Affinage

TOR1A

Torsin-1A · UniProt O14656

Length
332 aa
Mass
37.8 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TorsinA, encoded by TOR1A, is an AAA+/HSP/Clp-superfamily chaperone-like ATPase that resides in the ER lumen and contiguous nuclear envelope and supports nuclear envelope integrity, ER protein secretion, lipid metabolism, and dopaminergic neurotransmission (PMID:10644435, PMID:17428918). In the ER it acts as a chaperone facilitating protein processing through the secretory pathway, as DYT1 patient fibroblasts and torsinA-null cells secrete a reporter poorly (PMID:17428918). At the nuclear envelope torsinA regulates the LINC complex: its loss causes excess LINC accumulation that disrupts radial glial polarity, cytoskeletal organization, and brain morphogenesis, all preventable by genetically reducing LINC complexes (PMID:29868845), and ATP-locked torsinA accumulates at the nuclear envelope via LAP1 (PMID:21627841). TorsinA loss also drives abnormal phosphatidic acid metabolism through excess Lipin phosphatidic acid phosphatase activity, and reducing Lpin1 rescues neurodegeneration, motor dysfunction, and nuclear membrane pathology in disease mice (PMID:32516804). The dystonia-causing in-frame GAG (ΔE) deletion is a hypomorphic loss-of-function allele rather than a toxic gain-of-function (PMID:26370418); mutant torsinA forms aberrant disulfide-linked oligomers, redistributes from the ER to the nuclear envelope via an abnormal SUN1 interaction, and is cleared preferentially through the autophagy-lysosome pathway (PMID:18940237, PMID:21627841, PMID:24930953). This redistribution and altered degradation is a shared cellular hallmark of pathogenic TOR1A variants (PMID:24930953, PMID:29053766). The functional paralog torsinB compensates bidirectionally for torsinA loss (PMID:32202496), and TOR1A expression is transcriptionally repressed by the dystonia-6 protein THAP1 (PMID:20976771). Downstream, torsinA dysfunction within dopaminergic neurons cell-intrinsically reduces striatal dopamine release (PMID:33894367), lowers striatal D2 receptor levels via increased lysosomal degradation governed by RGS9-2/β-arrestin competition (PMID:30552094), and disrupts corticostriatal synaptic plasticity through excess VAChT/acetylcholine and altered BDNF–AMPAR signaling (PMID:29504938, PMID:34173686); in human patient motor neurons, mutant torsinA upregulates LMNB1 and impairs nucleocytoplasmic transport, with LMNB1 reduction reversing these defects (PMID:33468570). Conditional knockouts establish that spinal/DRG circuits are a pathophysiological substrate for the dystonia phenotype (PMID:37134150). TOR1A mutations cause early-onset torsion dystonia (DYT1) and, biallelically, a severe arthrogryposis phenotype (PMID:29053766).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1999 Medium

    Establishing TOR1A as an AAA+/HSP/Clp-family chaperone-like ATPase defined the molecular class through which all downstream functions could be interpreted.

    Evidence Genomic cloning, sequence and domain analysis, and phylogenetic comparison across species

    PMID:10644435

    Open questions at the time
    • No direct ATPase activity or substrate demonstrated
    • Subcellular localization not yet established
  2. 2007 High

    Demonstrating impaired secretion in patient and null cells assigned torsinA a concrete ER chaperone role in the secretory pathway.

    Evidence Gaussia luciferase secretion reporter in DYT1 fibroblasts and torsinA-null MEFs with pharmacological inhibition and fractionation

    PMID:17428918

    Open questions at the time
    • Specific secretory client substrates not identified
    • Link between secretion defect and neuronal phenotype unresolved
  3. 2007 Medium

    Identification of the D216H polymorphism as a penetrance modifier showed that torsinA dosage/activity, not the mutation alone, governs disease manifestation.

    Evidence Population genetics and haplotype analysis of GAG-deletion carriers with cellular model reference

    PMID:17503336

    Open questions at the time
    • Biochemical basis of D216H protection not fully defined
    • Cell-type context of modifier effect unknown
  4. 2008 Medium

    Showing that the ΔE mutation redistributes torsinA to the nuclear envelope and shifts its degradation defined the core cellular pathology of mutant protein.

    Evidence Subcellular localization, disulfide-bond biochemistry, and pharmacological autophagy/proteasome inhibition with pulse-chase in transfected cells

    PMID:18940237

    Open questions at the time
    • Functional consequence of NE redistribution not established here
    • Driver of NE retention unknown at this stage
  5. 2010 High

    Identifying THAP1 as a direct transcriptional repressor of TOR1A connected two genetic dystonia loci into a shared regulatory pathway.

    Evidence Promoter characterization, ChIP-type binding, and reporter assays comparing wild-type vs mutant THAP1

    PMID:20976771

    Open questions at the time
    • In vivo relevance of TOR1A transcriptional dysregulation to dystonia not shown
    • Other THAP1 target genes not delineated
  6. 2011 Medium

    Defining SUN1 as the driver of mutant torsinA NE accumulation, distinct from LAP1-mediated ATP-locked accumulation, explained the abnormal localization mechanism.

    Evidence Co-immunoprecipitation, LINC-component siRNA depletion, and site-directed mutagenesis with immunofluorescence

    PMID:21627841

    Open questions at the time
    • Functional consequence of aberrant SUN1 binding unresolved
    • Single-lab interaction data
  7. 2011 Medium

    Cell-type-specific knockouts dissected which neural populations require torsinA, mapping Purkinje cell morphology, striatal motor/D2R, and cortical motor functions to distinct circuits.

    Evidence Purkinje-, striatum-, and cortex-specific conditional Dyt1 knockouts with morphology, behavior, D2R binding, and HPLC

    PMID:17956903 PMID:21479250 PMID:21931745

    Open questions at the time
    • Molecular mechanism linking torsinA loss to each phenotype not resolved
    • Cross-circuit interactions not addressed
  8. 2011 High

    The Drosophila ortholog established torsinA as a positive regulator of GTP cyclohydrolase and dopamine biosynthesis, providing a biosynthetic link to dopaminergic deficits.

    Evidence dtorsin null mutants with dopamine HPLC, GTP cyclohydrolase activity assay, genetic interaction with Punch, and dopamine-feeding rescue

    PMID:22022556

    Open questions at the time
    • Direct biochemical mechanism of GTP cyclohydrolase regulation unknown
    • Conservation of this pathway in mammalian dopaminergic neurons not confirmed
  9. 2014 Medium

    Comparative biochemistry of multiple rare variants established NE redistribution, altered oligomerization, and autophagy-lysosome degradation as common signatures of pathogenic torsinA.

    Evidence Subcellular localization, co-IP oligomerization, autophagy/proteasome inhibition, and stability assays across variants

    PMID:24930953 PMID:24931141

    Open questions at the time
    • Oligomerization domain structure unresolved
    • Quantitative relationship between degradation route and dysfunction unclear
  10. 2015 Medium

    Gene-dosage studies showed ΔE-torsinA is hypomorphic with no toxic gain-of-function, reorienting the disease model toward loss of function.

    Evidence Cre-convertible conditional knock-in allele with homozygous/heterozygous/WT comparison at molecular, neuropathological, and behavioral levels

    PMID:26370418

    Open questions at the time
    • Why heterozygous loss suffices for human dystonia not explained
    • Threshold of activity loss needed for phenotype undefined
  11. 2018 Medium

    Linking torsinA loss to LINC complex over-accumulation defined a concrete nuclear envelope mechanism for developmental brain pathology.

    Evidence Tor1a-/- embryo morphology, LINC and radial glial immunohistochemistry, and genetic rescue by LINC complex reduction

    PMID:29868845

    Open questions at the time
    • Mechanism by which torsinA limits LINC accumulation not defined
    • Relevance to adult dystonia circuits unclear
  12. 2018 High

    Identifying premature LTP, absent LTD, and BDNF-dependent AMPAR changes linked torsinA loss to a developmental synaptic plasticity defect.

    Evidence Striatal LTP/LTD electrophysiology, spine morphometry, AMPAR/BDNF Western blot, and pharmacological BDNF antagonism in Tor1a+/Δgag mice

    PMID:29504938

    Open questions at the time
    • Mechanism linking torsinA to BDNF elevation unknown
    • Causal sequence between plasticity and motor signs unresolved
  13. 2019 High

    Defining RGS9-2/β-arrestin-controlled lysosomal degradation of D2R, and the cholinergic dependence of torsinA, mechanistically linked torsinA loss to striatal dopamine/acetylcholine imbalance.

    Evidence Reciprocal RGS9-2 KO/overexpression, radioligand binding, electrophysiology, lysosomal inhibition, and D2R-cell-specific conditional KO

    PMID:30552094 PMID:31618684

    Open questions at the time
    • How torsinA loss lowers RGS9-2/spinophilin not defined
    • Connection between D2R reduction and motor output indirect
  14. 2019 Medium

    Pharmacological dissection showed trihexyphenidyl restores striatal dopamine release via altered nAChR neurotransmission, framing anticholinergic therapy mechanistically.

    Evidence Fast-scan cyclic voltammetry and microdialysis with nAChR antagonists, AChE inhibitors, and L-DOPA in Dyt1 mice

    PMID:30707939

    Open questions at the time
    • Molecular basis of altered nAChR sensitivity unknown
    • L-DOPA insensitivity mechanism unexplained
  15. 2020 High

    Establishing torsinB as a dose-dependent functional paralog and Lipin/phosphatidic acid metabolism as a torsinA-controlled pathway identified two distinct rescue-capable mechanisms.

    Evidence Bidirectional torsinB manipulation in DYT1 mice; Lipin PAP activity assays in patient iPSC neurons and mouse brains with Lpin1 KO genetic rescue

    PMID:32202496 PMID:32516804

    Open questions at the time
    • Biochemical mechanism by which torsinA restrains Lipin activity unknown
    • How torsinB substitutes for torsinA molecularly undefined
  16. 2021 High

    Human patient motor neurons localized the disease mechanism to LMNB1 upregulation and impaired nucleocytoplasmic transport, with LMNB1 reduction reversing defects.

    Evidence iPSC and direct-conversion cholinergic motor neurons, reciprocal mutant TOR1A overexpression and shRNA knockdown, morphometry, nuclear lamina measurement, and transport assays

    PMID:33468570

    Open questions at the time
    • Mechanistic link between torsinA loss and LMNB1 upregulation unresolved
    • Cell-type specificity of LMNB1 dysregulation not fully explained
  17. 2021 High

    Cell-intrinsic conditional expression studies and VAChT findings pinpointed the dopamine-release deficit to dopaminergic neurons and the plasticity deficit to excess vesicular acetylcholine.

    Evidence Cell-type-specific Tor1a(ΔE) expression with voltammetry/microdialysis; VAChT Western blot, ACh and AChE assays, and vesamicol rescue

    PMID:33894367 PMID:34173686

    Open questions at the time
    • Presynaptic molecular target of torsinA in dopamine neurons unidentified
    • Mechanism elevating VAChT unknown
  18. 2022 High

    Defining M4 muscarinic receptors on cholinergic interneurons as the mediator of anticholinergic dopamine-release enhancement refined the circuit pharmacology of therapy.

    Evidence Selective mAChR antagonists, M4 cell-type-specific conditional knockout, and fast-scan cyclic voltammetry

    PMID:35314320

    Open questions at the time
    • Upstream link from torsinA loss to M4 signaling not established
    • Generalizability to human therapy untested in this model
  19. 2023 High

    Spinal cord/DRG conditional knockout identified spinal neural circuits as a sufficient pathophysiological substrate for generalized dystonia.

    Evidence Spinal- and DRG-specific conditional knockouts with behavior, EMG, isolated spinal cord recording, and monosynaptic reflex analysis

    PMID:37134150

    Open questions at the time
    • Molecular mechanism within spinal neurons undefined
    • Integration of spinal substrate with striatal circuit findings unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How torsinA's ER/NE chaperone-ATPase activity mechanistically converges on its diverse downstream effects (LINC, Lipin, LMNB1, dopamine release, cholinergic signaling) remains unresolved.
  • No defined enzymatic substrate connecting torsinA ATPase activity to downstream phenotypes
  • No structural model of the relevant torsinA complexes in the corpus
  • Mechanism translating molecular dysfunction into circuit-level dystonia not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 2 GO:0098772 molecular function regulator activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005635 nuclear envelope 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
LAP1LMNB1SUN1THAP1TOR1B
Complex memberships
LINC complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TOR1A (torsinA) and its homologue TOR1B are located adjacent on chromosome 9q34, each comprising five similar exons spanning ~10 kb. The encoded proteins share functional domains with the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, representing a distinct evolutionary branch. A family of at least nine related genes exists across human, mouse, rat, pig, zebrafish, fruitfly, and nematode. Genomic cloning, sequence analysis, database search, and phylogenetic comparison Genomics Medium 10644435
2007 Mutant torsinA (ΔE) interferes with protein processing through the secretory/ER pathway. Primary fibroblasts from DYT1 patients secreted markedly less Gaussia luciferase reporter activity compared with controls, and mouse embryonic fibroblasts lacking torsinA also showed reduced secretion, supporting a role for torsinA as an ER chaperone. TorsinA was found to associate (co-fractionate) with Gluc reporter in the ER lumen. Gaussia luciferase secretion reporter assay in primary DYT1 patient fibroblasts and torsinA-null MEFs; brefeldin A/nocodazole inhibition; subcellular fractionation; fluorescent protein fusion colocalization Proceedings of the National Academy of Sciences of the United States of America High 17428918
2010 THAP1 (DYT6 protein), a transcription factor, directly binds the core promoter of TOR1A and represses TOR1A expression. Dystonia-6-associated mutant THAP1 shows decreased repression of TOR1A, indicating transcriptional dysregulation of TOR1A as a disease mechanism. TOR1A promoter characterization; THAP1 binding to TOR1A promoter demonstrated by reporter assay and ChIP-type analysis; luciferase reporter assay comparing wild-type vs. mutant THAP1 Annals of neurology High 20976771
2008 The DYT1 ΔE mutation causes mutant torsinA to redistribute from the endoplasmic reticulum to the nuclear envelope. The mutation also triggers formation of abnormal intermolecular disulfide bond-dependent oligomers in torsinA. Wild-type torsinA is degraded primarily through autophagy, while the mutant form additionally requires the proteasome for efficient clearance; disulfide-linked oligomers of mutant torsinA interfere with proteasomal degradation, relying instead on autophagy. Subcellular localization studies; biochemical analysis of disulfide bonds; pharmacological inhibition of autophagy (rapamycin) and proteasome; pulse-chase degradation assays in transfected cells Neuroscience Medium 18940237
2011 The DYT1 disease-causing ΔE mutation promotes an abnormal association between torsinA and SUN1, a LINC complex component at the inner nuclear membrane. siRNA depletion of SUN1 (but not other LINC complex proteins) removes torsinA-ΔE from the nuclear envelope. This SUN1-dependent localization requires the torsinA membrane association domain and residue Y147. In contrast, ATP-locked torsinA accumulates at the NE via LAP1, not SUN1, indicating two distinct NE-localized binding interactions. Co-immunoprecipitation; siRNA knockdown of LINC complex components; subcellular localization by immunofluorescence; site-directed mutagenesis of torsinA BMC cell biology Medium 21627841
2011 Conditional knockout of Dyt1 specifically in Purkinje cells recapitulates the dendritic morphology defects (shortened primary dendrites, decreased distal dendritic spines) seen in Dyt1 ΔGAG knock-in mice, demonstrating that the torsinA effect on Purkinje cell morphology is cell-autonomous. Purkinje cell-specific Cre-mediated conditional knockout; Golgi staining for dendritic morphology quantification; comparison with ΔGAG knock-in mice PloS one Medium 21479250
2011 Loss of torsinA specifically in the striatum (striatum-specific Dyt1 conditional knockout) is sufficient to produce motor deficits and reduced striatal dopamine receptor 2 (D2R) binding activity, without significant alteration of striatal monoamine contents or nuclear envelope abnormalities in adult neurons. Striatum-specific Cre-mediated conditional knockout; behavioral motor testing; D2R radioligand binding assay; monoamine HPLC; nuclear envelope electron microscopy PloS one Medium 21931745
2011 Loss-of-function of Drosophila dtorsin (the sole TOR1A ortholog) results in severely reduced dopamine levels in larval and adult brains. dtorsin mutants show a strong genetic interaction with Punch (GTP cyclohydrolase/DYT14 ortholog), and biochemical analysis revealed severe reduction in GTP cyclohydrolase protein and activity, establishing that dtorsin acts as a positive regulator of GTP cyclohydrolase and dopamine biosynthesis. Drosophila null mutant generation; dopamine HPLC measurement; GTP cyclohydrolase activity assay; genetic interaction by double mutant analysis; locomotion rescue by dopamine feeding PloS one High 22022556
2007 The D216H coding-sequence polymorphism in TOR1A moderates the effects of the DYT1 GAG deletion in cellular models and modifies clinical penetrance. In GAG-deletion carriers, the H allele in trans is highly protective against dystonia manifestation, while the D216 allele in cis with the GAG deletion is associated with disease penetrance. Population genetic analysis of DYT1 GAG-deletion carriers with/without dystonia; haplotype analysis of three TOR1A SNPs including D216H; cellular models previously established American journal of human genetics Medium 17503336
2008 Novel TOR1A missense mutation p.Arg288Gln causes enlarged perinuclear space in HEK293 cells overexpressing the mutant protein, similar to the common ΔGAG mutation, supporting that Arg288 in subdomain alpha5 is functionally important for torsinA activity at the nuclear envelope. Overexpression of mutant TOR1A p.Arg288Gln in HEK293 cells; subcellular localization and nuclear envelope morphology by fluorescence/electron microscopy Journal of neurology, neurosurgery, and psychiatry Low 18477710
2009 A novel TOR1A missense mutation F205I (in the AAA-ATPase domain) produces frequent intracellular inclusions when expressed in cells, similar to the ΔGAG mutation, providing functional evidence that this mutation impairs torsinA function. Expression assay with F205I and ΔGAG TOR1A variants; intracellular inclusion formation scored by microscopy Journal of medical genetics Low 19955557
2014 Rare TOR1A variants R288Q and F205I share biochemical and cellular properties with pathogenic torsinAΔE (altered oligomerization, subcellular redistribution toward nuclear envelope, altered degradation via autophagy-lysosome pathway), whereas wild-type torsinA does not display these features. Autophagy-lysosome pathway is the preferred degradation route for both wild-type and most mutant torsinA forms. Subcellular localization assays; co-immunoprecipitation for oligomerization; autophagy/proteasome pharmacological inhibition; protein stability assays; comparison across multiple variants Human mutation Medium 24930953
2014 TOR1A mutant variants (including ΔGAG) show preferred degradation through the autophagy-lysosome pathway. Blocking autophagy with bafilomycin significantly increases inclusion formation for the E121K variant. The p.A14_P15del mutation affects the proposed oligomerization domain but does not abolish dimerization. Autophagy inhibition (bafilomycin), protein stability assays, co-immunoprecipitation for dimerization, inclusion body scoring in transfected cells Human mutation Medium 24931141
2015 Gene dosage studies using a conditional knock-in allele demonstrate that ΔE-torsinA is a hypomorphic (loss-of-function) allele with no evidence for gain-of-function toxic properties. The ΔE mutation does not produce dominant negative or toxic gain-of-function effects at the molecular or organismal level. Conditional Tor1a knock-in allele converted by Cre recombinase; gene dosage study comparing homozygous, heterozygous and wild-type animals at molecular, neuropathological, and behavioral levels Human molecular genetics Medium 26370418
2019 D2 receptor protein is reduced in the striatum of juvenile Dyt1 mice through increased lysosomal degradation, controlled by competition between β-arrestin 2 and D2 receptor binding proteins. Striatal RGS9-2 and spinophilin levels are lower in Dyt1 mice. RGS9-2 overexpression rescues both D2 receptor levels and electrophysiological responses in Dyt1 striatal neurons, while RGS9-2 knockout mimics the D2 receptor loss phenotype. Radioligand binding; Western blot; genetic RGS9-2 knockout and overexpression (viral); electrophysiology in striatal neurons; lysosomal pathway inhibition EMBO molecular medicine High 30552094
2020 Lipin phosphatidic acid phosphatase (PAP) enzyme activity is abnormally elevated in human DYT-TOR1A patient iPSC-derived neurons and in four different Tor1a mouse model brains, correlating with Tor1a mutation dosage. Genetic reduction of Lpin1 improves survival of recessive Tor1a disease mice and suppresses neurodegeneration, motor dysfunction, and nuclear membrane pathology, establishing that torsinA loss causes abnormal phosphatidic acid metabolism through excess Lipin activity. Lipin PAP enzyme activity assay in patient iPSC-derived neurons and mouse brains; genetic interbreeding of Tor1a and Lpin1 knockout mice; behavioral, histopathological, and nuclear membrane analysis Brain : a journal of neurology High 32516804
2020 TorsinB levels bidirectionally regulate DYT1 disease phenotypes. Reducing torsinB levels worsens abnormal movements and neuropathology in DYT1 mouse models in a dose-dependent manner, while torsinB overexpression rescues torsinA loss-of-function-mediated abnormal movements and neurodegeneration, identifying torsinB as a functional paralog capable of compensating for torsinA loss. Genetic reduction and overexpression of torsinB in DYT1 mouse models; behavioral testing; neuropathological analysis eLife High 32202496
2021 Human DYT1 patient-specific motor neurons (from iPSCs or direct conversion) show LMNB1 upregulation and abnormal subcellular distribution specifically in cholinergic motor neurons. Ectopic expression of mutant TOR1A or shRNA knockdown of TOR1A in healthy control motor neurons recapitulates LMNB1 dysregulation. Downregulation of LMNB1 ameliorates all major cellular defects in DYT1 motor neurons (reduced neurite length/branching, thickened nuclear lamina, disrupted nuclear morphology, impaired nucleocytoplasmic transport). iPSC differentiation and direct conversion to cholinergic motor neurons from DYT1 patients; shRNA knockdown; mutant TOR1A overexpression; neurite morphometry; nuclear lamina thickness measurement; nucleocytoplasmic transport assays; Western blot The Journal of neuroscience : the official journal of the Society for Neuroscience High 33468570
2018 In the Tor1a+/Δgag DYT1 mouse model, long-term potentiation (LTP) appears prematurely in a critical developmental window in striatal spiny neurons while LTD is absent. This is accompanied by increased dendritic spine width, mature mushroom spines, and enhanced AMPA receptor accumulation. BDNF and proBDNF levels are elevated in Tor1a+/Δgag mice, and BDNF antagonism rescues both synaptic plasticity deficits and AMPA currents. Electrophysiological recording (LTP/LTD) in striatal spiny neurons; dendritic spine morphometry; Western blot for AMPAR and BDNF; pharmacological BDNF antagonism eLife High 29504938
2021 Increased vesicular acetylcholine transporter (VAChT) protein levels in the striatum of Tor1a+/- mice lead to elevated basal acetylcholine content and compensatory enhancement of acetylcholinesterase (AChE) activity. Dopamine D2 receptor activation abnormally elevates ACh content (rather than reducing it). Pharmacological blockade of VAChT with vesamicol rescues corticostriatal long-term synaptic plasticity deficits in DYT1 mice. Western blot for VAChT; acetylcholine content assay; AChE enzymatic activity assay; patch-clamp electrophysiology; pharmacological VAChT inhibition (vesamicol) Movement disorders : official journal of the Movement Disorder Society High 34173686
2021 Conditional expression of Tor1a(ΔE) in dopamine neurons (but not in cholinergic interneurons) reduces striatal dopamine release to ~50% of normal, demonstrating that the dopamine release deficit in DYT1 dystonia is cell-intrinsic to dopaminergic neurons. Other presynaptic mechanisms (electrical excitability, vesicle recycling, Ca2+ signaling, D2 autoreceptor function, GABAB receptor function) are intact in these neurons. Cell-type-specific conditional expression of Tor1a(ΔE) via Cre drivers; ex vivo fast-scan cyclic voltammetry; in vivo microdialysis; multiple presynaptic mechanism assays Neurobiology of disease High 33894367
2022 M4 muscarinic receptors on striatal cholinergic interneurons mediate the dopamine-release-enhancing and therapeutic effects of trihexyphenidyl in Tor1a+/ΔE knockin mice. Selective M4 antagonist VU6021625 recapitulates the effect of trihexyphenidyl in restoring striatal dopamine release. Pharmacological challenges with selective mAChR antagonists; cell-type-specific M4 conditional knockout mice; ex vivo fast-scan cyclic voltammetry Neurobiology of disease High 35314320
2023 Conditional knockout of Tor1a in the spinal cord and dorsal root ganglia (but not DRG alone) recapitulates early-onset generalized torsion dystonia in mice. Physiological features include spontaneous contractions at rest, excessive/disorganized contractions, co-contractions of antagonist muscles, impaired monosynaptic reflexes, and affected motor neurons in isolated spinal cords, establishing spinal neural circuits as the pathophysiological substrate in this model. Spinal cord-specific and DRG-specific conditional knockout; behavioral scoring; EMG; electrophysiological recording from isolated spinal cords; monosynaptic reflex arc analysis Science translational medicine High 37134150
2018 Loss of torsinA in the nuclear envelope disrupts LINC complex regulation, causing excess LINC complex accumulation in radial glial cells of Tor1a-/- mouse embryo proliferative zones. This leads to abnormal radial glial polarity and cytoskeletal organization and brain morphogenesis defects in ~30% of Tor1a-/- embryos. Genetic reduction of LINC complexes prevents abnormal brain morphogenesis. Tor1a-/- embryo brain morphology analysis; immunohistochemistry for LINC complex components and radial glial markers; genetic rescue by LINC complex reduction Human molecular genetics Medium 29868845
2019 Trihexyphenidyl increases striatal dopamine release through nicotinic acetylcholine receptor (nAChR)-dependent mechanisms. Dyt1 mice are more sensitive to nAChR antagonism (IC50 ~12 nM vs. ~29 nM in WT) and less sensitive to acetylcholinesterase inhibitors, indicating altered nAChR neurotransmission in DYT1 mice. L-DOPA does not increase dopamine release in Dyt1 mice. Ex vivo fast-scan cyclic voltammetry; in vivo microdialysis; pharmacological dissection with nAChR antagonists, AChE inhibitors, and L-DOPA Neurobiology of disease Medium 30707939
2007 Loss of torsinA function in the cerebral cortex alone (cerebral cortex-specific Dyt1 conditional knockout) is sufficient to produce motor deficits and hyperactivity. Cortex-specific KO mice did not show significant alterations in striatal dopamine and metabolites, unlike Dyt1 ΔGAG knock-in mice. Cerebral cortex-specific Cre-mediated conditional knockout; behavioral testing (open field, rotarod); monoamine HPLC; barrel cortex anatomy Journal of biochemistry Medium 17956903
2019 Torsin A loss in D2 receptor-expressing cells (including striatal cholinergic interneurons) leads to significant reductions in: striatal torsinA, acetylcholine metabolic enzymes, TrkA, cholinergic interneuron number, D2R dimers, and tyrosine hydroxylase. This demonstrates that torsinA in D2R-expressing cells is critical for the development/survival of striatal cholinergic interneurons and expression of mature D2R. D2R-expressing-cell-specific Cre conditional knockout; stereological counting of cholinergic interneurons; Western blot; rotarod and beam-walking tests; monoamine HPLC Neurobiology of disease Medium 31618684
2017 Novel TOR1A mutation p.Asp194Val (in a patient with early-onset segmental dystonia) induces intracellular inclusion formation in SK-N-AS cells, similar to ΔGAG TOR1A. Co-occurrence with a THAP1 mutation (Leu180Ser) with decreased THAP1 repression of TOR1A suggests a potential additive pathogenic effect. TOR1A overexpression in SK-N-AS cells; inclusion body scoring; luciferase reporter assay for THAP1 repression of TOR1A promoter Movement disorders : official journal of the Movement Disorder Society Low 24862462
2017 TOR1A variants p.Gly318Ser and p.Glu303del (homozygous) cause redistribution of torsinA from the ER to the nuclear envelope in cell assays, establishing this NE redistribution as a common cellular hallmark of pathogenic TOR1A mutations and linking biallelic mutations to a severe arthrogryposis phenotype. Cell-based torsinA subcellular localization assay (overexpression); comparison of WT vs. mutant localization Brain : a journal of neurology Low 29053766

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Functional brain networks in DYT1 dystonia. Annals of neurology 244 9749595
2005 Generation and characterization of Dyt1 DeltaGAG knock-in mouse as a model for early-onset dystonia. Experimental neurology 170 16242683
2006 HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. The Journal of clinical investigation 158 16878175
2006 Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 155 16527694
2001 Novel mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and polymorphisms in dystonia and early onset parkinsonism. Neurogenetics 130 11523564
1992 Strong allelic association between the torsion dystonia gene (DYT1) andloci on chromosome 9q34 in Ashkenazi Jews. American journal of human genetics 123 1347197
2003 Different patterns of electrophysiological deficits in manifesting and non-manifesting carriers of the DYT1 gene mutation. Brain : a journal of neurology 122 12821514
1999 The TOR1A (DYT1) gene family and its role in early onset torsion dystonia. Genomics 120 10644435
2007 Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia. American journal of human genetics 110 17503336
2009 Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nature immunology 107 19718029
2007 Mutant torsinA interferes with protein processing through the secretory pathway in DYT1 dystonia cells. Proceedings of the National Academy of Sciences of the United States of America 107 17428918
2004 Brainstem pathology in DYT1 primary torsion dystonia. Annals of neurology 102 15455404
2011 Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice. Proceedings of the National Academy of Sciences of the United States of America 101 21464304
1998 Expression of the early-onset torsion dystonia gene (DYT1) in human brain. Annals of neurology 89 9585364
2016 Feedback Regulation of DYT1 by Interactions with Downstream bHLH Factors Promotes DYT1 Nuclear Localization and Anther Development. The Plant cell 88 27113773
2008 Abnormal motor function and dopamine neurotransmission in DYT1 DeltaGAG transgenic mice. Experimental neurology 80 18299128
2010 Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia. Neurobiology of disease 79 20227500
2014 Different binding motifs of the celiac disease-associated HLA molecules DQ2.5, DQ2.2, and DQ7.5 revealed by relative quantitative proteomics of endogenous peptide repertoires. Immunogenetics 76 25502872
2010 The dystonia gene DYT1 is repressed by the transcription factor THAP1 (DYT6). Annals of neurology 75 20976771
2003 Toward therapy for DYT1 dystonia: allele-specific silencing of mutant TorsinA. Annals of neurology 75 12783425
2010 Increased sensorimotor network activity in DYT1 dystonia: a functional imaging study. Brain : a journal of neurology 73 20207699
2011 Altered dendritic morphology of Purkinje cells in Dyt1 ΔGAG knock-in and purkinje cell-specific Dyt1 conditional knockout mice. PloS one 70 21479250
2012 Structural and functional studies of trans-encoded HLA-DQ2.3 (DQA1*03:01/DQB1*02:01) protein molecule. The Journal of biological chemistry 65 22362761
2018 Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum. eLife 64 29504938
2007 Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorganic & medicinal chemistry 64 17681795
2011 Motor deficits and decreased striatal dopamine receptor 2 binding activity in the striatum-specific Dyt1 conditional knockout mice. PloS one 62 21931745
2007 Motor deficits and hyperactivity in cerebral cortex-specific Dyt1 conditional knockout mice. Journal of biochemistry 62 17956903
2008 Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1). Journal of neurology, neurosurgery, and psychiatry 57 18477710
2014 Ex-vivo whole blood secretion of interferon (IFN)-γ and IFN-γ-inducible protein-10 measured by enzyme-linked immunosorbent assay are as sensitive as IFN-γ enzyme-linked immunospot for the detection of gluten-reactive T cells in human leucocyte antigen (HLA)-DQ2·5(+) -associated coeliac disease. Clinical and experimental immunology 55 24192268
2008 Commentary: Dopaminergic dysfunction in DYT1 dystonia. Experimental neurology 55 18513716
2004 Mutations in DYT1: extension of the phenotypic and mutational spectrum. Neurology 55 14872019
2012 Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A. Genetics in medicine : official journal of the American College of Medical Genetics 53 22722545
2003 Frequency and phenotypic variability of the GAG deletion of the DYT1 gene in an unselected group of patients with dystonia. Archives of neurology 53 12975293
2008 Complexes of two cohorts of CLIP peptides and HLA-DQ2 of the autoimmune DR3-DQ2 haplotype are poor substrates for HLA-DM. Journal of immunology (Baltimore, Md. : 1950) 52 18832702
2009 Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia. Journal of medical genetics 51 19955557
2020 A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease. Proceedings of the National Academy of Sciences of the United States of America 50 31974305
2012 Genetic background modulates the phenotype of a mouse model of DYT1 dystonia. PloS one 46 22393392
2019 RGS9-2 rescues dopamine D2 receptor levels and signaling in DYT1 dystonia mouse models. EMBO molecular medicine 44 30552094
2021 Disease Modeling with Human Neurons Reveals LMNB1 Dysregulation Underlying DYT1 Dystonia. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 33468570
2016 TCR sequencing of single cells reactive to DQ2.5-glia-α2 and DQ2.5-glia-ω2 reveals clonal expansion and epitope-specific V-gene usage. Mucosal immunology 39 26838051
2008 Consequences of the DYT1 mutation on torsinA oligomerization and degradation. Neuroscience 39 18940237
2000 Frequency of the DYT1 mutation in primary torsion dystonia without family history. Archives of neurology 38 10714658
2018 Discriminative T-cell receptor recognition of highly homologous HLA-DQ2-bound gluten epitopes. The Journal of biological chemistry 35 30455354
2011 The nuclear envelope localization of DYT1 dystonia torsinA-ΔE requires the SUN1 LINC complex component. BMC cell biology 35 21627841
2006 Neuropsychological profile of DYT1 dystonia. Movement disorders : official journal of the Movement Disorder Society 33 17013905
2017 TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor. Brain : a journal of neurology 32 29053766
2015 A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation. Human molecular genetics 30 26370418
2014 Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Movement disorders : official journal of the Movement Disorder Society 30 24500857
2014 Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations. Human mutation 30 24931141
2014 Negative allosteric modulation of mGlu5 receptor rescues striatal D2 dopamine receptor dysfunction in rodent models of DYT1 dystonia. Neuropharmacology 30 24951854
2010 Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China. European journal of neurology 30 20825472
2019 Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia. Neurobiology of disease 29 30707939
2016 Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury. Acta neuropathologica communications 29 27716431
2012 Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out. Behavioural brain research 28 22391119
2011 The DYT1 carrier state increases energy demand in the olivocerebellar network. Neuroscience 28 21241782
2009 The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm. Movement disorders : official journal of the Movement Disorder Society 28 19202559
2009 High-throughput mutational analysis of TOR1A in primary dystonia. BMC medical genetics 28 19284587
2017 The Role of TOR1A Polymorphisms in Dystonia: A Systematic Review and Meta-Analysis. PloS one 27 28081261
2002 TNF alpha and LT alpha gene polymorphisms as additional markers of celiac disease susceptibility in a DQ2-positive population. Immunogenetics 27 12439617
2023 Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction. Science translational medicine 26 37134150
2010 HLA-DQ2+ individuals are susceptible to Hu-Ab associated paraneoplastic neurological syndromes. Journal of neuroimmunology 26 20547426
2006 Clinical characterization and evaluation of DYT1 gene in Indian primary dystonia patients. Acta neurologica Scandinavica 26 16911351
2021 Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia. Brain : a journal of neurology 24 33638639
2019 Decreased number of striatal cholinergic interneurons and motor deficits in dopamine receptor 2-expressing-cell-specific Dyt1 conditional knockout mice. Neurobiology of disease 24 31618684
2014 Decreased dopamine receptor 1 activity and impaired motor-skill transfer in Dyt1 ΔGAG heterozygous knock-in mice. Behavioural brain research 23 25451552
2011 Dtorsin, the Drosophila ortholog of the early-onset dystonia TOR1A (DYT1), plays a novel role in dopamine metabolism. PloS one 23 22022556
2015 Phenotype of non-c.907_909delGAG mutations in TOR1A: DYT1 dystonia revisited. Parkinsonism & related disorders 22 26297380
2002 Phenotypic variability of DYT1-PTD: does the clinical spectrum include psychogenic dystonia? Movement disorders : official journal of the Movement Disorder Society 22 12360559
2020 Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia. Brain : a journal of neurology 21 32516804
2017 The cognitive features of idiopathic and DYT1 dystonia. Movement disorders : official journal of the Movement Disorder Society 21 28627117
2017 Enhanced mu opioid receptor-dependent opioidergic modulation of striatal cholinergic transmission in DYT1 dystonia. Movement disorders : official journal of the Movement Disorder Society 21 29150865
2015 Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice. PloS one 21 25799505
2021 The evolution of dystonia-like movements in TOR1A rats after transient nerve injury is accompanied by dopaminergic dysregulation and abnormal oscillatory activity of a central motor network. Neurobiology of disease 20 33753289
2006 Non-DYT1 early-onset primary torsion dystonia: comparison with DYT1 phenotype and review of the literature. Movement disorders : official journal of the Movement Disorder Society 20 16773641
2005 DYT1 mutation in a cohort of Taiwanese primary dystonias. Parkinsonism & related disorders 20 16198613
2005 IL6, IL10 and TGFB1 gene polymorphisms in coeliac disease: differences between DQ2 positive and negative patients. Allergologia et immunopathologia 20 16287542
2020 The abnormal firing of Purkinje cells in the knockin mouse model of DYT1 dystonia. Brain research bulletin 19 32976982
2014 Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A. Human mutation 19 24930953
2010 Clinical feature and DYT1 mutation screening in primary dystonia patients from South-West China. European journal of neurology 19 20113340
1993 HLA-DQA1, DQB1 and DPB1 alleles on HLA-DQ2- and DQ9-carrying extended haplotypes. Tissue antigens 19 8096094
2014 Combined occurrence of a novel TOR1A and a THAP1 mutation in primary dystonia. Movement disorders : official journal of the Movement Disorder Society 18 24862462
2008 Impaired body movement representation in DYT1 mutation carriers. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 18 18571468
2008 Characterization of the porcine TOR1A gene: The first step towards generation of a pig model for dystonia. Gene 18 19028553
2015 Dopamine receptor and Gα(olf) expression in DYT1 dystonia mouse models during postnatal development. PloS one 17 25860259
2011 THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression. Journal of neurology 17 21800139
2016 Membrane defects and genetic redundancy: Are we at a turning point for DYT1 dystonia? Movement disorders : official journal of the Movement Disorder Society 16 27911022
2010 TorsinA and DYT1 dystonia: a synaptopathy? Biochemical Society transactions 16 20298201
2003 Developments in the molecular biology of DYT1 dystonia. Movement disorders : official journal of the Movement Disorder Society 16 14534912
2022 Blockade of M4 muscarinic receptors on striatal cholinergic interneurons normalizes striatal dopamine release in a mouse model of TOR1A dystonia. Neurobiology of disease 15 35314320
2016 Sensorimotor tests unmask a phenotype in the DYT1 knock-in mouse model of dystonia. Behavioural brain research 15 27769743
2015 Genetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy. Mutation research. Reviews in mutation research 15 26596547
2020 TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models. eLife 14 32202496
2014 18FDG-microPET and MR DTI findings in Tor1a+/- heterozygous knock-out mice. Neurobiology of disease 14 25447231
2023 The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders. Brain : a journal of neurology 13 36757831
2022 Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease. The Journal of biological chemistry 13 35065967
2021 Vesicular Acetylcholine Transporter Alters Cholinergic Tone and Synaptic Plasticity in DYT1 Dystonia. Movement disorders : official journal of the Movement Disorder Society 13 34173686
2010 Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia. Neurobiology of disease 13 20053375
2021 Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of TOR1A dystonia. Neurobiology of disease 12 33894367
2019 Epidemiology of DYT1 dystonia: Estimating prevalence via genetic ascertainment. Neurology. Genetics 12 31583275
2018 Excess LINC complexes impair brain morphogenesis in a mouse model of recessive TOR1A disease. Human molecular genetics 12 29868845

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