TRIT1

Summary

TRIT1 (tRNA isopentenyltransferase 1, HGNC:20286) is a protein-coding gene on chromosome 1p34.2, encoding tRNA dimethylallyltransferase (Q9H3H1). Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i6A37). It is a selective cancer dependency (DepMap: 26.3% of cell lines).

This gene encodes a protein that that is targeted to the mitochondrion and modifies transfer RNAs (tRNAs) by adding a dimethylallyl group onto the adenine at position 37. This modification is important for maintaining the correct reading frame during protein translation. This gene is considered a tumor suppressor and its expression can decrease cell growth. Alternative splicing results in multiple transcripts variants, most of which are likely non-functional.

Source: NCBI Gene 54802 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 158 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 22
• Cancer dependency (DepMap): dependent in 26.3% of screened cell lines
• MANE Select transcript: NM_017646

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20286
Approved symbol	TRIT1
Name	tRNA isopentenyltransferase 1
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20061, IPT
Ensembl gene	ENSG00000043514
Ensembl biotype	protein_coding
OMIM	617840
Entrez	54802

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 nonsense_mediated_decay, 5 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000316891, ENST00000372818, ENST00000441669, ENST00000462243, ENST00000462797, ENST00000465417, ENST00000467774, ENST00000469476, ENST00000486825, ENST00000489945, ENST00000491865, ENST00000492612, ENST00000495175, ENST00000537440, ENST00000541099, ENST00000648678

RefSeq mRNA: 3 — MANE Select: NM_017646 NM_001312691, NM_001312692, NM_017646

CCDS: CCDS30681, CCDS81302, CCDS81303

Canonical transcript exons

ENST00000316891 — 11 exons

Exon	Start	End
ENSE00003471390	39852731	39852876
ENSE00003483729	39844531	39844640
ENSE00003496918	39844101	39844218
ENSE00003506974	39850119	39850261
ENSE00003518646	39883318	39883504
ENSE00003585490	39853970	39854068
ENSE00003601452	39847220	39847297
ENSE00003629791	39847548	39847660
ENSE00003647684	39857277	39857417
ENSE00003674130	39847986	39848097
ENSE00003894552	39838110	39841913

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 94.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.9125 / max 327.8531, expressed in 1802 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11886	22.5990	1802
11885	0.3135	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	94.89	gold quality
body of pancreas	UBERON:0001150	92.56	gold quality
skin of leg	UBERON:0001511	92.21	gold quality
vagina	UBERON:0000996	91.94	gold quality
skin of abdomen	UBERON:0001416	91.56	gold quality
oviduct epithelium	UBERON:0004804	91.51	gold quality
right uterine tube	UBERON:0001302	91.21	gold quality
secondary oocyte	CL:0000655	91.15	gold quality
left lobe of thyroid gland	UBERON:0001120	90.94	gold quality
prostate gland	UBERON:0002367	90.88	gold quality
thyroid gland	UBERON:0002046	90.78	gold quality
body of uterus	UBERON:0009853	90.66	gold quality
right lobe of thyroid gland	UBERON:0001119	90.64	gold quality
zone of skin	UBERON:0000014	90.28	gold quality
ectocervix	UBERON:0012249	90.21	gold quality
cerebellar hemisphere	UBERON:0002245	90.18	gold quality
adenohypophysis	UBERON:0002196	90.11	gold quality
lower esophagus mucosa	UBERON:0035834	90.09	gold quality
fallopian tube	UBERON:0003889	90.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.04	gold quality
cerebellar cortex	UBERON:0002129	90.03	gold quality
minor salivary gland	UBERON:0001830	89.95	gold quality
cervix squamous epithelium	UBERON:0006922	89.92	gold quality
pituitary gland	UBERON:0000007	89.81	gold quality
esophagus mucosa	UBERON:0002469	89.79	gold quality
pancreas	UBERON:0001264	89.65	gold quality
left ovary	UBERON:0002119	89.61	gold quality
esophagus	UBERON:0001043	89.42	gold quality
metanephros cortex	UBERON:0010533	89.42	gold quality
ovary	UBERON:0000992	89.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.31
E-GEOD-109979	no	119.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

34 targeting TRIT1, 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-4482-3P	99.98	72.50	3147
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4284	99.36	65.25	1293
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-2467-5P	97.36	67.71	991
HSA-MIR-6750-3P	96.79	67.50	740
HSA-MIR-3976	96.67	67.79	1187
HSA-MIR-4491	96.53	66.20	935
HSA-MIR-4657	96.53	66.57	895
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-6726-5P	95.97	63.72	841

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 26.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• The rare allele of TRIT1 Phe202Leu SNP was approximately seven-fold more frequent in Asian than in Caucasian subjects and three additional SNPs in the TRIT1 gene showed ethnic differences in allelic frequencies (PMID:17145094)
• One TRIT1 haplotype, CCGT, was associated with lymph node metastasis. (PMID:23349019)
• TRIT1 may control the levels of some tRNAs as well as their specific activity. (PMID:24126054)
• patient cells bearing the p.Arg323Gln TRIT1 mutation are severely deficient in i6A37 in both cytosolic and mitochondrial tRNAs (PMID:24901367)
• In light of this additional nuclear role for Mod5 we discuss the proposed role of the human homologue of Mod5, TRIT1, as a tumor suppressor protein.[review] (PMID:25261850)
• characterize TRIT1 as a novel human amyloid fiber forming protein. We discuss these data in light of TRIT1’s functional roles and possible implications for disease (PMID:27984194)
• We show that dysfunctional TRIT1 results in decreased levels of select mitochondrial proteins. Our findings confirm the TRIT1 disease association and advance the phenotypic and molecular understanding of this disorder. (PMID:28185376)
• Targeting mitochondrial and cytosolic substrates of TRIT1 isopentenyltransferase: Specificity determinants and tRNA-i6A37 profiles (PMID:32324744)
• The Effect of tRNA([Ser]Sec) Isopentenylation on Selenoprotein Expression. (PMID:34768885)
• TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity, and normal lactate levels. (PMID:36047296)
• TRIT1 deficiency: Two novel patients with four novel variants. (PMID:36049610)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	trit1	ENSDARG00000032876
mus_musculus	Trit1	ENSMUSG00000028653
rattus_norvegicus	Trit1	ENSRNOG00000014274
drosophila_melanogaster	CG31381	FBGN0043799
caenorhabditis_elegans		WBGENE00001740

Protein

Protein identifiers

tRNA dimethylallyltransferase — Q9H3H1 (reviewed: Q9H3H1)

Alternative names: Isopentenyl-diphosphate:tRNA isopentenyltransferase, hGRO1, tRNA isopentenyltransferase 1

All UniProt accessions (9): A0A3B3ITK2, B4DK89, Q9H3H1, Q3T7B4, S4R2X1, S4R2Z0, S4R3C5, S4R3F4, S4R3U8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 of both cytosolic and mitochondrial tRNAs, leading to the formation of N6-(dimethylallyl)adenosine (i6A37). Mediates modification of a limited subset of tRNAs: tRNA(Ser)(AGA), tRNA(Ser)(CGA), tRNA(Ser)(UGA), as well as partial modification of the selenocysteine tRNA(Ser)(UCA). TRIT1 is therefore required for selenoprotein expression.

Subcellular location. Mitochondrion Mitochondrion Cytoplasm Cytoplasm Cytoplasm.

Disease relevance. Combined oxidative phosphorylation deficiency 35 (COXPD35) [MIM:617873] An autosomal recessive disorder caused by defective mitochondrial metabolism and deficiencies of mitochondrial respiratory enzyme complexes. Clinical manifestations include global developmental delay, intellectual disability, microcephaly, and early-onset seizures. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the IPP transferase family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9H3H1-1	1	yes
Q9H3H1-2	2
Q9H3H1-3	3
Q9H3H1-4	4
Q9H3H1-5	5
Q9H3H1-6	6

RefSeq proteins (3): NP_001299620, NP_001299621, NP_060116* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003604	Matrin/U1-like-C_Znf_C2H2	Domain
IPR018022	IPT	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030666	IPP_transferase_euk	Family
IPR036236	Znf_C2H2_sf	Homologous_superfamily
IPR039657	Dimethylallyltransferase	Family

Pfam: PF01715

Enzyme classification (BRENDA):

• EC 2.5.1.75 — tRNA dimethylallyltransferase (BRENDA: 16 organisms, 49 substrates, 7 inhibitors, 42 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DIMETHYLALLYL DIPHOSPHATE	0.0032–114	13
SEVENTEEN-BASE RNA OLIGONUCLEOTIDE	1.5–75	13
DELTA2-ISOPENTENYL DIPHOSPHATE	0.0006–0.003	2
ADENOSINE 37 IN TRNA	0.013	1
ADENOSINE 37 IN TRNA-PHE	0.0001	1
GCGGACUCAAAAUCCGC	0.0065	1
GGCCAUUGAAAAUGGCC	0.0045	1
GGGAAUUGAAAAUUCCC	0.022	1
GGGCAUUGAAAAUGCCC	0.012	1
GGGGAUUGAAAAAGGGG	0.019	1
GGGGAUUGAAAAUCCCC	0.0047	1
GGGGAUUGAAAGUCCCC	0.0033	1
GGGGAUUGAGAAUCCCC	0.0031	1
GGGGGUUGAAAACCCCC	0.059	1

Catalyzed reactions (Rhea), 1 shown:

• adenosine(37) in tRNA + dimethylallyl diphosphate = N(6)-dimethylallyladenosine(37) in tRNA + diphosphate (RHEA:26482)

UniProt features (33 total): sequence variant 8, region of interest 7, splice variant 6, compositionally biased region 2, site 2, modified residue 2, sequence conflict 2, transit peptide 1, chain 1, binding site 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3H1-F1	85.08	0.61

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 (2): 122 (interaction with substrate trna); 206 (interaction with substrate trna)

Ligand- & substrate-binding residues (1): 32–37

Post-translational modifications (2): 443, 455

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol
R-HSA-6787450	tRNA modification in the mitochondrion
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 181 (showing top): GCANCTGNY_MYOD_Q6, GOBP_TRNA_METABOLIC_PROCESS, CAGCTG_AP4_Q5, CAGCAGG_MIR370, GOBP_RNA_MODIFICATION, chr1p34, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, TGACATY_UNKNOWN, TCCAGAT_MIR5165P, GOBP_TRNA_THREONYLCARBAMOYLADENOSINE_METABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_UP, MODULE_207, AGCTCCT_MIR28, GOBP_TRNA_PROCESSING

GO Biological Process (3): tRNA modification (GO:0006400), mitochondrial tRNA modification (GO:0070900), tRNA processing (GO:0008033)

GO Molecular Function (8): nucleic acid binding (GO:0003676), ATP binding (GO:0005524), zinc ion binding (GO:0008270), tRNA dimethylallyltransferase activity (GO:0052381), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	2
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
binding	2
tRNA processing	1
RNA modification	1
tRNA modification	1
mitochondrial tRNA processing	1
mitochondrial RNA modification	1
RNA processing	1
tRNA metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
catalytic activity, acting on a tRNA	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cation binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2865 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIT1	ANKRD49	Q8WVL7	922
TRIT1	TRMT5	Q32P41	774
TRIT1	GTPBP3	Q969Y2	725
TRIT1	CDK5RAP1	Q96SZ6	717
TRIT1	TRMU	O75648	712
TRIT1	TRMT1	Q9NXH9	707
TRIT1	PUS1	Q9Y606	701
TRIT1	YRDC	Q86U90	693
TRIT1	MTO1	Q9Y2Z2	678
TRIT1	OSGEPL1	Q9H4B0	665
TRIT1	FTSJ1	Q9UET6	648
TRIT1	TRNT1	Q96Q11	621
TRIT1	TRMT10A	Q8TBZ6	615
TRIT1	DUS2	Q9NX74	614
TRIT1	MTFMT	Q96DP5	603

IntAct

8 interactions, top by confidence:

A	B	Type	Score
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
TRIT1	HNRNPCL2	psi-mi:“MI:0915”(physical association)	0.400
TRIT1	FNDC3A	psi-mi:“MI:0915”(physical association)	0.400
SMYD3	TRIT1	psi-mi:“MI:0915”(physical association)	0.370
SSB	RPS3A	psi-mi:“MI:0914”(association)	0.350
FAHD1	VWA8	psi-mi:“MI:0914”(association)	0.350
C8orf30A	TRIT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): TRIT1 (Two-hybrid), TRIT1 (Two-hybrid), TRIT1 (Two-hybrid), FNDC3A (Proximity Label-MS), TRIT1 (Proximity Label-MS), TRIT1 (Reconstituted Complex), TRIT1 (Proximity Label-MS), TRIT1 (Proximity Label-MS), TRIT1 (Affinity Capture-MS), TRIT1 (Affinity Capture-MS), TRIT1 (Negative Genetic), TRIT1 (Affinity Capture-MS), TRIT1 (Proximity Label-MS), TRIT1 (Biochemical Activity), TRIT1 (Co-fractionation)

ESM2 similar proteins: A0A4X1T4U3, A4IFD0, O00329, O14936, O35904, O61069, O65583, O70589, P07953, P16118, P25114, P49872, P70266, Q13057, Q16875, Q16877, Q24210, Q28901, Q298L5, Q2UM43, Q32M07, Q4R3W4, Q4R8B6, Q4V8A1, Q502L7, Q5B5L3, Q5M7G4, Q5R9C1, Q623S8, Q62915, Q68FP8, Q6DGQ8, Q6DTY7, Q6P618, Q80UN9, Q8IMX7, Q8MIR4, Q91309, Q91348, Q91YL3

Diamond homologs: A0AI95, A0Q0M8, A0RH88, A3DDI1, A4IMI5, A4XL45, A5D2K7, A5GEV6, A5I2S0, A5IJP9, A5ISI5, A6LMU4, A6QGK1, A6TR77, A6U1C1, A7FUK8, A7GE43, A7GR71, A7X1U8, A7Z500, A8F1N7, A8F5B3, A8FDI9, A8MFD2, A8YWA5, A8Z1X3, A9VR03, B0K1A4, B0K9L7, B1IM66, B1KSA1, B1YMH0, B2VAE4, B5EGD5, B5YE43, B7GIA2, B7HCI3, B7HKR9, B7IDS3, B7ISQ9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	76
Likely benign	38
Benign	10

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1300160	NM_017646.6(TRIT1):c.568C>T (p.Gln190Ter)	Pathogenic
1327207	NM_017646.6(TRIT1):c.334C>T (p.Arg112Ter)	Pathogenic
2150502	NM_017646.6(TRIT1):c.448C>T (p.Arg150Ter)	Pathogenic
2692355	NM_017646.6(TRIT1):c.1171_1172del (p.Lys391fs)	Pathogenic
2692358	NM_017646.6(TRIT1):c.882del (p.Glu295fs)	Pathogenic
1201174	NM_017646.6(TRIT1):c.1225G>A (p.Glu409Lys)	Likely pathogenic
2585517	NM_017646.6(TRIT1):c.1235-2A>G	Likely pathogenic
2630416	NM_017646.6(TRIT1):c.1018del (p.Ile340fs)	Likely pathogenic
3341369	NM_017646.6(TRIT1):c.1085_1086del (p.Pro362fs)	Likely pathogenic

SpliceAI

2173 predictions. Top by Δscore:

Variant	Effect	Δscore
1:39841910:TGCG:T	acceptor_gain	1.0000
1:39841912:CG:C	acceptor_gain	1.0000
1:39841914:C:CC	acceptor_gain	1.0000
1:39841923:C:CT	acceptor_gain	1.0000
1:39841924:A:T	acceptor_gain	1.0000
1:39841929:C:CT	acceptor_gain	1.0000
1:39841934:C:CT	acceptor_gain	1.0000
1:39844097:CTA:C	donor_loss	1.0000
1:39844103:G:A	donor_gain	1.0000
1:39844214:TGGCC:T	acceptor_gain	1.0000
1:39844215:GGCC:G	acceptor_gain	1.0000
1:39844216:GCC:G	acceptor_gain	1.0000
1:39844217:CC:C	acceptor_gain	1.0000
1:39844217:CCC:C	acceptor_gain	1.0000
1:39844218:CC:C	acceptor_gain	1.0000
1:39844219:C:CC	acceptor_gain	1.0000
1:39844219:C:T	acceptor_gain	1.0000
1:39844219:CTA:C	acceptor_loss	1.0000
1:39844220:T:A	acceptor_loss	1.0000
1:39844526:ATTAC:A	donor_loss	1.0000
1:39844527:TTACC:T	donor_loss	1.0000
1:39844528:TA:T	donor_loss	1.0000
1:39844529:ACCT:A	donor_loss	1.0000
1:39844530:CCT:C	donor_loss	1.0000
1:39844640:CC:C	acceptor_loss	1.0000
1:39844641:C:CG	acceptor_loss	1.0000
1:39847218:A:AC	donor_gain	1.0000
1:39847218:ACTG:A	donor_gain	1.0000
1:39847219:C:CT	donor_gain	1.0000
1:39847219:CT:C	donor_gain	1.0000

AlphaMissense

3077 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:39883333:G:C	S53R	0.999
1:39883333:G:T	S53R	0.999
1:39883335:T:G	S53R	0.999
1:39854019:G:A	T122I	0.998
1:39883337:A:T	V52D	0.998
1:39883385:T:A	K36I	0.998
1:39854031:A:T	V118D	0.997
1:39857298:G:C	F98L	0.997
1:39857298:G:T	F98L	0.997
1:39857300:A:G	F98L	0.997
1:39883327:G:C	D55E	0.997
1:39883327:G:T	D55E	0.997
1:39883328:T:A	D55V	0.997
1:39883331:G:T	A54D	0.997
1:39883394:C:T	G33D	0.997
1:39844146:A:G	C397R	0.996
1:39847231:C:G	R332P	0.996
1:39847251:T:A	Q325H	0.996
1:39847251:T:G	Q325H	0.996
1:39847261:G:T	A322D	0.996
1:39847285:A:G	L314P	0.996
1:39847625:C:T	G284D	0.996
1:39850258:G:C	S188R	0.996
1:39850258:G:T	S188R	0.996
1:39850260:T:G	S188R	0.996
1:39852739:T:A	K184N	0.996
1:39852739:T:G	K184N	0.996
1:39857385:C:A	K69N	0.996
1:39857385:C:G	K69N	0.996
1:39883326:A:G	S56P	0.996

dbSNP variants (sampled 300 via entrez): RS1000048679 (1:39881477 T>C), RS1000093057 (1:39875473 G>C), RS1000129359 (1:39884526 C>G), RS1000204220 (1:39880160 C>A,T), RS1000287360 (1:39841352 T>C), RS1000312114 (1:39865089 C>G), RS1000324503 (1:39847921 C>T), RS1000500817 (1:39863643 A>C), RS1000533677 (1:39838002 A>G), RS1000574115 (1:39841077 C>T), RS1000581966 (1:39851023 T>C), RS1000667892 (1:39846376 A>C), RS1000996492 (1:39855745 GA>G), RS1001035506 (1:39865467 G>A), RS1001042600 (1:39858694 C>A,T)

Disease associations

OMIM: gene MIM:617840 | disease phenotypes: MIM:617873

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 35	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): combined oxidative phosphorylation deficiency 35 (MONDO:0054742), mitochondrial disease (MONDO:0044970)

Orphanet (1): Mitochondrial disease (Orphanet:68380)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0002059	Cerebral atrophy
HP:0002123	Generalized myoclonic seizure
HP:0002353	EEG abnormality
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0003593	Infantile onset
HP:0007766	Optic disc hypoplasia
HP:0008347	Decreased activity of mitochondrial complex IV
HP:0011923	Decreased activity of mitochondrial complex I
HP:0031936	Delayed ability to walk
HP:0200134	Epileptic encephalopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_380	Refractive error	4.000000e-10

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
bufotalin	increases expression	1
bisphenol A	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
monomethylarsonous acid	decreases expression	1
abrine	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Aspirin	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	decreases phosphorylation	1
Doxorubicin	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Sulindac	decreases expression	1
Tretinoin	decreases expression	1
Vitamin E	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TU66	HAP1 TRIT1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies