TTC19

Summary

TTC19 (tetratricopeptide repeat domain 19, HGNC:26006) is a protein-coding gene on chromosome 17p12, encoding Tetratricopeptide repeat protein 19, mitochondrial (Q6DKK2). Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1.

This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 54902 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 303 total — 15 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017775

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26006
Approved symbol	TTC19
Name	tetratricopeptide repeat domain 19
Location	17p12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20343, MGC19520
Ensembl gene	ENSG00000011295
Ensembl biotype	protein_coding
OMIM	613814
Entrez	54902

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000261647, ENST00000465567, ENST00000466729, ENST00000470399, ENST00000470649, ENST00000475723, ENST00000481107, ENST00000497842, ENST00000578103, ENST00000583704, ENST00000873204, ENST00000873205, ENST00000873206, ENST00000873207, ENST00000918096, ENST00000971711

RefSeq mRNA: 2 — MANE Select: NM_017775 NM_001271420, NM_017775

CCDS: CCDS11174

Canonical transcript exons

ENST00000261647 — 10 exons

Exon	Start	End
ENSE00001013755	15999824	16000032
ENSE00002830010	16000118	16000245
ENSE00003460847	16027374	16029404
ENSE00003504906	16001915	16002025
ENSE00003505987	16003831	16003887
ENSE00003583635	16025017	16025171
ENSE00003617037	16026540	16026702
ENSE00003627549	16006474	16006568
ENSE00003658040	16002793	16002831
ENSE00003671881	16004201	16004262

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 94.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3927 / max 499.6035, expressed in 1820 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159679	20.2969	1814
159678	2.7185	1352
159677	1.6838	1010
159676	0.6935	424

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	94.55	gold quality
ileal mucosa	UBERON:0000331	94.47	gold quality
upper leg skin	UBERON:0004262	94.45	gold quality
cerebellar cortex	UBERON:0002129	94.36	gold quality
cerebellar hemisphere	UBERON:0002245	94.36	gold quality
type B pancreatic cell	CL:0000169	94.34	gold quality
cerebellum	UBERON:0002037	94.28	gold quality
buccal mucosa cell	CL:0002336	94.13	gold quality
ventricular zone	UBERON:0003053	93.93	gold quality
colonic mucosa	UBERON:0000317	93.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.91	gold quality
duodenum	UBERON:0002114	93.69	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.66	gold quality
right frontal lobe	UBERON:0002810	93.65	gold quality
sural nerve	UBERON:0015488	93.62	gold quality
left ventricle myocardium	UBERON:0006566	93.50	gold quality
frontal cortex	UBERON:0001870	93.34	gold quality
frontal lobe	UBERON:0016525	93.34	gold quality
prefrontal cortex	UBERON:0000451	93.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.26	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.24	gold quality
neocortex	UBERON:0001950	93.21	gold quality
cingulate cortex	UBERON:0003027	93.15	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.14	gold quality
anterior cingulate cortex	UBERON:0009835	93.14	gold quality
superior frontal gyrus	UBERON:0002661	93.13	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.12	gold quality
ganglionic eminence	UBERON:0004023	93.09	gold quality
orbitofrontal cortex	UBERON:0004167	93.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting TTC19, 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-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 7)

• TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies. (PMID:21278747)
• The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. (PMID:23532514)
• A TTC19 mutation in spinocerebellar ataxia is identified in an Asian population. (PMID:24397319)
• This study showed that TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder; normal MRC complex III activity does not exclude the diagnosis. (PMID:25887401)
• TTC19-deficient mitochondrial complex III deficiency displays substantial phenotypic variation. (Review) (PMID:25899669)
• TTC19 preserves the structural and functional integrity of mitochondrial respiratory complex III. UQCRFS1 produces N-terminal polypeptides, which remain bound to holocomplex III. UQCRFS1 fragments are rapidly removed, but when TTC19 is absent they accumulate within complex III, causing its structural and functional impairment. (PMID:28673544)
• Integrated genomics analysis highlights important SNPs and genes implicated in moderate-to-severe asthma based on GWAS and eQTL datasets. (PMID:33066754)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttc19	ENSDARG00000074435
mus_musculus	Ttc19	ENSMUSG00000042298
rattus_norvegicus	Ttc19	ENSRNOG00000002977
drosophila_melanogaster	Ttc19	FBGN0032744
caenorhabditis_elegans		WBGENE00013217

Protein

Protein identifiers

Tetratricopeptide repeat protein 19, mitochondrial — Q6DKK2 (reviewed: Q6DKK2)

All UniProt accessions (6): Q6DKK2, K7EJA1, K7EKH7, K7EKS0, K7ELX2, K7ERR1

UniProt curated annotations — full annotation on UniProt →

Function. Required for the preservation of the structural and functional integrity of mitochondrial respiratory complex III by allowing the physiological turnover of the Rieske protein UQCRFS1. Involved in the clearance of UQCRFS1 N-terminal fragments, which are produced upon incorporation of UQCRFS1 into the complex III and whose presence is detrimental for its catalytic activity.

Subunit / interactions. Binds to the mature mitochondrial complex III dimer, after the incorporation of the Rieske protein UQCRFS1. Interacts with UQCRC1 and UQCRFS1. Interacts with ZFYVE26 and CHMP4B.

Subcellular location. Mitochondrion inner membrane.

Post-translational modifications. Proteolytically cleaved by PARL.

Disease relevance. Mitochondrial complex III deficiency, nuclear type 2 (MC3DN2) [MIM:615157] A disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TTC19 family.

RefSeq proteins (2): NP_001258349, NP_060245* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR040395	TTC19	Family

Pfam: PF13374, PF13424

UniProt features (10 total): repeat 5, sequence conflict 2, transit peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6DKK2-F1	80.28	0.73

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 (1): 71–72 (cleavage; by parl)

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9865881	Complex III assembly

MSigDB gene sets: 225 (showing top): GOBP_MITOTIC_CYTOKINESIS, chr17p12, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, TGACCTY_ERR1_Q2, GOCC_MICROTUBULE_ORGANIZING_CENTER, COUP_01, GOBP_CYTOCHROME_COMPLEX_ASSEMBLY, GOBP_CYTOKINESIS, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, GOCC_CENTROSOME, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_MITOTIC_CELL_CYCLE, TGGNNNNNNKCCAR_UNKNOWN, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, GOBP_CYTOSKELETON_DEPENDENT_CYTOKINESIS

GO Biological Process (3): mitotic cytokinesis (GO:0000281), mitochondrial respiratory chain complex III assembly (GO:0034551), cell division (GO:0051301)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), centrosome (GO:0005813), midbody (GO:0030496), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
mitochondrion	1
respiratory chain complex III assembly	1
mitochondrial respiratory chain complex assembly	1
cellular process	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
centriole	1
microtubule organizing center	1

Protein interactions and networks

STRING

1973 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTC19	ZFYVE26	Q68DK2	866
TTC19	LYRM7	Q5U5X0	806
TTC19	BCS1L	Q9Y276	772
TTC19	UQCC3	Q6UW78	689
TTC19	UQCC2	Q9BRT2	678
TTC19	UQCC1	Q9NVA1	669
TTC19	UQCRFS1	P47985	637
TTC19	DNAJB12	Q9NXW2	606
TTC19	UQCRB	P14927	585
TTC19	BLMH	Q13867	583
TTC19	UQCRC2	P22695	573
TTC19	HCCS	P53701	548
TTC19	WDR73	Q6P4I2	533
TTC19	UQCRQ	O14949	530
TTC19	ZSWIM7	Q19AV6	530

IntAct

248 interactions, top by confidence:

A	B	Type	Score
NDUFAF8	NDUFAF5	psi-mi:“MI:0914”(association)	0.750
GPANK1	TTC19	psi-mi:“MI:0915”(physical association)	0.740
TTC19	IHO1	psi-mi:“MI:0915”(physical association)	0.720
IHO1	TTC19	psi-mi:“MI:0915”(physical association)	0.720
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
TCAP	TTC19	psi-mi:“MI:0915”(physical association)	0.670
ATXN1	TTC19	psi-mi:“MI:0915”(physical association)	0.670
TTC19	HTRA2	psi-mi:“MI:0915”(physical association)	0.660
GUK1	TTC19	psi-mi:“MI:0915”(physical association)	0.590
TTC19	REL	psi-mi:“MI:0915”(physical association)	0.560
NAB2	TTC19	psi-mi:“MI:0915”(physical association)	0.560
L3MBTL3	TTC19	psi-mi:“MI:0915”(physical association)	0.560
EIF4ENIF1	TTC19	psi-mi:“MI:0915”(physical association)	0.560
TTC19		psi-mi:“MI:0915”(physical association)	0.560
REL	TTC19	psi-mi:“MI:0915”(physical association)	0.560
TTC19	NAB2	psi-mi:“MI:0915”(physical association)	0.560
TTC19	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.560
	TTC19	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (160): TTC19 (Two-hybrid), TTC19 (Two-hybrid), EIF4ENIF1 (Two-hybrid), CCDC33 (Two-hybrid), L3MBTL3 (Two-hybrid), CCDC36 (Two-hybrid), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS), TTC19 (Affinity Capture-MS)

ESM2 similar proteins: A0A0D1E2P6, A0A0D2XVZ5, A0A0P0VG31, A0AVF1, A2WYG9, A4III8, A4QP73, A8JA42, B5X0I6, C4NYP8, D3J162, F4JIN3, J9VKM5, O00170, O08915, O42668, O97628, P91240, Q0WT48, Q13217, Q17430, Q20255, Q27968, Q4R7Z9, Q54M21, Q5FWY5, Q5JJI4, Q5JNB5, Q5PR66, Q5U2N8, Q5ZI13, Q61LA1, Q6DKK2, Q7TT47, Q7XVN7, Q86DS1, Q8BS45, Q8CC21, Q8LQJ9, Q8S2A7

Diamond homologs: A4QP73, D4A6D7, Q6DKK2, Q8CC21

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ZFYVE26	“up-regulates activity”	TTC19	binding
KIF13A	“up-regulates activity”	TTC19	binding
TTC19	“up-regulates activity”	CHMP4B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Budding and maturation of HIV virion	6	35.0×	6e-06
Endosomal Sorting Complex Required For Transport (ESCRT)	6	31.6×	6e-06
Late endosomal microautophagy	6	28.0×	8e-06

GO biological processes:

GO term	Partners	Fold	FDR
nuclear membrane reassembly	5	49.1×	6e-06
late endosome to lysosome transport	5	49.1×	6e-06
viral budding via host ESCRT complex	5	39.7×	1e-05
multivesicular body sorting pathway	5	39.7×	1e-05
midbody abscission	5	36.3×	2e-05
regulation of mitotic spindle assembly	5	36.3×	2e-05
plasma membrane repair	5	28.8×	5e-05
nucleus organization	5	27.8×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	10
Uncertain significance	132
Likely benign	75
Benign	31

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
102437	NM_017775.4(TTC19):c.601_604del (p.Gly201fs)	Pathogenic
102438	TTC19, TRP186TER	Pathogenic
102439	TTC19, 4-BP DEL, 964GGCT	Pathogenic
102440	NM_017775.4(TTC19):c.829C>T (p.Gln277Ter)	Pathogenic
1323720	NM_017775.4(TTC19):c.581+1G>A	Pathogenic
1386909	NM_017775.4(TTC19):c.793C>T (p.Gln265Ter)	Pathogenic
1806678	NM_017775.4(TTC19):c.646_647del (p.Glu216fs)	Pathogenic
2573001	NM_017775.4(TTC19):c.451C>T (p.Gln151Ter)	Pathogenic
2579225	GRCh38/hg38 17p12(chr17:16018139-16028011)x0	Pathogenic
31073	NM_017775.4(TTC19):c.656T>G (p.Leu219Ter)	Pathogenic
31074	NM_017775.4(TTC19):c.517C>T (p.Gln173Ter)	Pathogenic
3252023	NM_017775.4(TTC19):c.718_719insA (p.Leu240fs)	Pathogenic
437076	NM_017775.4(TTC19):c.817G>T (p.Glu273Ter)	Pathogenic
4723786	NM_017775.4(TTC19):c.296dup (p.Leu100fs)	Pathogenic
489153	NM_017775.4(TTC19):c.304C>T (p.Arg102Ter)	Pathogenic
1515047	NM_017775.4(TTC19):c.423+1G>C	Likely pathogenic
2023762	NM_017775.4(TTC19):c.520-2A>G	Likely pathogenic
2172325	NM_017775.4(TTC19):c.424-1G>A	Likely pathogenic
2441843	NM_017775.4(TTC19):c.903dup (p.Met302fs)	Likely pathogenic
2683759	NM_017775.4(TTC19):c.519+2T>A	Likely pathogenic
2690770	NM_017775.4(TTC19):c.463-1G>C	Likely pathogenic
3065645	NM_017775.4(TTC19):c.184+1G>A	Likely pathogenic
3393129	NM_017775.4(TTC19):c.93dup (p.Leu32fs)	Likely pathogenic
3632370	NM_017775.4(TTC19):c.581+1G>C	Likely pathogenic
873487	NM_017775.4(TTC19):c.581+1_581+5del	Likely pathogenic

SpliceAI

1896 predictions. Top by Δscore:

Variant	Effect	Δscore
17:16001910:TTCA:T	acceptor_loss	1.0000
17:16001911:TCA:T	acceptor_loss	1.0000
17:16001912:CAG:C	acceptor_loss	1.0000
17:16001913:A:AG	acceptor_gain	1.0000
17:16001913:AG:A	acceptor_loss	1.0000
17:16001913:AGTT:A	acceptor_gain	1.0000
17:16001914:G:GA	acceptor_gain	1.0000
17:16001914:GT:G	acceptor_gain	1.0000
17:16001914:GTT:G	acceptor_gain	1.0000
17:16001914:GTTG:G	acceptor_gain	1.0000
17:16001914:GTTGA:G	acceptor_gain	1.0000
17:16001998:G:GT	donor_gain	1.0000
17:16002024:TG:T	donor_loss	1.0000
17:16002026:GTAA:G	donor_loss	1.0000
17:16002060:G:GT	donor_gain	1.0000
17:16002061:A:T	donor_gain	1.0000
17:16002832:G:GA	donor_loss	1.0000
17:16002832:G:GG	donor_gain	1.0000
17:16002834:AAGT:A	donor_loss	1.0000
17:16002835:AGTA:A	donor_loss	1.0000
17:16004198:CA:C	acceptor_loss	1.0000
17:16004199:A:AG	acceptor_gain	1.0000
17:16004199:AGG:A	acceptor_loss	1.0000
17:16004200:G:GG	acceptor_gain	1.0000
17:16004200:GGA:G	acceptor_gain	1.0000
17:16004259:ACAG:A	donor_gain	1.0000
17:16004260:CAG:C	donor_gain	1.0000
17:16004261:AG:A	donor_gain	1.0000
17:16004261:AGG:A	donor_loss	1.0000
17:16004262:GG:G	donor_gain	1.0000

AlphaMissense

2462 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:16006502:T:C	F204L	0.997
17:16006504:C:A	F204L	0.997
17:16006504:C:G	F204L	0.997
17:16006507:C:G	C205W	0.996
17:16002796:G:C	A143P	0.995
17:16004235:T:C	L185P	0.994
17:16003848:A:C	K160N	0.993
17:16003848:A:T	K160N	0.993
17:16006506:G:A	C205Y	0.993
17:16025127:G:C	A263P	0.993
17:16000240:G:C	A103P	0.992
17:16002797:C:A	A143D	0.992
17:16004229:T:C	L183P	0.992
17:16006505:T:C	C205R	0.992
17:16025071:C:A	A244D	0.992
17:16027409:G:C	A344P	0.991
17:16001966:G:C	A122P	0.990
17:16001979:C:A	A126D	0.990
17:16002797:C:T	A143V	0.990
17:16004238:C:A	A186D	0.990
17:16006485:C:A	A198D	0.990
17:16003832:C:A	A155D	0.989
17:16004233:G:C	K184N	0.989
17:16004233:G:T	K184N	0.989
17:16006494:G:A	G201D	0.989
17:16006518:T:C	L209P	0.989
17:16027421:G:C	A348P	0.989
17:16002796:G:A	A143T	0.988
17:16002805:G:C	A146P	0.988
17:16004225:T:C	S182P	0.988

dbSNP variants (sampled 300 via entrez): RS1000054974 (17:16029835 G>A), RS1000090855 (17:16020688 A>G), RS1000165182 (17:16014969 A>G), RS1000196543 (17:16005440 C>T), RS1000197059 (17:16014609 T>C), RS1000338482 (17:16033252 C>T), RS1000392077 (17:16043014 C>G), RS1000475234 (17:16012318 A>G), RS1000517869 (17:16037561 T>C), RS1000526384 (17:16023792 C>G,T), RS1000768730 (17:16037878 G>A), RS1000782720 (17:16012108 T>G), RS1000815460 (17:16013627 G>A,C), RS1000846160 (17:16035837 C>T), RS1000900255 (17:16025139 T>C,G)

Disease associations

OMIM: gene MIM:613814 | disease phenotypes: MIM:615157, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial complex III deficiency nuclear type 2	Definitive	Autosomal recessive
Leigh syndrome	Definitive	Autosomal recessive
mitochondrial complex III deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (5): mitochondrial complex III deficiency nuclear type 2 (MONDO:0014063), mitochondrial disease (MONDO:0044970), autism (MONDO:0005260), Leigh syndrome (MONDO:0009723), mitochondrial complex III deficiency (MONDO:0015448)

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

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000745	Abnormal diminished volition
HP:0000764	Peripheral axonal degeneration
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001259	Coma
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002066	Gait ataxia
HP:0002067	Bradykinesia
HP:0002070	Limb ataxia
HP:0002075	Dysdiadochokinesis

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
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

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	3
Cadmium	decreases expression, increases expression	2
ginger extract	decreases expression, increases abundance	1
bisphenol A	affects cotreatment, increases methylation	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
sodium arsenite	decreases expression	1
manganese chloride	increases abundance, increases expression	1
K 7174	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Manganese	increases abundance, increases expression	1
Oils, Volatile	decreases expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Tretinoin	decreases expression	1
Tunicamycin	increases expression	1
Cadmium Chloride	decreases expression	1
Thapsigargin	increases expression	1
Acrylamide	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

206 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
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder