MTFMT

Summary

MTFMT (mitochondrial methionyl-tRNA formyltransferase, HGNC:29666) is a protein-coding gene on chromosome 15q22.31, encoding Methionyl-tRNA formyltransferase, mitochondrial (Q96DP5). Methionyl-tRNA formyltransferase that formylates methionyl-tRNA in mitochondria and is crucial for translation initiation.

The protein encoded by this nuclear gene localizes to the mitochondrion, where it catalyzes the formylation of methionyl-tRNA.

Source: NCBI Gene 123263 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 297 total — 19 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 41
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_139242

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29666
Approved symbol	MTFMT
Name	mitochondrial methionyl-tRNA formyltransferase
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	FMT1
Ensembl gene	ENSG00000103707
Ensembl biotype	protein_coding
OMIM	611766
Entrez	123263

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000220058, ENST00000543678, ENST00000558460, ENST00000558614, ENST00000559633, ENST00000560717, ENST00000561025, ENST00000901059, ENST00000901060, ENST00000901061, ENST00000901062, ENST00000901063, ENST00000901064, ENST00000901065, ENST00000901066, ENST00000901067, ENST00000917318, ENST00000965373, ENST00000965374

RefSeq mRNA: 1 — MANE Select: NM_139242 NM_139242

CCDS: CCDS45280

Canonical transcript exons

ENST00000220058 — 9 exons

Exon	Start	End
ENSE00001201060	65029405	65029639
ENSE00001201066	65001512	65003256
ENSE00003483841	65004854	65004936
ENSE00003522222	65023672	65023794
ENSE00003533757	65026831	65027040
ENSE00003556275	65016436	65016527
ENSE00003613470	65021514	65021616
ENSE00003633553	65006113	65006191
ENSE00003651434	65020197	65020272

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 90.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.8232 / max 59.4992, expressed in 1786 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150516	8.0739	1772
150515	2.7492	1508

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	90.52	gold quality
buccal mucosa cell	CL:0002336	87.02	gold quality
cardiac muscle of right atrium	UBERON:0003379	84.91	gold quality
heart left ventricle	UBERON:0002084	84.56	gold quality
myocardium	UBERON:0002349	84.55	gold quality
gastrocnemius	UBERON:0001388	84.49	gold quality
cardiac ventricle	UBERON:0002082	84.06	gold quality
muscle of leg	UBERON:0001383	84.05	gold quality
mucosa of transverse colon	UBERON:0004991	83.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.78	gold quality
tibial artery	UBERON:0007610	83.20	gold quality
popliteal artery	UBERON:0002250	83.19	gold quality
right atrium auricular region	UBERON:0006631	82.84	gold quality
heart	UBERON:0000948	82.63	gold quality
skeletal muscle organ	UBERON:0014892	82.39	gold quality
stromal cell of endometrium	CL:0002255	82.37	gold quality
cardiac atrium	UBERON:0002081	82.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.30	gold quality
lower esophagus	UBERON:0013473	82.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.05	gold quality
left uterine tube	UBERON:0001303	81.91	gold quality
apex of heart	UBERON:0002098	81.85	gold quality
aorta	UBERON:0000947	81.83	gold quality
body of uterus	UBERON:0009853	81.80	gold quality
right ovary	UBERON:0002118	81.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.55	gold quality
mucosa of stomach	UBERON:0001199	81.45	gold quality
left ovary	UBERON:0002119	81.35	gold quality
rectum	UBERON:0001052	81.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

107 targeting MTFMT, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4495	99.82	72.08	3080

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 6)

• Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. (PMID:21907147)
• We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases (PMID:24461907)
• Data indicate that methionyl-tRNA formyltransferase (MTF) mutation initiated poor formylation of mitochondrial methionyl-tRNA and thereby reduced mitochondrial translation efficiency, causing Leigh syndrome. (PMID:25288793)
• Recessive mutations in MTFMT underlie defects of the mitochondrial respiratory chain, leading to multi-system disease that includes Leigh syndrome. This paper reports on the biochemical activity of such mutant alleles. (PMID:25288793)
• First report of childhood progressive cerebellar atrophy due to compound heterozygous MTFMT variants. (PMID:32133637)
• MTFMT deficiency correlates with reduced mitochondrial integrity and enhanced host susceptibility to intracellular infection. (PMID:32636430)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtfmt	ENSDARG00000005448
mus_musculus	Mtfmt	ENSMUSG00000059183
rattus_norvegicus	Mtfmt	ENSRNOG00000014602
drosophila_melanogaster	CG1750	FBGN0039836

Protein

Protein identifiers

Methionyl-tRNA formyltransferase, mitochondrial — Q96DP5 (reviewed: Q96DP5)

All UniProt accessions (2): Q96DP5, H3BTN9

UniProt curated annotations — full annotation on UniProt →

Function. Methionyl-tRNA formyltransferase that formylates methionyl-tRNA in mitochondria and is crucial for translation initiation.

Subcellular location. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 15 (COXPD15) [MIM:614947] An autosomal recessive, mitochondrial, neurologic disorder characterized by features of Leigh syndrome and combined oxidative phosphorylation deficiency. Clinical features include mild global developmental delay, white matter abnormalities, ataxia, incoordination, speech and reading difficulties, T2-weighted hyperintensities in the basal ganglia, corpus callosum, and brainstem. The disease is caused by variants affecting the gene represented in this entry. Mitochondrial complex I deficiency, nuclear type 27 (MC1DN27) [MIM:618248] A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN27 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of an N- and a C-terminal domain. The N-terminal domain carries the tetrahydrofolate (THF)-binding site and the C-terminal domain is presumably involved in positioning the Met-tRNA substrate for the formylation reaction.

Similarity. Belongs to the Fmt family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96DP5-1	1	yes
Q96DP5-2	2

RefSeq proteins (1): NP_640335* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002376	Formyl_transf_N	Domain
IPR005793	Formyl_trans_C	Domain
IPR005794	Fmt	Family
IPR011034	Formyl_transferase-like_C_sf	Homologous_superfamily
IPR036477	Formyl_transf_N_sf	Homologous_superfamily
IPR041711	Met-tRNA-FMT_N	Domain

Pfam: PF00551, PF02911

Enzyme classification (BRENDA):

• EC 2.1.2.9 — methionyl-tRNA formyltransferase (BRENDA: 15 organisms, 101 substrates, 17 inhibitors, 49 Km, 29 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-METHIONYL-TRNAFMET	0.0003–0.0096	21
E. COLI L-METHIONYL-TRNAFMET	0.0001–0.0005	3
10-FORMYLTETRAHYDROFOLATE	0.0133–0.0135	2
E. COLI L-METHIONYL-TRNAMMET	0.0001–0.01	2
E. COLI L-VALYL-TRNAFMET	0.0005–0.0014	2
TRNAFMET	0.0001–0.0012	2
BOVINE MITOCHONDRIAL L-METHIONYL-TRNA	—	1
E. COLI L-ISOLEUCYL-TRNAFMET	0.0003	1
E. COLI L-METHIONYL-TRNA1VAL(CAU)	0.01	1
E.COLI L-METHIONYL-TRNAFMET	0.0011	1
L-METHIONYL-TRNAMET	0.01	1
PHENYLALANYL-TRNAFMET	0.0013	1
VALYL-TRNAFMET	0.0014	1
L-ISOLEUCYL-TRNAFMET	—	0
L-VALYL-TRNAFMET	—	0

Catalyzed reactions (Rhea), 1 shown:

• L-methionyl-tRNA(fMet) + (6R)-10-formyltetrahydrofolate = N-formyl-L-methionyl-tRNA(fMet) + (6S)-5,6,7,8-tetrahydrofolate + H(+) (RHEA:24380)

UniProt features (8 total): sequence variant 4, splice variant 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DP5-F1	86.08	0.77

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5368286	Mitochondrial translation initiation

MSigDB gene sets: 219 (showing top): TGCGCANK_UNKNOWN, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_TRANSLATIONAL_INITIATION, GOBP_TRANSLATION, KEGG_ONE_CARBON_POOL_BY_FOLATE, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_RNA_MODIFICATION, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, GOBP_TRNA_PROCESSING, KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_DN, GOBP_TRNA_MODIFICATION, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_DN, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_ONE_CARBON_GROUPS

GO Biological Process (4): conversion of methionyl-tRNA to N-formyl-methionyl-tRNA (GO:0071951), translation (GO:0006412), translational initiation (GO:0006413), biosynthetic process (GO:0009058)

GO Molecular Function (3): methionyl-tRNA formyltransferase activity (GO:0004479), catalytic activity (GO:0003824), transferase activity (GO:0016740)

GO Cellular Component (1): mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial translation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	2
metabolic process	2
charged-tRNA amino acid modification	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
formation of translation initiation ternary complex	1
translation	1
hydroxymethyl-, formyl- and related transferase activity	1
conversion of methionyl-tRNA to N-formyl-methionyl-tRNA	1
catalytic activity, acting on a tRNA	1
molecular_function	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTFMT	TUFM	P49411	907
MTFMT	PDF	Q9HBH1	806
MTFMT	VARS2	Q5ST30	747
MTFMT	VARS1	P26640	733
MTFMT	EIF5B	O60841	706
MTFMT	WARS2	Q9UGM6	706
MTFMT	WARS1	P23381	672
MTFMT	MTO1	Q9Y2Z2	666
MTFMT	MTIF2	P46199	665
MTFMT	MARS2	Q96GW9	657
MTFMT	TRMU	O75648	646
MTFMT	RARS2	Q5T160	643
MTFMT	MARS1	P56192	640
MTFMT	SHMT2	P34897	625
MTFMT	PUS1	Q9Y606	624

IntAct

13 interactions, top by confidence:

A	B	Type	Score
TRUB1	CAPG	psi-mi:“MI:0914”(association)	0.500
TRUB1	USP11	psi-mi:“MI:0914”(association)	0.350
PPM1K	PMPCB	psi-mi:“MI:0914”(association)	0.350
GATD3	NME1	psi-mi:“MI:0914”(association)	0.350
GATD3	NDUFS2	psi-mi:“MI:0914”(association)	0.350
MIX23	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
PRSS35	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
RAMP2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
MTFMT	UNC45B	psi-mi:“MI:0914”(association)	0.350
YARS2	VWA8	psi-mi:“MI:0914”(association)	0.350
	EIF3F	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): MTFMT (Reconstituted Complex), MTFMT (Synthetic Lethality), MTFMT (Affinity Capture-MS), MTFMT (Affinity Capture-MS), MTFMT (Affinity Capture-MS), MTFMT (Affinity Capture-MS), MTFMT (Affinity Capture-MS), ACOT1 (Proximity Label-MS), ACOT2 (Proximity Label-MS), AFG3L2 (Proximity Label-MS), BCS1L (Proximity Label-MS), C17orf80 (Proximity Label-MS), DAP3 (Proximity Label-MS), DLST (Proximity Label-MS), ELAC2 (Proximity Label-MS)

ESM2 similar proteins: A0JPF9, A4D126, A4IHY0, A4QNL8, A6QPR9, B2GUS6, C0LT23, E1BCH6, E1BVR9, E9PYK3, O77480, Q32PY6, Q3U3W5, Q49MI3, Q4KM51, Q4R3W5, Q56YN3, Q5E9H9, Q5E9N9, Q5I0C5, Q5I0K5, Q5ND52, Q5R4D2, Q5R5S1, Q5REX5, Q5RJG7, Q5S6T3, Q5SSK3, Q5T8I9, Q66KI9, Q68G58, Q6DC53, Q6GPJ4, Q6P2P2, Q6PE15, Q7T0X7, Q8BTK5, Q8BZ20, Q8CAE2, Q8L5Z4

Diamond homologs: A0L3X7, A0LUE0, A1AZR0, A1KIJ5, A1KRE6, A1VU45, A1WD32, A1WZH3, A2SCF7, A3DCX5, A3N2N5, A3PMS1, A4G1G8, A4WNU8, A4XL81, A5FVK3, A5IAY3, A5U2A8, A5V070, A5VDM0, A6SU87, A6WYK8, A7NNY4, A9AC69, A9BS67, A9IFQ1, A9M463, A9WAR0, B0BRR3, B0UP41, B0UWZ4, B1XW99, B1YPX6, B2FIR3, B2SL54, B2U795, B3CLK1, B3EAP0, B3GYS0, B4RPX5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	9
Uncertain significance	109
Likely benign	79
Benign	38

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
120309	NM_139242.4(MTFMT):c.452C>T (p.Pro151Leu)	Pathogenic
1323298	NM_139242.4(MTFMT):c.27G>A (p.Trp9Ter)	Pathogenic
1323299	NM_139242.4(MTFMT):c.694C>T (p.Gln232Ter)	Pathogenic
1323300	NM_139242.4(MTFMT):c.13_23dup (p.Cys8fs)	Pathogenic
133324	NM_139242.4(MTFMT):c.878G>A (p.Ser293Asn)	Pathogenic
133325	NM_139242.4(MTFMT):c.73C>T (p.Gln25Ter)	Pathogenic
1365559	NM_139242.4(MTFMT):c.834G>A (p.Trp278Ter)	Pathogenic
1402449	NM_139242.4(MTFMT):c.690_693del (p.Arg231fs)	Pathogenic
1460392	NM_139242.4(MTFMT):c.144G>A (p.Trp48Ter)	Pathogenic
1968577	NM_139242.4(MTFMT):c.910C>T (p.Gln304Ter)	Pathogenic
1972453	NM_139242.4(MTFMT):c.719dup (p.Tyr240Ter)	Pathogenic
2014351	NM_139242.4(MTFMT):c.632_633del (p.Leu211fs)	Pathogenic
2132320	NM_139242.4(MTFMT):c.38_49delinsC (p.Leu13fs)	Pathogenic
2570906	NM_139242.4(MTFMT):c.834_835delinsAT (p.Trp278_Met279delinsTer)	Pathogenic
2987175	NM_139242.4(MTFMT):c.881C>G (p.Ser294Ter)	Pathogenic
39827	NM_139242.4(MTFMT):c.626C>T (p.Ser209Leu)	Pathogenic
39830	NM_139242.4(MTFMT):c.994C>T (p.Arg332Ter)	Pathogenic
435899	NM_139242.4(MTFMT):c.219_222del (p.Glu74fs)	Pathogenic
488549	NM_139242.4(MTFMT):c.91C>T (p.Arg31Ter)	Pathogenic
1334390	NM_139242.4(MTFMT):c.459G>A (p.Trp153Ter)	Likely pathogenic
1711383	NM_139242.4(MTFMT):c.419+2T>C	Likely pathogenic
216965	NM_139242.4(MTFMT):c.1116del (p.Pro373fs)	Likely pathogenic
2429485	NM_139242.4(MTFMT):c.722-2A>G	Likely pathogenic
3767214	NM_139242.4(MTFMT):c.1022del (p.Thr341fs)	Likely pathogenic
418335	NM_139242.4(MTFMT):c.353A>G (p.Tyr118Cys)	Likely pathogenic
4277422	NM_139242.4(MTFMT):c.419+1G>C	Likely pathogenic
4277423	NM_139242.4(MTFMT):c.310C>T (p.Gln104Ter)	Likely pathogenic
4849459	NM_139242.4(MTFMT):c.209+2_209+14del	Likely pathogenic

SpliceAI

1388 predictions. Top by Δscore:

Variant	Effect	Δscore
15:65003252:CCATC:C	acceptor_gain	1.0000
15:65003253:CATC:C	acceptor_gain	1.0000
15:65003253:CATCC:C	acceptor_gain	1.0000
15:65003254:ATCC:A	acceptor_loss	1.0000
15:65003257:C:A	acceptor_loss	1.0000
15:65003258:T:C	acceptor_loss	1.0000
15:65006055:ATTT:A	donor_gain	1.0000
15:65006126:A:C	donor_gain	1.0000
15:65006133:A:C	donor_gain	1.0000
15:65016434:A:AC	donor_gain	1.0000
15:65016435:C:CC	donor_gain	1.0000
15:65020195:A:AC	donor_gain	1.0000
15:65020196:C:CC	donor_gain	1.0000
15:65020269:TGAG:T	acceptor_gain	1.0000
15:65020273:C:CC	acceptor_gain	1.0000
15:65026829:A:AC	donor_gain	1.0000
15:65026830:C:CC	donor_gain	1.0000
15:65026848:AAGAG:A	donor_gain	1.0000
15:65026888:C:CA	donor_gain	1.0000
15:65026888:CCA:C	donor_gain	1.0000
15:65027036:TTTCC:T	acceptor_gain	1.0000
15:65027037:TTCC:T	acceptor_gain	1.0000
15:65027038:TCC:T	acceptor_gain	1.0000
15:65027038:TCCC:T	acceptor_loss	1.0000
15:65027039:CC:C	acceptor_gain	1.0000
15:65027039:CCC:C	acceptor_gain	1.0000
15:65027039:CCCT:C	acceptor_loss	1.0000
15:65027040:CC:C	acceptor_gain	1.0000
15:65027040:CCTAA:C	acceptor_loss	1.0000
15:65027041:C:CC	acceptor_gain	1.0000

AlphaMissense

2500 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:65023770:A:C	S148R	0.996
15:65023770:A:T	S148R	0.996
15:65023772:T:G	S148R	0.996
15:65023778:G:C	H146D	0.996
15:65016492:A:G	W253R	0.995
15:65016492:A:T	W253R	0.995
15:65026872:A:C	F126L	0.994
15:65026872:A:T	F126L	0.994
15:65026874:A:G	F126L	0.994
15:65023753:C:G	R154P	0.990
15:65026891:A:T	V120D	0.990
15:65026922:A:G	W110R	0.990
15:65026922:A:T	W110R	0.990
15:65026999:A:T	V84D	0.990
15:65029453:C:T	G54D	0.990
15:65021610:A:C	D183E	0.989
15:65021610:A:T	D183E	0.989
15:65023757:A:G	W153R	0.989
15:65023757:A:T	W153R	0.989
15:65016490:C:A	W253C	0.988
15:65016490:C:G	W253C	0.988
15:65023776:A:C	H146Q	0.988
15:65023776:A:T	H146Q	0.988
15:65021613:A:C	F182L	0.987
15:65021613:A:T	F182L	0.987
15:65021615:A:G	F182L	0.987
15:65023696:G:T	T173K	0.987
15:65026888:C:T	G121E	0.987
15:65021611:T:A	D183V	0.985
15:65016527:G:T	A241D	0.983

dbSNP variants (sampled 300 via entrez): RS1000106383 (15:65027454 C>T), RS1000338630 (15:65024846 G>T), RS1000526101 (15:65005284 C>T), RS1000583692 (15:65019436 C>G,T), RS1000695666 (15:65017800 AAAAG>A), RS1000807013 (15:65009656 T>TTG), RS1000814905 (15:65030304 G>C), RS1000998726 (15:65011482 T>C,G), RS1001109055 (15:65013621 T>C), RS1001284957 (15:65022609 C>T), RS1001335440 (15:65025982 T>C), RS1001372999 (15:65007281 G>C), RS1001743972 (15:65002895 G>A), RS1001980807 (15:65006408 CGTT>C), RS1001996864 (15:65015372 A>G)

Disease associations

OMIM: gene MIM:611766 | disease phenotypes: MIM:614947, MIM:618248, MIM:256000, MIM:619947

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 15	Definitive	Autosomal recessive
Leigh syndrome with leukodystrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR

Mondo (7): combined oxidative phosphorylation defect type 15 (MONDO:0013987), mitochondrial complex I deficiency, nuclear type 27 (MONDO:0032631), Leigh syndrome (MONDO:0009723), Waardenburg syndrome 2F (MONDO:0030983), mitochondrial oxidative phosphorylation disorder (MONDO:0016387), microcephaly (MONDO:0001149), (MONDO:0016815)

Orphanet (3): Combined oxidative phosphorylation defect type 15 (Orphanet:319524), Leigh syndrome (Orphanet:506), Mitochondrial oxidative phosphorylation disorder (Orphanet:223713)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000023	Inguinal hernia
HP:0000252	Microcephaly
HP:0000486	Strabismus
HP:0000511	Vertical supranuclear gaze palsy
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000822	Hypertension
HP:0000954	Single transverse palmar crease
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001337	Tremor
HP:0001513	Obesity
HP:0001629	Ventricular septal defect
HP:0001716	Wolff-Parkinson-White syndrome
HP:0002151	Increased circulating lactate concentration
HP:0002311	Incoordination
HP:0002317	Unsteady gait
HP:0002344	Progressive neurologic deterioration
HP:0002490	Increased CSF lactate
HP:0002500	Abnormal cerebral white matter morphology
HP:0002510	Spastic tetraplegia
HP:0003593	Infantile onset
HP:0004322	Short stature

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010101_13	White matter hyperintensities	6.000000e-09
GCST010726_62	Periventricular white matter hyperintensities	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	2
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
NSC 689534	affects binding, decreases expression	1
Atrazine	decreases expression	1
Copper	affects binding, decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tunicamycin	decreases expression	1
Urethane	decreases expression	1
Josamycin	decreases response to substance	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Thapsigargin	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.