TOR1A

Summary

TOR1A (torsin family 1 member A, HGNC:3098) is a protein-coding gene on chromosome 9q34.11, encoding Torsin-1A (O14656). Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates.

The protein encoded by this gene is a member of the AAA family of adenosine triphosphatases (ATPases), is related to the Clp protease/heat shock family and is expressed prominently in the substantia nigra pars compacta. Mutations in this gene result in the autosomal dominant disorder, torsion dystonia 1.

Source: NCBI Gene 1861 — RefSeq curated summary.

At a glance

• Gene–disease (curated): early-onset generalized limb-onset dystonia (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 243 total — 5 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 94
• MANE Select transcript: NM_000113

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3098
Approved symbol	TOR1A
Name	torsin family 1 member A
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	DQ2
Ensembl gene	ENSG00000136827
Ensembl biotype	protein_coding
OMIM	605204
Entrez	1861

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000351698, ENST00000473084, ENST00000473604, ENST00000474192, ENST00000651202

RefSeq mRNA: 1 — MANE Select: NM_000113 NM_000113

CCDS: CCDS6930

Canonical transcript exons

ENST00000351698 — 5 exons

Exon	Start	End
ENSE00000927279	129818520	129818647
ENSE00001622883	129823908	129824136
ENSE00001838107	129812942	129814222
ENSE00003548349	129822581	129822846
ENSE00003583459	129818745	129818920

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 94.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.6520 / max 230.0536, expressed in 1825 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102763	39.7055	1825
102764	0.9466	522

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	94.04	gold quality
secondary oocyte	CL:0000655	93.29	gold quality
monocyte	CL:0000576	93.24	gold quality
endothelial cell	CL:0000115	93.17	gold quality
mononuclear cell	CL:0000842	93.01	gold quality
leukocyte	CL:0000738	92.97	gold quality
endometrium epithelium	UBERON:0004811	91.95	gold quality
granulocyte	CL:0000094	91.46	gold quality
smooth muscle tissue	UBERON:0001135	90.72	gold quality
cortical plate	UBERON:0005343	90.71	gold quality
blood	UBERON:0000178	90.66	gold quality
right adrenal gland cortex	UBERON:0035827	90.60	gold quality
left adrenal gland	UBERON:0001234	90.34	gold quality
right adrenal gland	UBERON:0001233	90.19	gold quality
gall bladder	UBERON:0002110	90.11	gold quality
left adrenal gland cortex	UBERON:0035825	89.98	gold quality
rectum	UBERON:0001052	89.89	gold quality
islet of Langerhans	UBERON:0000006	89.86	gold quality
right coronary artery	UBERON:0001625	89.80	gold quality
adrenal gland	UBERON:0002369	89.46	gold quality
right lobe of liver	UBERON:0001114	89.40	gold quality
left coronary artery	UBERON:0001626	89.35	gold quality
descending thoracic aorta	UBERON:0002345	89.35	gold quality
decidua	UBERON:0002450	89.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.18	gold quality
thoracic aorta	UBERON:0001515	89.17	gold quality
ascending aorta	UBERON:0001496	89.09	gold quality
popliteal artery	UBERON:0002250	88.99	gold quality
tibial artery	UBERON:0007610	88.99	gold quality
aorta	UBERON:0000947	88.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): THAP1

miRNA regulators (miRDB)

63 targeting TOR1A, 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-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712

Literature-anchored findings (GeneRIF, showing 40)

• no evidence of allelic heterogeneity in the DYT1 gene of European patients with early onset torsion dystonia (PMID:11584049)
• 946delGAG appears important in the DYT1 gene in Serbian caes of primary torsion dystonia (PMID:11757956)
• Inherited and de novo mutations in sporadic cases of DYT1-dystonia. (PMID:11973627)
• We have cloned and sequenced the rat cDNA homologue of Torsin A and found a 91% identity with the human sequence. It is a single transcript of approximately 1.5 kb. Torsin A has a widespread distribution within the brain. (PMID:12007841)
• Normal localization of deltaF323-Y328 mutant torsinA in transfected human cells. (PMID:12098639)
• Multiple founder effects in Japanese families with primary torsion dystonia harboring the GAG deletion in the Tor1A (DYT1) gene. (PMID:12481989)
• Torsin A levels in dystonia and normal midbrain and neostriatal regions were similar. However, nigral dopaminergic neurons were larger in both GAG-deletion and non-GAG-deletion dystonia brains. (PMID:12609485)
• TorsinA may direct and/or stabilize the subcellular localization of specific kinases, which may in turn phosphorylate microtubule associated proteins. TorsinA may contribute to maintaining site-directed polarization and control neurite outgrowth. (PMID:12760408)
• The dystonia-associated mutation produces a structurally distinct, possibly misfolded, form of torsinA. (PMID:12780349)
• Findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. (PMID:12838525)
• Pre-synaptic localization of torsinA protein was noted in adult striatum, consistent with a role of torsinA in modulating striatal signaling, although the widespread localization of the protein suggests it may also participate in signaling in other areas (PMID:12965225)
• DYT1 gene mutation is associated with early onset generalised dystonia, however, only 30-40 per cent of gene carriers develop symptoms–REVIEW (PMID:14615676)
• Analysis of recombinant torsinA and its deltaE (302/303) dystonia-associated mutant reveals that the glutamic acid mutation does not cause gross changes in catalytic or structural properties of the protein. (PMID:14690443)
• torsinA is present in the nuclear envelope (NE), where it appears to interact with substrate, and the DeltaE302/3 mutation causes a striking redistribution of torsinA from the endoplasmic reticulum to the NE (PMID:14711988)
• We assessed reciprocal inhibition (RI) in a group of 8 manifesting carriers of the DYT1 gene (DYT1) and 10 healthy controls. A significant increase in inhibition was noted in the third and possibly the first phase of RI in the DYT1 group. (PMID:14743361)
• The frequency & type of DYT1 mutations & associated phenotypes was studied in a mixed movement disorders patient cohort & controls. A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a healthy blood donor. (PMID:14872019)
• At low expression levels, mutant torsinA was localized predominantly around the nucleus, while at high levels it was also concentrated within cytosolic spheroid inclusions. (PMID:15099679)
• FDG PET was used to scan [brain glucose metabolism] in 12 nonmanifesting and 11 manifesting DYT1 gene carriers, 6 nonmanifesting DYT6 gene carriers and 7 manifesting DYT6 gene carriers (PMID:15111678)
• This case report presents the first molecularly diagnosed pedigree of an Australian family with DYT1 dystonia, which presented as writer’s cramp in the 15-year-old proband and two of his cousins. (PMID:15177405)
• Early-onset recurrent major depression is associated with the DYT1 GAG mutation, Independent of motor manifestations of dystonia. These findings suggest that early-onset recurrent depression is a clinical expression of the DYT1 gene mutation. (PMID:15326234)
• Deep brain stimulation treatment of a boy suffering from dystonia due to DYT1. (PMID:15359520)
• This study describe perinuclear inclusion bodies in the midbrain reticular formation and periaqueductal gray in four clinically documented and genetically confirmed DYT1 patients. (PMID:15455404)
• TorsinA can regulate the cellular trafficking of the dopamine transporter, and G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsinA. (PMID:15505207)
• These results thus indicate that torsinADeltaE must achieve a specific conformation to induce formation of intracellular membrane inclusions. (PMID:15555920)
• identifed lamina-associated polypeptide 1 (LAP1) as a torsinA-interacting protein; also identifed a novel transmembrane protein, lumenal domain like LAP1 (LULL1), which also appears to interact with torsinA (PMID:15767459)
• Results provide direct evidence for a role of torsinA as an active ATPase and suggest that mutations in torsinA might affect normal functions of the protein by reducing its enzymatic activity. (PMID:15781971)
• TorsinA protein expression is temporally and spatially regulated and is present in all brain regions studied by the age of 2 months on into adulthood. (PMID:15939081)
• The authors report a Chinese boy with a DYT1 gene mutation having muscle stiffness, severe painful muscle spasm, myoclonus, and dystonia compatible with stiff child syndrome (PMID:16275837)
• DYT1 carriers have abnormal brain-behavior relationships. (PMID:16366514)
• Our findings point to a structural basis for the defects associated with the disease-linked DeltaGAG deletion in torsinA. They also suggest possible connections between the allelic polymorphism at residue 216 and the penetrance of DYT1 dystonia. (PMID:16537570)
• Our data support the existence of an imbalance between striatal dopaminergic and cholinergic signaling in DYT1 dystonia. (PMID:16934985)
• We describe a large Serbian family with significant intrafamilial variability of the DYT1 phenotype, from asymptomatic carrier status to late-onset focal, and generalized jerky dystonia. (PMID:17027035)
• findings show that torsinA is not an integral membrane protein; the mature protein associates peripherally with the endoplasmic reticulum membrane, most likely through an interaction with an integral membrane protein (PMID:17037984)
• Obsessive-compulsive disorder and symptoms are not increased in DYT1 mutation carriers compared with non-carriers. (PMID:17066475)
• Here we report a strong association of two single nucleotide polymorphisms within or in close proximity to the TOR1A 3’UTR, with the lowest p value being 0.000008, in a larger cohort of German and Austrian patients with focal sporadic dystonia. (PMID:17130424)
• A role for torsinA and the ubiquitin proteasome system in the recognition and processing of misfolded epsilon-sarcoglycan. (PMID:17200151)
• Only one allele carries a mutation, which allows to determine its incidence at birth as 1/12,000 per year in a mediterraneean population. (PMID:17290457)
• These studies demonstrate the exquisite sensitivity of this reporter system for quantitation of processing through the secretory pathway and support a role for torsinA as an endoplasmic reticulum chaperone protein. (PMID:17428918)
• Intragenic Cis and Trans modification of genetic susceptibility in TOR1A torsion dystonia was studied. (PMID:17503336)
• The deletion was identified in four probands presenting with early-onset generalized disease (7%). Further studies in probands’ families revealed two symptomatic and nine asymptomatic mutation carriers (PMID:17539945)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	tor1l3	ENSDARG00000026895
danio_rerio	tor1l1	ENSDARG00000055856
danio_rerio	tor1	ENSDARG00000077950
danio_rerio	tor1l2	ENSDARG00000090741
mus_musculus	Tor1a	ENSMUSG00000026849
rattus_norvegicus	Tor1a	ENSRNOG00000006894
drosophila_melanogaster	Torsin	FBGN0025615
caenorhabditis_elegans		WBGENE00003870
caenorhabditis_elegans		WBGENE00006597
caenorhabditis_elegans		WBGENE00006598

Paralogs (4): TOR1B (ENSG00000136816), TOR2A (ENSG00000160404), TOR3A (ENSG00000186283), TOR4A (ENSG00000198113)

Protein

Protein identifiers

Torsin-1A — O14656 (reviewed: O14656)

Alternative names: Dystonia 1 protein, Torsin ATPase-1A, Torsin family 1 member A

All UniProt accessions (2): O14656, A0A494BZT7

UniProt curated annotations — full annotation on UniProt →

Function. Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.

Subunit / interactions. Homohexamer. Interacts with TOR1B; the interaction may be specific of neural tissues. Interacts (ATP-bound) with TOR1AIP1 and TOR1AIP2; the interactions induce ATPase activity. Interacts with KLHL14; preferentially when ATP-free. Interacts with KLC1 (via TPR repeats); the interaction associates TOR1A with the kinesin oligomeric complex. Interacts with COPS4; the interaction associates TOR1A with the CSN complex. Interacts with SNAPIN; the interaction is direct and associates SNAPIN with the CSN complex. Interacts with STON2. Interacts (ATP-bound) with SYNE3 (via KASH domain); the interaction is required for SYNE3 nuclear envelope localization. Interacts with VIM; the interaction associates TOR1A with the cytoskeleton. Interacts with PLEC. Interacts (ATP-bound) with SLC6A3; regulates SLC6A3 transport to the plasma membrane.

Subcellular location. Endoplasmic reticulum lumen. Nucleus membrane. Cell projection. Growth cone. Cytoplasmic vesicle membrane. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle. Cytoplasm. Cytoskeleton.

Tissue specificity. Widely expressed. Highest levels in kidney and liver. In the brain, high levels found in the dopaminergic neurons of the substantia nigra pars compacta, as well as in the neocortex, hippocampus and cerebellum. Also highly expressed in the spinal cord.

Post-translational modifications. N-glycosylated.

Disease relevance. Dystonia 1, torsion, autosomal dominant (DYT1) [MIM:128100] A primary torsion dystonia, and the most common and severe form. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. Dystonia type 1 is characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body, in the absence of other neurological symptoms. Typically, symptoms develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. ‘Torsion’ refers to the twisting nature of body movements observed in DYT1, often affecting the trunk. Distribution and severity of symptoms vary widely between affected individuals, ranging from mild focal dystonia to severe generalized dystonia, even within families. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis multiplex congenita 5 (AMC5) [MIM:618947] A form of arthrogryposis multiplex congenita, a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. AMC5 is an autosomal recessive form characterized by severe congenital contractures, developmental delay, strabismus and tremor. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ClpA/ClpB family. Torsin subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O14656-1	1	yes
O14656-2	2

RefSeq proteins (1): NP_000104* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010448	Torsin	Family
IPR017378	Torsin_1/2	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR049337	TOR1A_C	Domain

Pfam: PF06309, PF21376

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (51 total): helix 16, sequence variant 8, mutagenesis site 7, strand 7, region of interest 3, turn 3, glycosylation site 2, signal peptide 1, chain 1, sequence conflict 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5J1S	X-RAY DIFFRACTION	1.4
5J1T	X-RAY DIFFRACTION	1.4
6OIF	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14656-F1	85.82	0.68

Antibody-complex structures (SAbDab): 2 — 5J1S, 5J1T

Functional residue map

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

Ligand- & substrate-binding residues (1): 102–109

Glycosylation sites (2): 143, 158

Mutagenesis-validated functional residues (7):

Position	Phenotype
18	inhibits sequence signal cleavage.
20	inhibits sequence signal cleavage.
33	n-glycosylated.
108	loss of atp-binding. no effect on interaction with klhl14. increases interaction with tor1aip1 and tor1aip2. abolishes i
143	reduces n-glycosylation.
158	reduces n-glycosylation.
171	loss of atp hydrolysis. loss of interaction with klhl14. localizes in the nuclear envelope. no effect on interaction wit

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis

MSigDB gene sets: 420 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_SYNAPTIC_VESICLE_LOCALIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_VESICLE_LOCALIZATION, GOBP_NEUROTRANSMITTER_UPTAKE, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS

GO Biological Process (17): protein deneddylation (GO:0000338), protein folding (GO:0006457), response to oxidative stress (GO:0006979), nuclear envelope organization (GO:0006998), cell adhesion (GO:0007155), neuron projection development (GO:0031175), protein localization to nucleus (GO:0034504), ERAD pathway (GO:0036503), wound healing, spreading of cells (GO:0044319), intermediate filament cytoskeleton organization (GO:0045104), synaptic vesicle transport (GO:0048489), synaptic vesicle membrane organization (GO:0048499), regulation of dopamine uptake involved in synaptic transmission (GO:0051584), nuclear membrane organization (GO:0071763), positive regulation of synaptic vesicle endocytosis (GO:1900244), regulation of protein localization to cell surface (GO:2000008), obsolete chaperone cofactor-dependent protein refolding (GO:0051085)

GO Molecular Function (11): ATP binding (GO:0005524), cytoskeletal protein binding (GO:0008092), ATP hydrolysis activity (GO:0016887), kinesin binding (GO:0019894), identical protein binding (GO:0042802), obsolete unfolded protein binding (GO:0051082), misfolded protein binding (GO:0051787), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (20): nuclear envelope (GO:0005635), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoskeleton (GO:0005856), synaptic vesicle (GO:0008021), membrane (GO:0016020), secretory granule (GO:0030141), growth cone (GO:0030426), cytoplasmic vesicle membrane (GO:0030659), nuclear membrane (GO:0031965), extracellular exosome (GO:0070062), nucleus (GO:0005634), cytoplasm (GO:0005737), endomembrane system (GO:0012505), transport vesicle (GO:0030133), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Clathrin-mediated endocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
endomembrane system	4
cellular process	3
membrane organization	3
protein binding	3
cytoplasm	3
endomembrane system organization	2
ATP-dependent activity	2
nucleus	2
intracellular membrane-bounded organelle	2
organelle membrane	2
cytoplasmic vesicle	2
protein modification by small protein removal	1
protein maturation	1
response to stress	1
nucleus organization	1
neuron development	1
plasma membrane bounded cell projection organization	1
protein localization to organelle	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
cell migration	1
epiboly involved in wound healing	1
cytoskeleton organization	1
intermediate filament-based process	1
transport	1
establishment of vesicle localization	1
synaptic vesicle localization	1
regulation of neurotransmitter uptake	1
dopamine uptake involved in synaptic transmission	1
nuclear envelope organization	1
positive regulation of endocytosis	1
synaptic vesicle endocytosis	1
regulation of synaptic vesicle endocytosis	1
positive regulation of synaptic vesicle recycling	1
regulation of protein localization	1
protein localization to cell surface	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

1076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOR1A	TNFRSF25	P78507	999
TOR1A	TOR1AIP2	Q8NFQ8	983
TOR1A	THAP1	Q9NVV9	958
TOR1A	SGCE	O43556	939
TOR1A	Q5Y7H0	Q5Y7H0	935
TOR1A	TGM2	P21980	925
TOR1A	TUBB4A	P04350	895
TOR1A	TNFRSF10A	O00220	878
TOR1A	SYNE3	Q6ZMZ3	833
TOR1A	GCH1	P30793	793
TOR1A	WDR11	Q9BZH6	784
TOR1A	NUDT10	Q8NFP7	774
TOR1A	TOR1AIP1	Q5JTV8	773
TOR1A	HLA-DQB1	P01917	770
TOR1A	HLA-DRB1	P01911	763
TOR1A	HPCA	P32076	763

IntAct

92 interactions, top by confidence:

A	B	Type	Score
TOR1A	TOR1AIP2	psi-mi:“MI:0915”(physical association)	0.810
TOR1A	TOR1AIP2	psi-mi:“MI:0407”(direct interaction)	0.810
TOR1AIP2	TOR1A	psi-mi:“MI:0407”(direct interaction)	0.810
KRTAP10-7	TOR1A	psi-mi:“MI:0915”(physical association)	0.720
TOR1A	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.720
BNIP1	NBAS	psi-mi:“MI:0914”(association)	0.640
TOR1A	MDFI	psi-mi:“MI:0915”(physical association)	0.560
IGFBP4	TOR1A	psi-mi:“MI:0915”(physical association)	0.560
COPS3	TOR1A	psi-mi:“MI:0915”(physical association)	0.560
ASIC4	TOR1A	psi-mi:“MI:0915”(physical association)	0.560
ABHD17C	TOR1A	psi-mi:“MI:0915”(physical association)	0.560
TOR1A	APP	psi-mi:“MI:0915”(physical association)	0.560
TOR1A	TOR1AIP1	psi-mi:“MI:0915”(physical association)	0.540
TOR1A	TOR1AIP1	psi-mi:“MI:0407”(direct interaction)	0.540

BioGRID (136): KRTAP10-7 (Two-hybrid), TOR1A (Affinity Capture-MS), TOR1A (Affinity Capture-MS), CANX (Affinity Capture-MS), ASPHD2 (Affinity Capture-MS), FAM20B (Affinity Capture-MS), TOR2A (Affinity Capture-MS), TOR1A (Affinity Capture-MS), TOR1A (Affinity Capture-Western), TOR1AIP1 (Reconstituted Complex), TOR1AIP2 (Reconstituted Complex), TOR1AIP1 (Affinity Capture-Western), TOR1AIP2 (Affinity Capture-Western), TOR1A (Affinity Capture-Western), TOR1A (Affinity Capture-Western)

ESM2 similar proteins: A0A0U1RPR8, A0A4Z3, A1Y9I9, A4FUH1, B6CZ56, B6CZ62, D3ZBP4, D3ZX08, F1MH07, O08644, O14656, O14657, O77277, O88941, P0C0K7, P0C7W1, P0C7W2, P0C7W3, P14616, P14617, P26010, P26011, P41226, P51839, P55205, P58780, Q14CH7, Q16854, Q5JU69, Q5M936, Q60HG2, Q64716, Q68F68, Q68G38, Q6AYR4, Q6TL19, Q80UM7, Q8N2E6, Q8R1J9, Q8TDZ2

Diamond homologs: A4FUH1, O14656, O14657, O77277, P0C7W1, P0C7W2, P0C7W3, Q5JU69, Q5M936, Q60HG2, Q68F68, Q68G38, Q6AYR4, Q8N2E6, Q8R1J9, Q95NU5, Q9ER38, Q9ER39, Q9ER41, Q9ERA9, Q9H497, Q568B8, Q8BH02

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TOR1A	“up-regulates activity”	SNAPIN	binding
KLC1	“up-regulates activity”	TOR1A	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	9
Uncertain significance	132
Likely benign	53
Benign	23

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1172768	NM_000113.3(TOR1A):c.214C>T (p.Gln72Ter)	Pathogenic
1686266	NM_000113.3(TOR1A):c.958A>G (p.Lys320Glu)	Pathogenic
1686267	NM_000113.3(TOR1A):c.461G>A (p.Trp154Ter)	Pathogenic
4813706	NM_000113.3(TOR1A):c.349_352delinsTAGT (p.Glu117_Asn118delinsTer)	Pathogenic
974679	NM_000113.3(TOR1A):c.952G>A (p.Gly318Ser)	Pathogenic
2445982	NM_000113.3(TOR1A):c.844C>T (p.Arg282Ter)	Likely pathogenic
2630777	NM_000113.3(TOR1A):c.748+1G>A	Likely pathogenic
3341475	NM_000113.3(TOR1A):c.287_288del (p.Leu96fs)	Likely pathogenic
3377609	NM_000113.3(TOR1A):c.790_793del (p.Asp264fs)	Likely pathogenic
3393413	NM_000113.3(TOR1A):c.486T>A (p.Cys162Ter)	Likely pathogenic
4813705	NM_000113.3(TOR1A):c.621-2A>G	Likely pathogenic
4845909	NM_000113.3(TOR1A):c.462G>A (p.Trp154Ter)	Likely pathogenic
503652	NM_000113.3(TOR1A):c.856C>T (p.Gln286Ter)	Likely pathogenic
974680	NM_000113.3(TOR1A):c.961del (p.Thr321fs)	Likely pathogenic

SpliceAI

883 predictions. Top by Δscore:

Variant	Effect	Δscore
9:129818518:A:AC	donor_gain	1.0000
9:129818519:C:CC	donor_gain	1.0000
9:129818519:CTGTT:C	donor_gain	1.0000
9:129818643:CATTG:C	acceptor_gain	1.0000
9:129818645:TTG:T	acceptor_gain	1.0000
9:129818646:TG:T	acceptor_gain	1.0000
9:129818648:C:CC	acceptor_gain	1.0000
9:129818739:CCTTA:C	donor_loss	1.0000
9:129818740:CTTA:C	donor_loss	1.0000
9:129818741:TTAC:T	donor_loss	1.0000
9:129818743:A:AC	donor_gain	1.0000
9:129818743:A:C	donor_loss	1.0000
9:129818744:C:CA	donor_loss	1.0000
9:129818744:C:CC	donor_gain	1.0000
9:129818926:T:C	acceptor_gain	1.0000
9:129818926:T:TC	acceptor_gain	1.0000
9:129822549:T:TA	donor_gain	1.0000
9:129822570:T:TA	donor_gain	1.0000
9:129822571:C:A	donor_gain	1.0000
9:129822574:T:TA	donor_gain	1.0000
9:129822647:A:AC	donor_gain	1.0000
9:129822648:C:CC	donor_gain	1.0000
9:129822660:C:A	donor_gain	1.0000
9:129822847:C:CC	acceptor_gain	1.0000
9:129823906:AC:A	donor_gain	1.0000
9:129823906:ACCCT:A	donor_gain	1.0000
9:129823907:CC:C	donor_gain	1.0000
9:129823907:CCCTC:C	donor_gain	1.0000
9:129823910:T:TA	donor_gain	1.0000
9:129814155:C:CT	acceptor_gain	0.9900

AlphaMissense

2209 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:129822711:C:T	G105D	1.000
9:129814011:T:A	K320N	0.999
9:129814011:T:G	K320N	0.999
9:129814015:C:G	C319S	0.999
9:129814016:A:T	C319S	0.999
9:129814019:C:A	G318C	0.999
9:129814019:C:G	G318R	0.999
9:129814131:A:C	C280W	0.999
9:129814132:C:G	C280S	0.999
9:129814132:C:T	C280Y	0.999
9:129814133:A:T	C280S	0.999
9:129814171:A:T	V267D	0.999
9:129818853:T:A	E171V	0.999
9:129818865:A:G	F167S	0.999
9:129822701:T:A	K108N	0.999
9:129822701:T:G	K108N	0.999
9:129822702:T:A	K108I	0.999
9:129822703:T:G	K108Q	0.999
9:129822705:C:A	G107V	0.999
9:129822705:C:T	G107D	0.999
9:129822712:C:A	G105C	0.999
9:129822712:C:G	G105R	0.999
9:129822720:C:T	G102E	0.999
9:129822721:C:A	G102W	0.999
9:129822721:C:G	G102R	0.999
9:129822721:C:T	G102R	0.999
9:129822813:C:T	G71E	0.999
9:129814012:T:A	K320I	0.998
9:129814013:T:C	K320E	0.998
9:129814015:C:T	C319Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000132228 (9:129824593 G>A,C), RS1000221821 (9:129814603 G>C), RS1001450393 (9:129822067 A>C), RS1001625096 (9:129815716 C>T), RS1001860535 (9:129822339 A>G), RS1002322347 (9:129816120 C>T), RS1002691709 (9:129817129 C>T), RS1002789173 (9:129823022 C>T), RS1003069554 (9:129814827 A>G), RS1003134775 (9:129818090 T>G), RS1003419611 (9:129819214 T>C), RS1003748081 (9:129824249 T>C), RS1003962417 (9:129820130 A>G), RS1004143288 (9:129819412 G>A), RS1004747066 (9:129813927 T>A)

Disease associations

OMIM: gene MIM:605204 | disease phenotypes: MIM:128100, MIM:618947

GenCC curated gene-disease

Disease	Classification	Inheritance
early-onset generalized limb-onset dystonia	Definitive	Autosomal dominant
arthrogryposis multiplex congenita 5	Definitive	Autosomal recessive

Mondo (4): dystonic disorder (MONDO:0003441), early-onset generalized limb-onset dystonia (MONDO:0007492), arthrogryposis multiplex congenita 5 (MONDO:0100218), hereditary ataxia (MONDO:0100309)

Orphanet (2): Early-onset generalized limb-onset dystonia (Orphanet:256), Hereditary ataxia (Orphanet:183518)

HPO phenotypes

94 total (30 of 94 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000252	Microcephaly
HP:0000269	Prominent occiput
HP:0000311	Round face
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000395	Prominent antihelix
HP:0000400	Macrotia
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000543	Optic disc pallor
HP:0000582	Upslanted palpebral fissure
HP:0000643	Blepharospasm
HP:0000716	Depression
HP:0000722	Compulsive behaviors
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000878	11 pairs of ribs
HP:0001181	Adducted thumb
HP:0001188	Hand clenching
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001270	Motor delay

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006083_13	Prostate cancer (advanced)	1.000000e-07
GCST006085_41	Prostate cancer	1.000000e-09
GCST006089_10	Prostate cancer (early onset)	1.000000e-07

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
C538005	Dystonia musculorum deformans type 1 (supp.)
C531684	Hereditary spinal ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression, decreases expression	3
Valproic Acid	decreases expression, affects expression	3
bisphenol A	decreases expression, increases expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Ethyl Methanesulfonate	decreases expression, increases expression	2
Methyl Methanesulfonate	decreases expression, increases expression	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
dinophysistoxin 1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
jinfukang	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Adenine	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Colchicine	decreases expression	1
Doxorubicin	decreases expression	1
Etoposide	decreases expression	1

Cellosaurus cell lines

23 cell lines: 12 induced pluripotent stem cell, 11 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A6XJ	CSUi002-A	Induced pluripotent stem cell	Male
CVCL_A8PL	UCSFi001-A-49	Induced pluripotent stem cell	Male
CVCL_A8PM	UCSFi001-A-50	Induced pluripotent stem cell	Male
CVCL_A8PN	UCSFi001-A-51	Induced pluripotent stem cell	Male
CVCL_B0GP	CSUi002-A-1	Induced pluripotent stem cell	Male
CVCL_C0JT	CSUi002-A-2	Induced pluripotent stem cell	Male
CVCL_C0JU	CSUi002-A-3	Induced pluripotent stem cell	Male
CVCL_E4H0	LUEi020-A	Induced pluripotent stem cell	Female
CVCL_E4H1	LUEi020-A-1	Induced pluripotent stem cell	Female
CVCL_E4H2	LUEi020-A-2	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT01435681	Not specified	COMPLETED	Can Short Latency Afferent Inhibition Give us Clues to Better DYT 1 Dystonia Treatments?
NCT07168850	Not specified	RECRUITING	Focused Ultrasound Unilateral Pallidotomy for Medication-Refractory Limb Dystonia
NCT00004421	PHASE2/PHASE3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT00608231	PHASE2/PHASE3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT04277247	PHASE2/PHASE3	UNKNOWN	Botulinum Toxin Type A for Foot Dystonia-associated Pain in Parkinson’s Disease
NCT02015039	PHASE1/PHASE2	COMPLETED	Pilot Trial of Botulinum Toxin and Occupational Therapy for Writer’s Cramp
NCT02911103	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Deep Brain Stimulation Surgery for Focal Hand Dystonia
NCT04727177	EARLY_PHASE1	UNKNOWN	Precision-targeted Transcranial Magnetic Stimulation in the Treatment of Primary Dystonia
NCT00006336	Not specified	COMPLETED	Sensory Training to Treat Focal Dystonia
NCT00017875	Not specified	COMPLETED	Transcranial Magnetic Stimulation (TMS) Studies of Dystonia
NCT00029601	Not specified	COMPLETED	Surround Inhibition in Patients With Dystonia
NCT00031369	Not specified	TERMINATED	Brain Anatomy in Dystonia
NCT00047957	Not specified	COMPLETED	Brain Inhibition of Muscle Movement in Normal Volunteers
NCT00050024	Not specified	COMPLETED	Transcranial Magnetic Stimulation and Electrical Stimulation of Nerves to Study Focal Dystonia
NCT00072956	Not specified	COMPLETED	The Physiology of Tricks
NCT00082615	Not specified	COMPLETED	Neurophysiological Markers in Patients With Craniofacial Dystonia and Their Relatives
NCT00102999	Not specified	COMPLETED	Brain Function in Focal Dystonia