50.9×	1e-05
double-strand break repair via nonhomologous end joining	5	45.8×	1e-05
double-strand break repair	8	35.3×	3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

346 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	12
Uncertain significance	115
Likely benign	104
Benign	35

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027441	NM_001195248.2(APTX):c.544-1G>C	Pathogenic
1334465	NM_001195248.2(APTX):c.587dup (p.Ala198fs)	Pathogenic
1372599	NM_001195248.2(APTX):c.302del (p.Glu101fs)	Pathogenic
1459533	NM_001195248.2(APTX):c.694G>T (p.Glu232Ter)	Pathogenic
1706448	NM_001195248.2(APTX):c.638del (p.Leu213fs)	Pathogenic
2019865	NM_001195248.2(APTX):c.588_595del (p.Lys197fs)	Pathogenic
214128	NM_001195248.2(APTX):c.667C>T (p.Leu223Phe)	Pathogenic
2571331	NM_001195248.2(APTX):c.739C>T (p.Arg247Ter)	Pathogenic
2804720	NM_001195248.2(APTX):c.796C>T (p.Gln266Ter)	Pathogenic
2821016	NM_001195248.2(APTX):c.229dup (p.Gln77fs)	Pathogenic
2910226	NM_001195248.2(APTX):c.336_337del (p.His112fs)	Pathogenic
426093	NM_001195248.2(APTX):c.697A>T (p.Lys233Ter)	Pathogenic
4425	NM_001195248.2(APTX):c.689dup (p.Glu232fs)	Pathogenic
4426	NM_001195248.2(APTX):c.617C>T (p.Pro206Leu)	Pathogenic
4427	NM_001195248.2(APTX):c.841del (p.Ser281fs)	Pathogenic
4428	NM_001195248.2(APTX):c.788T>G (p.Val263Gly)	Pathogenic
4429	NM_001195248.2(APTX):c.602A>G (p.His201Arg)	Pathogenic
4430	NM_001195248.2(APTX):c.875-1G>A	Pathogenic
4431	NM_001195248.2(APTX):c.837G>A (p.Trp279Ter)	Pathogenic
4432	NC_000009.12:g.(?32973498)(33001604_?)del	Pathogenic
634641	NM_001195248.2(APTX):c.484-1G>T	Pathogenic
635168	NM_001195248.2(APTX):c.776del (p.Val259fs)	Pathogenic
870837	NM_001195248.2(APTX):c.559C>T (p.Gln187Ter)	Pathogenic
2501668	NM_001195248.2(APTX):c.729del (p.Lys243fs)	Likely pathogenic
2663301	NM_001195248.2(APTX):c.935_941delinsAAG (p.Leu312fs)	Likely pathogenic
3065435	NM_001195248.2(APTX):c.484-1G>C	Likely pathogenic
3381048	NM_001195248.2(APTX):c.397_407dup (p.Gly137fs)	Likely pathogenic
3775216	NM_001195248.2(APTX):c.874+1del	Likely pathogenic
3896779	NM_001195248.2(APTX):c.603T>A (p.His201Gln)	Likely pathogenic
4433	NM_001195248.2(APTX):c.668T>C (p.Leu223Pro)	Likely pathogenic

SpliceAI

1561 predictions. Top by Δscore:

Variant	Effect	Δscore
9:32973650:CAG:C	acceptor_gain	1.0000
9:32974557:CATGG:C	acceptor_gain	1.0000
9:32974562:C:CC	acceptor_gain	1.0000
9:32974566:T:C	acceptor_gain	1.0000
9:32974566:T:TC	acceptor_gain	1.0000
9:32987687:T:TA	donor_gain	1.0000
9:32988125:CTGTA:C	acceptor_gain	1.0000
9:32988126:TGTA:T	acceptor_gain	1.0000
9:32988130:C:CC	acceptor_gain	1.0000
9:32989757:A:C	donor_loss	1.0000
9:32989758:CCTTG:C	donor_gain	1.0000
9:32989782:T:C	donor_gain	1.0000
9:32989891:TCACT:T	acceptor_gain	1.0000
9:32989892:CACT:C	acceptor_gain	1.0000
9:32989892:CACTC:C	acceptor_gain	1.0000
9:32989894:CT:C	acceptor_gain	1.0000
9:32989895:TC:T	acceptor_loss	1.0000
9:32989896:C:CC	acceptor_gain	1.0000
9:32989896:CTAAG:C	acceptor_loss	1.0000
9:32989897:T:A	acceptor_loss	1.0000
9:32973648:CACAG:C	acceptor_gain	0.9900
9:32973653:C:CC	acceptor_gain	0.9900
9:32973711:C:CT	acceptor_gain	0.9900
9:32974558:ATGG:A	acceptor_gain	0.9900
9:32974559:TGG:T	acceptor_gain	0.9900
9:32974560:GG:G	acceptor_gain	0.9900
9:32974561:GCTAG:G	acceptor_loss	0.9900
9:32974562:C:G	acceptor_loss	0.9900
9:32974563:T:C	acceptor_loss	0.9900
9:32985965:TCTGA:T	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000055151 (9:32972472 T>C), RS1000065440 (9:33000173 T>A,C), RS1000112409 (9:33017521 A>C,G), RS1000149880 (9:33004723 C>T), RS1000152451 (9:33015050 T>A,C), RS1000199243 (9:32995766 T>C), RS1000259234 (9:32998954 C>A), RS1000370099 (9:32981486 C>T), RS1000401290 (9:32987057 G>C,T), RS1000411612 (9:33024341 G>A,C), RS1000475395 (9:33019789 C>T), RS1000484650 (9:32981791 G>A), RS1000540637 (9:33000164 G>A), RS1000596566 (9:33000501 G>A,C), RS1000682699 (9:32988059 A>C)

Disease associations

OMIM: gene MIM:606350 | disease phenotypes: MIM:208920, MIM:607426

GenCC curated gene-disease

Disease	Classification	Inheritance
ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia	Definitive	Autosomal recessive

Mondo (4): ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (MONDO:0008842), epilepsy (MONDO:0005027), hereditary ataxia (MONDO:0100309), coenzyme Q10 deficiency, primary, 1 (MONDO:0011829)

Orphanet (3): Ataxia-oculomotor apraxia type 1 (Orphanet:1168), Hereditary ataxia (Orphanet:183518), Leigh syndrome with nephrotic syndrome (Orphanet:255249)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000571	Hypometric saccades
HP:0000572	Visual loss
HP:0000590	Progressive external ophthalmoplegia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000657	Oculomotor apraxia
HP:0000707	Abnormality of the nervous system
HP:0000726	Dementia
HP:0000764	Peripheral axonal degeneration
HP:0000815	Hypergonadotropic hypogonadism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001298	Encephalopathy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005312_26	Menopause (age at onset)	2.000000e-08
GCST008163_79	Height	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
C538013	Early-onset ataxia with oculomotor apraxia and hypoalbuminemia (supp.)
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523362 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10971182	APTX		0.00	0

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Vehicle Emissions	decreases expression, decreases reaction, increases abundance, increases expression	2
Particulate Matter	decreases expression, decreases reaction, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
kojic acid	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
CPG-oligonucleotide	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment	1
Arbutin	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases abundance, affects cotreatment, increases oxidation	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419657	Binding	Inhibition of human APTX assessed as reduction in phosphatase activity by measuring release of inorganic phosphate at 50 uM using 5’-TAMRA-tagged 20-mer oligonucleotide as substrate incubated for 30 mins by fluorescence quenching based assa	Small molecule inhibitors of polynucleotide kinase/phosphatase, poly(ADP-ribose) polymerase and uses thereof

Cellosaurus cell lines

17 cell lines: 6 telomerase immortalized cell line, 4 cancer cell line, 3 induced pluripotent stem cell, 3 transformed cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A9I3	JUCTCi002-A	Induced pluripotent stem cell	Female
CVCL_A9I4	JUCTCi002-B	Induced pluripotent stem cell	Female
CVCL_A9I5	JUCTCi002-C	Induced pluripotent stem cell	Female
CVCL_B1JT	Abcam HeLa APTX KO	Cancer cell line	Female
CVCL_SD07	HAP1 APTX (-) 1	Cancer cell line	Male
CVCL_SD08	HAP1 APTX (-) 2	Cancer cell line	Male
CVCL_SD09	HAP1 APTX (-) 3	Cancer cell line	Male
CVCL_ZT69	FG4003	Finite cell line
CVCL_ZT70	FD104	Telomerase immortalized cell line	Sex unspecified
CVCL_ZT71	FD104-m21	Telomerase immortalized cell line	Sex unspecified

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy