TXN2

Summary

TXN2 (thioredoxin 2, HGNC:17772) is a protein-coding gene on chromosome 22q12.3, encoding Thioredoxin, mitochondrial (Q99757). Important for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability Is involved in various redox reactions including the reduction of protein disulfide bonds, through the reversible oxidation of its active center dithiol to a d….

This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis.

Source: NCBI Gene 25828 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 29 (Moderate, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 82 total — 1 pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes
• MANE Select transcript: NM_012473

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17772
Approved symbol	TXN2
Name	thioredoxin 2
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	MT-TRX
Ensembl gene	ENSG00000100348
Ensembl biotype	protein_coding
OMIM	609063
Entrez	25828

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000216185, ENST00000403313, ENST00000411915, ENST00000416967, ENST00000487725, ENST00000884007, ENST00000884008, ENST00000884009, ENST00000884010, ENST00000884011, ENST00000884012, ENST00000930523, ENST00000930524, ENST00000930525, ENST00000930526, ENST00000941475, ENST00000941476

RefSeq mRNA: 1 — MANE Select: NM_012473 NM_012473

CCDS: CCDS13928

Canonical transcript exons

ENST00000216185 — 4 exons

Exon	Start	End
ENSE00001666349	36480575	36480837
ENSE00001706774	36467046	36467917
ENSE00001942639	36481564	36481640
ENSE00003686895	36476733	36476856

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 69.0597 / max 289.8798, expressed in 1825 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193948	62.3783	1824
193946	2.8455	1456
193945	1.9937	1214
193949	1.2134	789
193947	0.6287	331

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.97	gold quality
right adrenal gland cortex	UBERON:0035827	98.91	gold quality
left adrenal gland	UBERON:0001234	98.76	gold quality
left adrenal gland cortex	UBERON:0035825	98.71	gold quality
adrenal cortex	UBERON:0001235	98.60	gold quality
apex of heart	UBERON:0002098	98.02	gold quality
adrenal gland	UBERON:0002369	98.00	gold quality
mucosa of transverse colon	UBERON:0004991	97.51	gold quality
right lobe of liver	UBERON:0001114	97.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.35	gold quality
gastrocnemius	UBERON:0001388	97.11	gold quality
right atrium auricular region	UBERON:0006631	97.03	gold quality
body of stomach	UBERON:0001161	96.89	gold quality
heart left ventricle	UBERON:0002084	96.86	gold quality
cardiac ventricle	UBERON:0002082	96.72	gold quality
muscle of leg	UBERON:0001383	96.67	gold quality
nucleus accumbens	UBERON:0001882	96.36	gold quality
cardiac atrium	UBERON:0002081	96.36	gold quality
amygdala	UBERON:0001876	96.33	gold quality
adrenal tissue	UBERON:0018303	96.32	gold quality
right lobe of thyroid gland	UBERON:0001119	96.29	gold quality
transverse colon	UBERON:0001157	96.28	gold quality
left ovary	UBERON:0002119	96.26	gold quality
right frontal lobe	UBERON:0002810	96.26	gold quality
esophagus mucosa	UBERON:0002469	96.13	gold quality
right ovary	UBERON:0002118	96.11	gold quality
left lobe of thyroid gland	UBERON:0001120	96.05	gold quality
metanephros cortex	UBERON:0010533	96.03	gold quality
rectum	UBERON:0001052	95.99	gold quality
putamen	UBERON:0001874	95.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, KMT2B, RUNX3

miRNA regulators (miRDB)

52 targeting TXN2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309

Literature-anchored findings (GeneRIF, showing 29)

• mitochondrial thioredoxin may play important roles in protection against oxidant-induced apoptosis (PMID:12032145)
• MT-TRX has a role in the regulation of the mitochondrial membrane potential and cell death (PMID:12080052)
• Thioredoxin 1 and thioredoxin 2 have opposed regulatory functions on hypoxia-inducible factor-1alpha. (PMID:17220299)
• The additive protection by Trx2 and GSH shows that Trx2 and GSH systems are both functionally important at low oxidative stress conditions. (PMID:17548047)
• The LC/ICPMS analyses showed that the trivalent arsenic species were able to form complexes with both human and E. coli Trx. (PMID:17939155)
• upon stimulation of Fas, thioredoxin-2 mediated denitrosylation of mitochondria-associated caspase-3, a process required for caspase-3 activation, and promoted apoptosis (PMID:18497292)
• Report the effects of acrolein on peroxiredoxins, thioredoxins, and thioredoxin reductase in human bronchial epithelial cells. (PMID:19135121)
• a novel Ins/Del polymorphism in the human TXN2 gene proximal promoter region that altered the transcriptional activity and is associated with spina bifida risk (PMID:19165900)
• Trx2 modulates transcription of GR and NF-kappaB reporter genes. (PMID:19570036)
• These results suggest that TRX2 not only functions as an antioxidant, but also supports mtTFA functions (PMID:19885567)
• Both thioredoxin 2 and glutaredoxin 2 contribute to the reduction of the mitochondrial 2-Cys peroxiredoxin Prx3. (PMID:20929858)
• TRX1 and TRX2 regulate the proliferation and survival of adipocyte derived stem cells; these processes are mediated by the activation of ERK1/2 (PMID:21158569)
• Data show that knockdown of S100P led to downregulation of thioredoxin 1 and beta-tubulin and upregulation of RhoGDIA, all potential therapeutic targets in cancer. (PMID:21327297)
• knockdown of TRX-1 or TRX-2 sensitizes cells to CYP2E1-induced oxidant stress partially via ASK-1 and JNK1 signaling pathways. Both TRX-1 and TRX-2 are important for defense against CYP2E1-induced oxidative stress. (PMID:21557999)
• We showed that overexpression of TRXs reduced cell death; TRX2 was expressed in the mitochondria, while TRX1 was expressed in the cytoplasm. (PMID:23485938)
• The Grx2 system could help to keep Trx2/1 reduced during an oxidative stress, thereby contributing to the anti-apoptotic signaling. (PMID:24295294)
• TGF-beta-mediated expression of the epithelial-mesenchymal transition marker fibronectin was inhibited not only by chemicals that interfere with reactive oxygen species signaling but also by exogenously expressed mitochondrial thioredoxin. (PMID:24342608)
• CERKL interacts with TRX2 and plays a novel key role in the regulation of the TRX2 antioxidant pathway. (PMID:24735978)
• Thioredoxin 2 Is a Novel E2-Interacting Protein That Inhibits the Replication of Classical Swine Fever Virus by promoting the nuclear translocation of the p65 subunit of NF-kappaB. (PMID:26041303)
• No evidence that SNPs in TRX2 have effects, but the rs4485648 polymorphism of the TrxR2 gene might exert an independent effect on the development of Diabetic retinopathy. (PMID:26763822)
• Prx3 and Trx2 comprise an adaptive system to sense changes in atmospheric oxygen tension and influence cellular injury responses through both detoxification of mitochondrial oxidants and regulation of mitochondrial redox-dependent signaling (PMID:28045936)
• Trx2 overexpression failed to attenuate hypoxia-induced human pulmonary arterial smooth muscle cells proliferation in vitro or hypoxia-induced Pulmonary hypertension in vivo. (PMID:28130258)
• study demonstrated that miR-27a and -b, which are widely expressed in host cells, suppress SNAP25 and TXN2 expression through posttranscriptional gene silencing. (PMID:28356525)
• Overexpression of mitochondrial Trx2 attenuates the intracellular ROS accumulation and ATP production. Most interestingly, mitochondrial Trx2 may be involved in the cardiac hypertrophy signaling of diabetes. (PMID:28914755)
• Thioredoxin 2 Negatively Regulates Innate Immunity to RNA Viruses by Disrupting the Assembly of the Virus-Induced Signaling Adaptor Complex. (PMID:31915282)
• Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression. (PMID:32920833)
• Mechanisms of Trx2/ASK1-Mediated Mitochondrial Injury in Pemphigus Vulgaris. (PMID:33763469)
• Association between genetic variants in oxidative stress-related genes and osteoporotic bone fracture. The Hortega follow-up study. (PMID:34688818)
• scAAV2-Mediated Expression of Thioredoxin 2 and C3 Transferase Prevents Retinal Ganglion Cell Death and Lowers Intraocular Pressure in a Mouse Model of Glaucoma. (PMID:38003443)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	txn2	ENSDARG00000034777
mus_musculus	Txn2	ENSMUSG00000005354
rattus_norvegicus	Txn2	ENSRNOG00000005614
drosophila_melanogaster	CG8517	FBGN0034472
drosophila_melanogaster	CG8993	FBGN0035334
caenorhabditis_elegans		WBGENE00007099

Paralogs (4): TXNL1 (ENSG00000091164), TXN (ENSG00000136810), TXNDC2 (ENSG00000168454), TXNDC8 (ENSG00000204193)

Protein

Protein identifiers

Thioredoxin, mitochondrial — Q99757 (reviewed: Q99757)

Alternative names: Thioredoxin-2

All UniProt accessions (3): Q99757, F8WDN2, M0QXH0

UniProt curated annotations — full annotation on UniProt →

Function. Important for the control of mitochondrial reactive oxygen species homeostasis, apoptosis regulation and cell viability Is involved in various redox reactions including the reduction of protein disulfide bonds, through the reversible oxidation of its active center dithiol to a disulfide.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion.

Tissue specificity. Widely expressed in adult (at protein level) and fetal tissues.

Disease relevance. Combined oxidative phosphorylation deficiency 29 (COXPD29) [MIM:616811] An autosomal recessive, infantile-onset, neurodegenerative disorder characterized by decreased activities of mitochondrial respiratory complexes I and III, severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the thioredoxin family.

RefSeq proteins (1): NP_036605* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005746	Thioredoxin	Family
IPR013766	Thioredoxin_domain	Domain
IPR017937	Thioredoxin_CS	Conserved_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00085

UniProt features (24 total): strand 5, helix 4, turn 3, site 3, active site 2, modified residue 2, transit peptide 1, chain 1, disulfide bond 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1W4V	X-RAY DIFFRACTION	1.8
1W89	X-RAY DIFFRACTION	2
1UVZ	X-RAY DIFFRACTION	2.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99757-F1	84.10	0.65

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): 90 (nucleophile); 93 (nucleophile); 84 (deprotonates c-terminal active site cys); 91 (contributes to redox potential value); 92 (contributes to redox potential value)

Post-translational modifications (2): 152, 152

Disulfide bonds (1): 90–93

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1614558	Degradation of cysteine and homocysteine
R-HSA-3299685	Detoxification of Reactive Oxygen Species
R-HSA-1430728	Metabolism
R-HSA-1614635	Sulfur amino acid metabolism
R-HSA-2262752	Cellular responses to stress
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9711123	Cellular response to chemical stress

MSigDB gene sets: 251 (showing top): MODULE_93, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, TTTGTAG_MIR520D, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GOBP_CELL_REDOX_HOMEOSTASIS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GOBP_SULFUR_AMINO_ACID_METABOLIC_PROCESS, MODULE_60, BENPORATH_OCT4_TARGETS, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (2): sulfur amino acid catabolic process (GO:0000098), cell redox homeostasis (GO:0045454)

GO Molecular Function (3): protein-disulfide reductase activity (GO:0015035), oxidoreductase activity, acting on a sulfur group of donors, disulfide as acceptor (GO:0016671), protein binding (GO:0005515)

GO Cellular Component (3): nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Sulfur amino acid metabolism	1
Cellular response to chemical stress	1
Metabolism of amino acids and derivatives	1
Cellular responses to stimuli	1
Metabolism	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sulfur amino acid metabolic process	1
sulfur compound catabolic process	1
carboxylic acid catabolic process	1
cellular homeostasis	1
disulfide oxidoreductase activity	1
catalytic activity, acting on a protein	1
oxidoreductase activity, acting on a sulfur group of donors	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TXN2	TXNIP	Q9H3M7	994
TXN2	MAP3K5	Q99683	961
TXN2	TXNRD1	Q16881	927
TXN2	PRDX1	P35703	907
TXN2	TXNRD2	Q9NNW7	862
TXN2	PTPN1	P18031	788
TXN2	PRDX3	P30048	766
TXN2	CSE1L	P55060	756
TXN2	GLRX	P35754	743
TXN2	GLRX2	Q9NS18	743
TXN2	GSR	P00390	689
TXN2	CASP3	P42574	662
TXN2	GPX7	Q96SL4	655
TXN2	GPX8	Q8TED1	653
TXN2	GPX2	P18283	649

IntAct

283 interactions, top by confidence:

A	B	Type	Score
TXN2	SSNA1	psi-mi:“MI:0915”(physical association)	0.720
TXN2	TRIM21	psi-mi:“MI:0915”(physical association)	0.720
TXN2	RPIA	psi-mi:“MI:0915”(physical association)	0.720
MAPRE2	TXN2	psi-mi:“MI:0915”(physical association)	0.720
TXN2	VPS52	psi-mi:“MI:0915”(physical association)	0.720
PPCDC	TXN2	psi-mi:“MI:0915”(physical association)	0.720
TXN2	MRFAP1L1	psi-mi:“MI:0915”(physical association)	0.720
MAPRE3	TXN2	psi-mi:“MI:0915”(physical association)	0.720
TRIM21	TXN2	psi-mi:“MI:0915”(physical association)	0.720
TXN2	MAPRE2	psi-mi:“MI:0915”(physical association)	0.720
SSNA1	TXN2	psi-mi:“MI:0915”(physical association)	0.720
VPS52	TXN2	psi-mi:“MI:0915”(physical association)	0.720
RPIA	TXN2	psi-mi:“MI:0915”(physical association)	0.720
TXN2	MAPRE3	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (169): NR3C1 (Reconstituted Complex), NR3C1 (Affinity Capture-Western), RELA (Affinity Capture-Western), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid), TXN2 (Two-hybrid)

ESM2 similar proteins: A0A0R0IHP4, A2Y5T7, A2YUQ6, F4K6X0, G4LTX4, K7MTW9, M1A3D5, O23193, O23344, O64654, O64764, O65693, O81770, P31166, P82403, P97615, Q0J3L4, Q5KQI6, Q5TKD8, Q6JE37, Q6JE38, Q6NPF9, Q6YTI3, Q7X9V3, Q8GSJ1, Q8GWS0, Q8H2V6, Q8L7S9, Q8LCT3, Q8LEK4, Q8VY88, Q8VY91, Q8VZT6, Q93W20, Q96326, Q99757, Q9C5C5, Q9C5D0, Q9CAF2, Q9FEB5

Diamond homologs: A0A8M1N5Y4, A3KPF5, O13811, O22263, O48773, P10473, P37395, P38660, P38661, P50254, P52232, P97493, P97615, Q00216, Q15084, Q1RQI9, Q4N4N8, Q5R6T1, Q5R875, Q5WA72, Q63081, Q66GQ3, Q67IX6, Q67UF5, Q6GNG3, Q86IA3, Q8BXZ1, Q8VX13, Q922R8, Q94F09, Q95108, Q96JJ7, Q99757, Q9FF55, Q9MAU6, Q9VYV3, A2YUQ6, M1A3D5, O17486, O22022

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RUNX3	“down-regulates quantity by repression”	TXN2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 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.

GO biological processes:

GO term	Partners	Fold	FDR
spindle assembly	5	35.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	43
Likely benign	23
Benign	7

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
222023	NM_012473.4(TXN2):c.71G>A (p.Trp24Ter)	Pathogenic

SpliceAI

865 predictions. Top by Δscore:

Variant	Effect	Δscore
22:36467793:AT:A	donor_gain	1.0000
22:36467793:ATC:A	donor_gain	1.0000
22:36467793:ATCC:A	donor_gain	1.0000
22:36467794:T:C	donor_gain	1.0000
22:36467795:C:A	donor_gain	1.0000
22:36476859:C:CT	acceptor_gain	1.0000
22:36480573:A:AC	donor_gain	1.0000
22:36480574:C:CG	donor_gain	1.0000
22:36480574:CT:C	donor_gain	1.0000
22:36480574:CTGTG:C	donor_gain	1.0000
22:36467793:A:AC	donor_gain	0.9900
22:36467794:T:TA	donor_gain	0.9900
22:36467815:G:C	donor_gain	0.9900
22:36467916:ACCTG:A	acceptor_loss	0.9900
22:36467918:C:A	acceptor_loss	0.9900
22:36467919:T:A	acceptor_loss	0.9900
22:36476727:CCATA:C	donor_loss	0.9900
22:36476728:CATA:C	donor_loss	0.9900
22:36476730:TAC:T	donor_loss	0.9900
22:36476731:A:AG	donor_loss	0.9900
22:36476732:C:A	donor_loss	0.9900
22:36476853:CCAC:C	acceptor_gain	0.9900
22:36476854:CACC:C	acceptor_gain	0.9900
22:36476855:ACC:A	acceptor_loss	0.9900
22:36476857:C:CG	acceptor_loss	0.9900
22:36476857:C:T	acceptor_gain	0.9900
22:36476858:T:G	acceptor_loss	0.9900
22:36476860:A:T	acceptor_gain	0.9900
22:36476867:G:T	acceptor_gain	0.9900
22:36480566:AATAC:A	donor_loss	0.9900

AlphaMissense

1081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:36467904:G:T	P134H	1.000
22:36467905:G:A	P134S	1.000
22:36476779:G:T	A114D	1.000
22:36476842:C:A	C93F	1.000
22:36476842:C:T	C93Y	1.000
22:36476843:A:G	C93R	1.000
22:36476851:C:T	C90Y	1.000
22:36476852:A:G	C90R	1.000
22:36476853:C:A	W89C	1.000
22:36476853:C:G	W89C	1.000
22:36476855:A:G	W89R	1.000
22:36476855:A:T	W89R	1.000
22:36467857:C:G	G150R	0.999
22:36467861:A:C	F148L	0.999
22:36467861:A:T	F148L	0.999
22:36467862:A:G	F148S	0.999
22:36467863:A:G	F148L	0.999
22:36467892:G:T	A138D	0.999
22:36467898:A:T	V136E	0.999
22:36467904:G:A	P134L	0.999
22:36467904:G:C	P134R	0.999
22:36467905:G:C	P134A	0.999
22:36467905:G:T	P134T	0.999
22:36467907:A:T	V133E	0.999
22:36476746:G:T	A125D	0.999
22:36476765:C:G	D119H	0.999
22:36476780:C:G	A114P	0.999
22:36476821:A:G	L100S	0.999
22:36476833:A:G	L96P	0.999
22:36476841:G:C	C93W	0.999

dbSNP variants (sampled 300 via entrez): RS1000063530 (22:36467152 C>A,T), RS1000368438 (22:36481666 T>A,G), RS1000409885 (22:36476303 G>A), RS1000422301 (22:36481856 C>T), RS1000505964 (22:36481676 G>C), RS1000740738 (22:36475768 C>T), RS1000818921 (22:36471469 G>A), RS1000850200 (22:36471344 T>C), RS1001136092 (22:36468344 G>A), RS1001335211 (22:36466611 GT>G), RS1001567769 (22:36466877 T>C), RS1001909118 (22:36475812 A>G), RS1001916640 (22:36481421 G>A,T), RS1002074166 (22:36471631 C>T), RS1002190409 (22:36467167 C>G)

Disease associations

OMIM: gene MIM:609063 | disease phenotypes: MIM:616811

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 29	Moderate	Autosomal recessive
combined oxidative phosphorylation defect type 29	Supportive	Autosomal recessive

Mondo (2): combined oxidative phosphorylation deficiency 29 (MONDO:0014781), (MONDO:0033187)

Orphanet (1): Combined oxidative phosphorylation defect type 29 (Orphanet:478029)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000488	Retinopathy
HP:0000648	Optic atrophy
HP:0001138	Optic neuropathy
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002151	Increased circulating lactate concentration
HP:0002180	Neurodegeneration
HP:0002188	Delayed CNS myelination
HP:0002283	Global brain atrophy
HP:0002311	Incoordination
HP:0002416	Subependymal cysts
HP:0002490	Increased CSF lactate
HP:0002579	Gastrointestinal dysmotility
HP:0002922	Increased CSF protein concentration
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0003739	Myoclonic spasms
HP:0003808	Abnormal muscle tone
HP:0009830	Peripheral neuropathy
HP:0011344	Severe global developmental delay
HP:0011451	Primary microcephaly
HP:0011923	Decreased activity of mitochondrial complex I

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2189153 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.88	Ki	1310	nM	GAMBOGIC ACID

PubChem BioAssay actives

1 with measured affinity, of 14 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(Z)-4-[(1S,2S,8R,17S,19R)-12-hydroxy-8,21,21-trimethyl-5-(3-methylbut-2-enyl)-8-(4-methylpent-3-enyl)-14,18-dioxo-3,7,20-trioxahexacyclo[15.4.1.02,15.02,19.04,13.06,11]docosa-4(13),5,9,11,15-pentaen-19-yl]-2-methylbut-2-enoic acid	716710: Inhibition of human recombinant TRX-2 up to 60 mins by insulin reduction assay	ki	1.3100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
chromium hexavalent ion	increases oxidation, decreases reaction, decreases expression	4
Hydrogen Peroxide	increases oxidation	3
sodium arsenite	decreases expression, increases oxidation	2
Acetaminophen	affects cotreatment, decreases expression, increases expression	2
Acrolein	increases oxidation	2
Dinitrochlorobenzene	increases expression, increases oxidation	2
Lipopolysaccharides	affects cotreatment, decreases expression, increases expression, increases reaction	2
Rotenone	increases response to substance, increases oxidation	2
Cadmium Chloride	increases abundance, increases expression, increases oxidation	2
tert-Butylhydroperoxide	decreases response to substance, increases oxidation	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
brilliant green	decreases expression, increases degradation, increases oxidation, affects response to substance	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
aluminum chlorhydrate	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
cinnamyl alcohol	increases expression	1
zinc chromate	increases oxidation	1
ochratoxin A	increases expression	1
sodium chromate(VI)	increases oxidation	1
nickel sulfate	increases expression	1
isoeugenol	increases expression	1
Bandrowski’s base	increases expression	1
di-n-butylphosphoric acid	affects expression	1
3-aminopyridine-2-carboxaldehyde thiosemicarbazone	affects binding, increases oxidation	1
hexyl cinnamic aldehyde	increases expression	1
tris(2-carboxyethyl)phosphine	increases oxidation, decreases reaction	1
pentabromodiphenyl ether	increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2212210	Binding	Covalent binding affinity to human recombinant TRX-2 C assessed as modification in C31/C34 residues by LC-MS/MS analysis	Gambogic acid deactivates cytosolic and mitochondrial thioredoxins by covalent binding to the functional domain. — J Nat Prod

Clinical trials (associated diseases)

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