COX10

Summary

COX10 (cytochrome c oxidase assembly factor heme A:farnesyltransferase COX10, HGNC:2260) is a protein-coding gene on chromosome 17p12, encoding Protoheme IX farnesyltransferase, mitochondrial (Q12887). Converts protoheme IX and farnesyl diphosphate to heme O. It is a selective cancer dependency (DepMap: 36.9% of cell lines).

Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes heme A:farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion.

Source: NCBI Gene 1352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 369 total — 6 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 62
• Cancer dependency (DepMap): dependent in 36.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001303

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2260
Approved symbol	COX10
Name	cytochrome c oxidase assembly factor heme A:farnesyltransferase COX10
Location	17p12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000006695
Ensembl biotype	protein_coding
OMIM	602125
Entrez	1352

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000261643, ENST00000429152, ENST00000458492, ENST00000580561, ENST00000581931, ENST00000664217, ENST00000670279, ENST00000886733, ENST00000886734, ENST00000886735

RefSeq mRNA: 1 — MANE Select: NM_001303 NM_001303

CCDS: CCDS11166

Canonical transcript exons

ENST00000261643 — 7 exons

Exon	Start	End
ENSE00001127086	14206810	14208677
ENSE00001127094	14069504	14069648
ENSE00003463890	14076735	14077056
ENSE00003506594	14159877	14159947
ENSE00003622720	14102118	14102242
ENSE00003655960	14191989	14192221
ENSE00003685620	14074323	14074456

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 94.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.7115 / max 36.4571, expressed in 1729 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159637	5.7115	1729

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	94.67	gold quality
diaphragm	UBERON:0001103	92.93	silver quality
left ventricle myocardium	UBERON:0006566	92.91	gold quality
deltoid	UBERON:0001476	92.03	gold quality
gastrocnemius	UBERON:0001388	91.95	gold quality
triceps brachii	UBERON:0001509	91.61	gold quality
muscle of leg	UBERON:0001383	91.55	gold quality
vastus lateralis	UBERON:0001379	91.47	gold quality
muscle organ	UBERON:0001630	91.39	gold quality
skeletal muscle organ	UBERON:0014892	91.39	gold quality
skeletal muscle tissue	UBERON:0001134	91.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.04	gold quality
quadriceps femoris	UBERON:0001377	90.87	gold quality
secondary oocyte	CL:0000655	90.84	gold quality
biceps brachii	UBERON:0001507	90.37	gold quality
muscle tissue	UBERON:0002385	90.21	gold quality
heart left ventricle	UBERON:0002084	90.14	gold quality
cardiac ventricle	UBERON:0002082	89.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.90	gold quality
sperm	CL:0000019	89.66	silver quality
gluteal muscle	UBERON:0002000	89.41	gold quality
cardiac muscle of right atrium	UBERON:0003379	88.81	gold quality
myocardium	UBERON:0002349	88.79	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.29	gold quality
apex of heart	UBERON:0002098	88.12	gold quality
male germ cell	CL:0000015	87.95	silver quality
ileal mucosa	UBERON:0000331	87.14	gold quality
heart right ventricle	UBERON:0002080	87.04	gold quality
heart	UBERON:0000948	86.95	gold quality
tongue squamous epithelium	UBERON:0006919	86.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting COX10, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-302E	99.96	70.74	2669
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-204-5P	99.79	71.62	2439

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 36.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• Cytochrome c oxidase is decreased significantly in platelets and hippocampus in Alzheimer patients compared to controls. (PMID:11959398)
• COX10 has a role in mitochondrial heme A biosynthesis (PMID:12928484)
• This study report a cytochrome c oxidase (COX)-deficient patient, clinically affected with Leigh-like disease, with a homozygous mutation in the COX10 start codon. (PMID:15455402)
• Geranylgeranyltransferase inhibitor-2147 (GGTI-2147), an inhibitor of this enzyme prenylation, elicited significant inhibition of glucose-stimulated insulin secretion from INS 832/13 islet cells. (PMID:17192483)
• COX 15 mRNA was significantly more abundant in the cerebral tissue of Alzheimer’s disease (AD) patients and COX10 and COX15 SNP were significantly less represented in the patient group, suggesting a possible protective role toward the risk for AD (PMID:19826901)
• The expression of the AOX, well-tolerated by the cells, compensates for both the growth defect and the pronounced oxidant-sensitivity of COX-deficient human cells. (PMID:20049701)
• ISCU and COX10 are target genes of miR-210 related to mitochondrial metabolism (PMID:20498629)
• On the basis of its pivotal role in regulating cell death upon COX dysfunction, CerS6 might potentially represent a novel target for therapeutic intervention in mitochondrial diseases caused by COX dysfunction. (PMID:25766330)
• A Novel COX10 Deletion Polymorphism as a Susceptibility Factor for Sudden Cardiac Death Risk in Chinese Populations. (PMID:33180568)
• Phenotypic assessment of Cox10 variants and their implications for Leigh Syndrome. (PMID:39152498)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cox10	ENSDARG00000034309
mus_musculus	Cox10	ENSMUSG00000042148
rattus_norvegicus	Cox10	ENSRNOG00000024972
drosophila_melanogaster	Cox10	FBGN0032222
caenorhabditis_elegans		WBGENE00012895

Paralogs (1): COQ2 (ENSG00000173085)

Protein

Protein identifiers

Protoheme IX farnesyltransferase, mitochondrial — Q12887 (reviewed: Q12887)

Alternative names: Heme O synthase

All UniProt accessions (5): Q12887, A0A590UJJ5, H7C101, J3KRW4, J3KSJ3

UniProt curated annotations — full annotation on UniProt →

Function. Converts protoheme IX and farnesyl diphosphate to heme O.

Subcellular location. Mitochondrion membrane.

Disease relevance. Mitochondrial complex IV deficiency, nuclear type 3 (MC4DN3) [MIM:619046] An autosomal recessive mitochondrial disorder characterized by cytochrome c oxidase deficiency. Clinical features include muscle weakness, hypotonia, ataxia, ptosis, metabolic acidosis, poor feeding, delayed motor development, anemia, sensorineural hearing loss, and cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the UbiA prenyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q12887-1	1	yes
Q12887-2	2

RefSeq proteins (1): NP_001294* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000537	UbiA_prenyltransferase	Family
IPR006369	Protohaem_IX_farnesylTrfase	Family
IPR016315	Protohaem_IX_farnesylTrfase_mt	Family
IPR030470	UbiA_prenylTrfase_CS	Conserved_site
IPR044878	UbiA_sf	Homologous_superfamily

Pfam: PF01040

Enzyme classification (BRENDA):

• EC 2.5.1.141 — heme o synthase (BRENDA: 8 organisms, 6 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• heme b + (2E,6E)-farnesyl diphosphate + H2O = Fe(II)-heme o + diphosphate (RHEA:28070)

UniProt features (26 total): sequence variant 13, transmembrane region 7, splice variant 2, sequence conflict 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12887-F1	77.11	0.61

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis

MSigDB gene sets: 221 (showing top): chr17p12, GOBP_RESPIRATORY_CHAIN_COMPLEX_IV_ASSEMBLY, REACTOME_METABOLISM_OF_PORPHYRINS, GOBP_GROWTH, HSIAO_HOUSEKEEPING_GENES, MODULE_335, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GCM_RING1, GOBP_ORGANELLE_FISSION, GOBP_MITOCHONDRIAL_FISSION, GCM_DPF2, GOBP_MULTICELLULAR_ORGANISM_GROWTH

GO Biological Process (11): mitochondrial fission (GO:0000266), leukocyte differentiation (GO:0002521), lipid metabolic process (GO:0006629), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), respiratory chain complex IV assembly (GO:0008535), aerobic respiration (GO:0009060), multicellular organism growth (GO:0035264), copper ion homeostasis (GO:0055070), mitochondrion organization (GO:0007005), cytochrome complex assembly (GO:0017004)

GO Molecular Function (5): geranylgeranyl diphosphate synthase activity (GO:0004311), protoheme IX farnesyltransferase activity (GO:0008495), prenyltransferase activity (GO:0004659), transferase activity (GO:0016740), transferase activity, transferring alkyl or aryl (other than methyl) groups (GO:0016765)

GO Cellular Component (8): nucleolus (GO:0005730), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), cytochrome complex (GO:0070069), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of porphyrins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
mitochondrion	2
cellular anatomical structure	2
mitochondrion organization	1
organelle fission	1
hemopoiesis	1
cell differentiation	1
primary metabolic process	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
heme biosynthetic process	1
cytochrome complex assembly	1
cellular respiration	1
multicellular organismal process	1
developmental growth	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
organelle organization	1
protein-containing complex assembly	1
prenyl diphosphate synthase activity	1
prenyltransferase activity	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
catalytic activity	1
transferase activity	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
catalytic complex	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1968 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COX10	SURF1	Q15526	963
COX10	SCO1	O75880	950
COX10	COX15	Q7KZN9	949
COX10	SCO2	O43819	939
COX10	COX6B1	P14854	894
COX10	MT-CO3	P00414	890
COX10	TACO1	Q9BSH4	876
COX10	MT-CO2	P00403	870
COX10	FBXW10B	O95170	868
COX10	COX11	Q9Y6N1	854
COX10	MT-CO1	P00395	853
COX10	LRPPRC	P42704	802
COX10	BCS1L	Q9Y276	797
COX10	COX17	Q14061	762
COX10	NDUFS1	P28331	755

IntAct

8 interactions, top by confidence:

A	B	Type	Score
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
FAM136A	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
COX10	MAGT1	psi-mi:“MI:0915”(physical association)	0.400
COX10	DGKZ	psi-mi:“MI:0915”(physical association)	0.400
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
COX10	SUOX	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): COX10 (Affinity Capture-MS), MAGT1 (Proximity Label-MS), COX10 (Affinity Capture-MS), COX10 (Affinity Capture-MS), DGKZ (Affinity Capture-MS), APOPT1 (Affinity Capture-MS), SUOX (Affinity Capture-MS), SCRN1 (Affinity Capture-MS)

ESM2 similar proteins: A5GZW8, A6H773, A6QPI4, D3ZAW2, O14521, O75208, P09925, Q05B67, Q08BI9, Q12887, Q15070, Q15526, Q2KHV4, Q2NL34, Q3B8P0, Q3SYV3, Q3TD49, Q4KLZ1, Q5EA03, Q5G2C6, Q5PQL3, Q5R460, Q5R5H4, Q5R7D0, Q5RC29, Q5RE99, Q5T6X4, Q5XIJ4, Q5XJY4, Q5ZIS0, Q5ZLJ4, Q68FN7, Q68FT1, Q6AZR3, Q6AZV0, Q6DGM2, Q6P355, Q6PCT8, Q800L1, Q8BSF4

Diamond homologs: A0AKG3, A0LXT1, A1KAQ4, A1TU04, A1TWQ8, A1URX1, A1VKM6, A3Q941, A4G936, A4VS42, A4XNK8, A4Z2D2, A5CXZ0, A5EA98, A5FJD0, A5G0I2, A5UPV7, A5VD56, A5VWP2, A6H1E4, A6T2T7, A6UXP9, A6WWG0, A7H8V9, A7HQW1, A7NRY4, A7Z2K2, A8FPN0, A8H9S9, A8IDL3, A9GEU3, A9IQQ6, B0KFZ0, B0TNS4, B1J467, B1KM58, B1ZMT0, B2AGR8, B2IGJ6, B6JDB7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	10
Uncertain significance	174
Likely benign	84
Benign	40

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
253545	GRCh37/hg19 17p12(chr17:14110043-14111913)x1	Pathogenic
688021	GRCh37/hg19 17p12(chr17:13879079-14013128)x1	Pathogenic
7522	NM_001303.4(COX10):c.612C>A (p.Asn204Lys)	Pathogenic
7523	NM_001303.4(COX10):c.587C>A (p.Thr196Lys)	Pathogenic
7526	NM_001303.4(COX10):c.1007A>G (p.Asp336Gly)	Pathogenic
7527	NM_001303.4(COX10):c.2T>C (p.Met1Thr)	Pathogenic
1162812	NM_001303.4(COX10):c.688C>T (p.Gln230Ter)	Likely pathogenic
2582413	NM_001303.4(COX10):c.620del (p.Asn207fs)	Likely pathogenic
3581652	NM_001303.4(COX10):c.177+1G>A	Likely pathogenic
3581660	NM_001303.4(COX10):c.412A>T (p.Lys138Ter)	Likely pathogenic
3581668	NM_001303.4(COX10):c.928+1G>A	Likely pathogenic
3581669	NM_001303.4(COX10):c.929-2A>C	Likely pathogenic
3835688	NM_001303.4(COX10):c.851_855dup (p.Trp286fs)	Likely pathogenic
430559	NM_001303.4(COX10):c.445C>T (p.Gln149Ter)	Likely pathogenic
7524	NM_001303.4(COX10):c.674C>T (p.Pro225Leu)	Likely pathogenic
807585	NM_001303.4(COX10):c.661A>G (p.Thr221Ala)	Likely pathogenic

SpliceAI

2250 predictions. Top by Δscore:

Variant	Effect	Δscore
17:14069646:CAGG:C	donor_loss	1.0000
17:14069648:GGTAC:G	donor_loss	1.0000
17:14069649:GTACT:G	donor_loss	1.0000
17:14074316:A:AG	acceptor_gain	1.0000
17:14074321:A:AG	acceptor_gain	1.0000
17:14074321:A:T	acceptor_loss	1.0000
17:14074322:G:GA	acceptor_gain	1.0000
17:14074322:GGTT:G	acceptor_gain	1.0000
17:14074402:G:GT	donor_gain	1.0000
17:14074403:A:T	donor_gain	1.0000
17:14074452:GCATG:G	donor_gain	1.0000
17:14074454:ATGGT:A	donor_loss	1.0000
17:14074455:TGGTA:T	donor_loss	1.0000
17:14074457:G:GG	donor_gain	1.0000
17:14074458:T:G	donor_loss	1.0000
17:14076733:A:AG	acceptor_gain	1.0000
17:14076734:G:GG	acceptor_gain	1.0000
17:14076734:GT:G	acceptor_gain	1.0000
17:14076734:GTAT:G	acceptor_gain	1.0000
17:14101479:A:T	donor_gain	1.0000
17:14101518:TGG:T	donor_gain	1.0000
17:14101520:G:GT	donor_gain	1.0000
17:14102116:A:AG	acceptor_gain	1.0000
17:14102117:G:GA	acceptor_gain	1.0000
17:14102239:TCAGG:T	donor_loss	1.0000
17:14102240:CAG:C	donor_loss	1.0000
17:14102241:AG:A	donor_loss	1.0000
17:14102242:GG:G	donor_loss	1.0000
17:14102243:G:GA	donor_loss	1.0000
17:14102244:T:A	donor_loss	1.0000

AlphaMissense

2851 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:14159906:G:A	M218I	1.000
17:14159906:G:C	M218I	1.000
17:14159906:G:T	M218I	1.000
17:14159911:G:T	R220M	1.000
17:14192126:A:T	K278I	1.000
17:14192127:A:C	K278N	1.000
17:14192127:A:T	K278N	1.000
17:14206857:T:C	F326L	1.000
17:14206859:C:A	F326L	1.000
17:14206859:C:G	F326L	1.000
17:14077042:A:T	K162I	0.999
17:14077043:A:C	K162N	0.999
17:14077043:A:T	K162N	0.999
17:14077051:T:A	L165H	0.999
17:14102239:T:A	N207K	0.999
17:14102239:T:G	N207K	0.999
17:14159896:A:T	D215V	0.999
17:14159911:G:C	R220T	0.999
17:14159912:G:C	R220S	0.999
17:14159912:G:T	R220S	0.999
17:14159923:G:C	R224T	0.999
17:14159924:A:C	R224S	0.999
17:14159924:A:T	R224S	0.999
17:14192125:A:G	K278E	0.999
17:14192145:C:A	N284K	0.999
17:14192145:C:G	N284K	0.999
17:14192155:G:A	G288R	0.999
17:14192155:G:C	G288R	0.999
17:14192156:G:A	G288E	0.999
17:14206842:T:A	W321R	0.999

dbSNP variants (sampled 300 via entrez): RS1000023519 (17:14130834 A>G,T), RS1000027068 (17:14091220 T>C), RS1000039927 (17:14181930 A>G), RS1000042022 (17:14144063 A>G), RS1000048656 (17:14192329 C>A), RS1000065203 (17:14138107 G>A,T), RS1000192256 (17:14189306 A>G), RS1000271130 (17:14150392 G>A), RS1000283715 (17:14104333 T>C), RS1000286275 (17:14169917 A>G,T), RS1000324426 (17:14195771 G>A,T), RS1000351761 (17:14156665 G>A), RS1000381576 (17:14196064 A>G), RS1000391491 (17:14067725 A>C), RS1000437958 (17:14111058 A>G,T)

Disease associations

OMIM: gene MIM:602125 | disease phenotypes: MIM:619046, MIM:256000, MIM:220110

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex IV deficiency, nuclear type 3	Definitive	Autosomal recessive
Leigh syndrome	Moderate	Autosomal recessive
cytochrome-c oxidase deficiency disease	Supportive	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	Moderate	AR

Mondo (4): mitochondrial complex IV deficiency, nuclear type 3 (MONDO:0033635), Leigh syndrome (MONDO:0009723), mitochondrial complex IV deficiency, nuclear type 1 (MONDO:0700250), (MONDO:0009068)

Orphanet (1): Leigh syndrome (Orphanet:506)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000124	Renal tubular dysfunction
HP:0000218	High palate
HP:0000407	Sensorineural hearing impairment
HP:0000508	Ptosis
HP:0000580	Pigmentary retinopathy
HP:0000597	Ophthalmoparesis
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000713	Agitation
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001348	Brisk reflexes
HP:0001410	Decreased liver function
HP:0001427	Mitochondrial inheritance
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001638	Cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001744	Splenomegaly
HP:0001903	Anemia
HP:0001942	Metabolic acidosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001531_2	Temperament	3.000000e-07
GCST004283_9	Midgestational circulating levels of PCBs	8.000000e-06
GCST010002_121	Refractive error	4.000000e-27

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004825	temperament and character inventory
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007964	gestational serum measurement

MeSH disease descriptors (1)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
Valproic Acid	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression	2
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
cylindrospermopsin	increases expression	1
GW 4064	affects cotreatment, decreases expression	1
GW 7647	increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	decreases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects methylation	1
Cadmium	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Farnesol	decreases expression	1
Gasoline	increases abundance, affects cotreatment, decreases expression	1
Lead	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1

Clinical trials (associated diseases)

14 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