MTRFR

Summary

MTRFR (mitochondrial translation release factor in rescue, HGNC:26784) is a protein-coding gene on chromosome 12q24.31, encoding Mitochondrial translation release factor in rescue (Q9H3J6). Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation.

This nuclear gene encodes a mitochondrial matrix protein that appears to contribute to peptide chain termination in the mitochondrial translation machinery. Two different 1 bp deletions (resulting in the same premature stop codon)result in decreased mitochondrial translation, decreased levels of oxidative phosphorylation complexes and encepthalomyopathy. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 91574 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 170 total — 18 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 83
• MANE Select transcript: NM_152269

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26784
Approved symbol	MTRFR
Name	mitochondrial translation release factor in rescue
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38663, SPG55, COXPD7, mtRF-R
Ensembl gene	ENSG00000130921
Ensembl biotype	protein_coding
OMIM	613541
Entrez	91574

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 3 nonsense_mediated_decay

ENST00000253233, ENST00000366329, ENST00000425637, ENST00000429587, ENST00000536130, ENST00000538888, ENST00000543139, ENST00000546132, ENST00000679849, ENST00000680325, ENST00000908733, ENST00000908734, ENST00000908735, ENST00000908736, ENST00000908737, ENST00000908738, ENST00000918248, ENST00000918249, ENST00000949450

RefSeq mRNA: 3 — MANE Select: NM_152269 NM_001143905, NM_001194995, NM_152269

CCDS: CCDS9244

Canonical transcript exons

ENST00000253233 — 3 exons

Exon	Start	End
ENSE00000898225	123253647	123253956
ENSE00001226572	123233436	123233531
ENSE00003893003	123256813	123257960

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 98.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1421 / max 839.3946, expressed in 1801 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128569	16.8828	1778
128565	3.3083	786
128567	0.4229	225
128568	0.3616	157
128566	0.1665	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	98.47	gold quality
oocyte	CL:0000023	92.23	gold quality
pancreatic ductal cell	CL:0002079	91.46	gold quality
epithelial cell of pancreas	CL:0000083	90.52	silver quality
ganglionic eminence	UBERON:0004023	89.18	gold quality
cerebellar vermis	UBERON:0004720	88.49	gold quality
adenohypophysis	UBERON:0002196	88.30	gold quality
ventricular zone	UBERON:0003053	87.99	gold quality
pituitary gland	UBERON:0000007	87.74	gold quality
cortical plate	UBERON:0005343	87.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.99	gold quality
vena cava	UBERON:0004087	86.99	silver quality
cardia of stomach	UBERON:0001162	86.85	gold quality
pylorus	UBERON:0001166	86.63	gold quality
lymph node	UBERON:0000029	86.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.47	gold quality
ventral tegmental area	UBERON:0002691	86.15	gold quality
islet of Langerhans	UBERON:0000006	85.98	gold quality
superior surface of tongue	UBERON:0007371	85.71	gold quality
renal medulla	UBERON:0000362	85.60	gold quality
secondary oocyte	CL:0000655	85.50	gold quality
subthalamic nucleus	UBERON:0001906	85.41	gold quality
body of tongue	UBERON:0011876	85.39	silver quality
trachea	UBERON:0003126	85.17	gold quality
dorsal plus ventral thalamus	UBERON:0001897	85.16	gold quality
tongue	UBERON:0001723	85.15	gold quality
pons	UBERON:0000988	85.00	gold quality
cerebellar hemisphere	UBERON:0002245	84.94	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.94	gold quality
pharyngeal mucosa	UBERON:0000355	84.92	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.95
E-GEOD-111727	no	1417.11
E-MTAB-6911	no	272.28
E-MTAB-9801	no	4.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting MTRFR, 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-4795-3P	100.00	74.62	4024
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-7843-3P	98.31	67.94	803
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-127-5P	97.78	67.64	869
HSA-MIR-1278	97.75	67.55	628
HSA-MIR-215-3P	97.02	68.01	1209

Literature-anchored findings (GeneRIF, showing 9)

• C12orf65 might play a role in recycling abortive peptidyl-tRNA species, released from the ribosome during the elongation phase of translation. (PMID:20598281)
• Knockdown of C12orf65 resulted in increased reactive oxidative species production and apoptosis, leading to inhibition of cell proliferation. (PMID:22821833)
• A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy. (PMID:23188110)
• Truncating mutations in C12ORF65 lead to a variable phenotype with intellectual disability, spastic paraplegia, and ophthalmoplegia in 2 patients. (PMID:24080142)
• This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy. (PMID:24198383)
• The C12orf65 gene encodes a mitochondrial matrix protein that is critical for the release of newly synthesized proteins from mitochondrial ribosomes. (PMID:24284555)
• our study delineates the broad spectrum of C12orf65 defects and establishes a distinct genotype-phenotype correlation. The obligatory clinical triad is optic atrophy, peripheral neuropathy, and spastic paraparesis. (PMID:24424123)
• We demonstrate that the identical nonsense mutation in C12orf65 can result in different clinical features (PMID:25995486)
• results showed two compound heterozygous mutations, c.394C>T and c.447_449delGGAinsGT, in the C12orf65 gene. The former mutation came from her father (PMID:31753091)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtrfr	ENSDARG00000097803
mus_musculus	Mtrfr	ENSMUSG00000047635
rattus_norvegicus	Mtrfr	ENSRNOG00000001073
drosophila_melanogaster	CG30100	FBGN0050100

Protein

Protein identifiers

Mitochondrial translation release factor in rescue — Q9H3J6 (reviewed: Q9H3J6)

All UniProt accessions (4): F5GWJ6, F5H4X5, F5H5V8, Q9H3J6

UniProt curated annotations — full annotation on UniProt →

Function. Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation. As heterodimer with MTRES1, ejects the unfinished nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for MTRES1 and MTRF during mitoribosome rescue.

Subunit / interactions. Interacts (via C-terminus) with MTRES1 (via S4 domain). Associates with mitoribosomal S39 large subunit, peptidyl tRNA and nascent chain.

Subcellular location. Mitochondrion.

Tissue specificity. Expressed in all areas of the brain tested.

Post-translational modifications. Methylation of glutamine in the GGQ triplet by HEMK1.

Disease relevance. Combined oxidative phosphorylation deficiency 7 (COXPD7) [MIM:613559] A mitochondrial disease resulting in encephalomyopathy. Clinical manifestations include psychomotor delay and regression, ataxia, optic atrophy, nystagmus and muscle atrophy and weakness. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 55, autosomal recessive (SPG55) [MIM:615035] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The GGQ domain interacts with the peptidyltransferase center (PTC) of the large ribosomal subunit to trigger nascent chain hydrolysis.

Similarity. Belongs to the prokaryotic/mitochondrial release factor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3J6-1	1	yes
Q9H3J6-2	2

RefSeq proteins (3): NP_001137377, NP_001181924, NP_689482* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000352	Pep_chain_release_fac_I	Domain
IPR045853	Pep_chain_release_fac_I_sf	Homologous_superfamily
IPR052405	Mito_Transl_Release_Factor	Family

Pfam: PF00472

UniProt features (15 total): sequence variant 5, region of interest 2, splice variant 2, transit peptide 1, chain 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7A5H	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3J6-F1	83.56	0.58

Functional residue map

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

Post-translational modifications (1): 73

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9937383	Mitochondrial ribosome-associated quality control

MSigDB gene sets: 263 (showing top): TGCGCANK_UNKNOWN, GOBP_MITOCHONDRIAL_TRANSLATION, AAAYRNCTG_UNKNOWN, GOBP_TRANSLATIONAL_TERMINATION, GOBP_TRANSLATION, GOBP_TRANSLATIONAL_ELONGATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, MYB_Q3, FISCHER_DREAM_TARGETS, ACEVEDO_LIVER_CANCER_UP, GOBP_ORGANELLE_DISASSEMBLY, MYB_Q5_01, GOCC_MITOCHONDRIAL_MATRIX, YGCGYRCGC_UNKNOWN, GEORGES_TARGETS_OF_MIR192_AND_MIR215

GO Biological Process (4): mitochondrial translational termination (GO:0070126), rescue of stalled cytosolic ribosome (GO:0072344), translation (GO:0006412), translational termination (GO:0006415)

GO Molecular Function (7): tRNA binding (GO:0000049), translation release factor activity (GO:0003747), peptidyl-tRNA hydrolase activity (GO:0004045), ribosomal large subunit binding (GO:0043023), RNA binding (GO:0003723), protein binding (GO:0005515), translation release factor activity, codon specific (GO:0016149)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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
mitochondrion	2
translational termination	2
mitochondrial translation	1
cytoplasmic translational elongation	1
ribosome disassembly	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
protein-containing complex disassembly	1
RNA binding	1
translation termination factor activity	1
carboxylic ester hydrolase activity	1
catalytic activity, acting on a tRNA	1
ribosome binding	1
nucleic acid binding	1
binding	1
translation release factor activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTRFR	MRPL58	Q14197	966
MTRFR	HOGA1	Q86XE5	826
MTRFR	MTRES1	Q9P0P8	747
MTRFR	MTRF1L	Q9UGC7	722
MTRFR	AP5Z1	O43299	688
MTRFR	CYP2U1	Q7Z449	653
MTRFR	B4GALNT1	Q00973	638
MTRFR	MRRF	Q96E11	590
MTRFR	SPG7	Q9UQ90	585
MTRFR	AFG3L2	Q9Y4W6	581
MTRFR	AP4B1	Q9Y6B7	579
MTRFR	SPG21	Q9NZD8	571
MTRFR	REEP2	Q9BRK0	570
MTRFR	GFM2	Q969S9	568
MTRFR	TECPR2	O15040	563

IntAct

6 interactions, top by confidence:

A	B	Type	Score
MTRFR	MYLK2	psi-mi:“MI:0915”(physical association)	0.590
CDK2	MTRFR	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
MTRFR	LPL	psi-mi:“MI:0914”(association)	0.350

BioGRID (231): MYLK2 (Affinity Capture-MS), MYLK2 (Affinity Capture-MS), C12orf65 (Affinity Capture-RNA), C12orf65 (Affinity Capture-MS), AARS2 (Proximity Label-MS), ABCB7 (Proximity Label-MS), ACADM (Proximity Label-MS), ACAT1 (Proximity Label-MS), ACOT1 (Proximity Label-MS), ACOT2 (Proximity Label-MS), AFG3L2 (Proximity Label-MS), AK4 (Proximity Label-MS), ALAS1 (Proximity Label-MS), ALDH2 (Proximity Label-MS), ALYREF (Proximity Label-MS)

ESM2 similar proteins: A4IHS0, A5WUX7, A6ZND9, B1P1W2, B3LIY9, B4KPG8, B5XAM2, D2HD32, E7EXT2, O44568, O94443, P25642, P34511, P82673, Q05863, Q08230, Q08DT6, Q08DU1, Q09691, Q12322, Q14197, Q2KI45, Q3T116, Q3UFY8, Q497V5, Q498P2, Q5RDI0, Q5U2R4, Q60R52, Q7JUX9, Q80VP5, Q8C1Z8, Q8K2Y7, Q8MT06, Q8N5C6, Q8R035, Q8VCE1, Q95Q11, Q9BRU9, Q9BVP2

Diamond homologs: A0KMZ8, A0LVP4, A0QU58, A1SHH9, A1U367, A1UDD2, A3PWV0, A4F8R2, A4ITK8, A4QCD3, A4SK64, A4XJN1, A5IM04, A5VYG5, A5WUX7, A6VC61, A6W1C2, A6WEK6, A7GV79, A8FID1, A8FYZ0, A8M3R1, A9G9L1, A9M1Q8, A9VSC7, A9W1A4, B0KNE4, B1JEP6, B1LB88, B1VV08, B2UL99, B2V5M0, B3PJP4, B3QRH7, B3QYI4, B3WDK7, B4RN52, B4S385, B5YDB2, B7L246

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	6
Uncertain significance	84
Likely benign	40
Benign	8

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
144068	NM_152269.5(MTRFR):c.413_417del (p.Lys138fs)	Pathogenic
144069	NM_152269.5(MTRFR):c.282+2T>A	Pathogenic
1681663	NM_152269.5(MTRFR):c.409A>T (p.Lys137Ter)	Pathogenic
1878304	NM_152269.5(MTRFR):c.207_220del (p.Pro70fs)	Pathogenic
214192	NM_152269.5(MTRFR):c.96_99dup (p.Pro34fs)	Pathogenic
2427351	NC_000012.11:g.(?123741340)(123741578_?)del	Pathogenic
2921346	NM_152269.5(MTRFR):c.193_194insCGAAAGCAGTTTG (p.Val65fs)	Pathogenic
2952530	NM_152269.5(MTRFR):c.135_142dup (p.Asp48fs)	Pathogenic
3244330	NC_000012.11:g.(?123738222)(123738523_?)del	Pathogenic
3340697	NM_152269.5(MTRFR):c.259del (p.Ile87fs)	Pathogenic
39582	NM_152269.5(MTRFR):c.394C>T (p.Arg132Ter)	Pathogenic
635867	NM_152269.5(MTRFR):c.-28-1489_283-968del	Pathogenic
813299	GRCh37/hg19 12q24.31(chr12:123738222-123738503)	Pathogenic
834522	NM_152269.5(MTRFR):c.307del (p.Gln103fs)	Pathogenic
859045	NM_152269.5(MTRFR):c.33dup (p.Pro12fs)	Pathogenic
91408	NM_152269.5(MTRFR):c.346del (p.Lys115_Val116insTer)	Pathogenic
915979	GRCh37/hg19 12q24.31(chr12:123738221-123738503)	Pathogenic
983270	NM_152269.5(MTRFR):c.127_146del (p.Met43fs)	Pathogenic
1048600	NM_152269.5(MTRFR):c.18_21del (p.Leu6fs)	Likely pathogenic
2633282	NM_152269.5(MTRFR):c.385_404dup (p.Lys138fs)	Likely pathogenic
2690555	NM_152269.5(MTRFR):c.283-1G>T	Likely pathogenic
418100	NM_152269.5(MTRFR):c.283T>C (p.Cys95Arg)	Likely pathogenic
444311	NM_152269.5(MTRFR):c.427_442dup (p.Thr148fs)	Likely pathogenic
88864	NM_152269.5(MTRFR):c.415C>T (p.Gln139Ter)	Likely pathogenic

SpliceAI

967 predictions. Top by Δscore:

Variant	Effect	Δscore
12:123233069:GCTTA:G	donor_loss	1.0000
12:123233072:TACC:T	donor_loss	1.0000
12:123233073:ACCTG:A	donor_loss	1.0000
12:123248410:T:G	acceptor_gain	1.0000
12:123248414:A:AG	acceptor_gain	1.0000
12:123248415:A:G	acceptor_gain	1.0000
12:123256811:A:AG	acceptor_gain	1.0000
12:123256812:G:GA	acceptor_gain	1.0000
12:123256812:GT:G	acceptor_gain	1.0000
12:123256812:GTGCC:G	acceptor_gain	1.0000
12:123233073:A:AC	donor_gain	0.9900
12:123233074:C:CC	donor_gain	0.9900
12:123233074:CCTGG:C	donor_gain	0.9900
12:123248409:A:AG	acceptor_gain	0.9900
12:123253922:TGCTG:T	donor_gain	0.9900
12:123256808:TACA:T	acceptor_loss	0.9900
12:123256810:CA:C	acceptor_loss	0.9900
12:123256811:AGT:A	acceptor_gain	0.9900
12:123256811:AGTGC:A	acceptor_loss	0.9900
12:123256812:G:A	acceptor_loss	0.9900
12:123256812:GTG:G	acceptor_gain	0.9900
12:123256812:GTGC:G	acceptor_gain	0.9900
12:123233277:G:T	donor_gain	0.9800
12:123234354:C:G	donor_gain	0.9800
12:123248416:C:G	acceptor_gain	0.9800
12:123248423:C:A	acceptor_gain	0.9800
12:123253944:C:T	donor_gain	0.9800
12:123253954:AAG:A	donor_gain	0.9800
12:123233277:G:GT	donor_gain	0.9700
12:123234354:C:CG	donor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000022321 (12:123257123 T>C), RS1000253430 (12:123251695 C>T), RS1000312353 (12:123243536 A>G,T), RS1000452532 (12:123234230 G>A,C), RS1000461269 (12:123239983 G>C), RS1000516193 (12:123240267 G>C), RS1000669121 (12:123233349 C>A), RS1000886679 (12:123234642 C>T), RS1000957247 (12:123251262 C>G,T), RS1000981229 (12:123239653 T>C), RS1001031342 (12:123246357 T>A), RS1001068606 (12:123251393 T>C), RS1001135782 (12:123242789 C>G,T), RS1001167629 (12:123232470 C>T), RS1001186772 (12:123243201 A>G)

Disease associations

OMIM: gene MIM:613541 | disease phenotypes: MIM:613559, MIM:303350, MIM:615035

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 7	Definitive	Autosomal recessive
Leigh syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Definitive	AR

Mondo (7): hereditary motor and sensory neuropathy type 6 (MONDO:0019551), combined oxidative phosphorylation defect type 7 (MONDO:0013306), hereditary spastic paraplegia (MONDO:0019064), hereditary spastic paraplegia 55 (MONDO:0014020), optic atrophy (MONDO:0003608), neurodevelopmental disorder (MONDO:0700092), Leigh syndrome (MONDO:0009723)

Orphanet (4): Hereditary motor and sensory neuropathy type 6 (Orphanet:90120), Combined oxidative phosphorylation defect type 7 (Orphanet:254930), Hereditary spastic paraplegia (Orphanet:685), Autosomal recessive spastic paraplegia type 55 (Orphanet:320375)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001123	Visual field defect
HP:0001138	Optic neuropathy
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001271	Polyneuropathy
HP:0001283	Bulbar palsy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001349	Facial diplegia
HP:0001508	Failure to thrive
HP:0001761	Pes cavus
HP:0001762	Talipes equinovarus
HP:0001999	Abnormal facial shape

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST002149_20	Schizophrenia	2.000000e-08
GCST002539_19	Schizophrenia	2.000000e-14
GCST002598_15	Educational attainment	7.000000e-08
GCST002935_10	Lead levels	2.000000e-06
GCST004521_72	Autism spectrum disorder or schizophrenia	8.000000e-12
GCST005038_81	Allergic disease (asthma, hay fever or eczema)	3.000000e-13
GCST006409_30	Allergic rhinitis	3.000000e-24
GCST006803_10	Schizophrenia	6.000000e-16
GCST007277_17	Tourette syndrome	2.000000e-06
GCST010703_43	Brain morphology (MOSTest)	1.000000e-08
GCST012227_569	Hip circumference adjusted for BMI	7.000000e-10
GCST90020024_438	A body shape index	6.000000e-11
GCST90020024_440	A body shape index	7.000000e-17
GCST90020024_445	A body shape index	2.000000e-10
GCST90020025_405	Waist-to-hip ratio adjusted for BMI	3.000000e-11
GCST90020025_407	Waist-to-hip ratio adjusted for BMI	8.000000e-27
GCST90020025_416	Waist-to-hip ratio adjusted for BMI	1.000000e-16
GCST90020027_1216	Waist-hip index	6.000000e-16
GCST90020027_1257	Waist-hip index	6.000000e-12
GCST90020027_1259	Waist-hip index	6.000000e-25
GCST90020028_1116	Hip circumference adjusted for BMI	1.000000e-13
GCST90020028_1259	Hip circumference adjusted for BMI	4.000000e-10
GCST90020028_1263	Hip circumference adjusted for BMI	1.000000e-23

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004784	self reported educational attainment
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (4)

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
D065886	Neurodevelopmental Disorders	F03.625
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
Acetaminophen	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
methylmercuric chloride	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ferrous chloride	decreases expression	1
Leflunomide	decreases expression	1
Atrazine	decreases expression	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ribonucleotides	affects binding	1
Smoke	decreases expression	1
Urethane	increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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)
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)