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Gene Review

TOR1A  -  torsin family 1, member A (torsin A)

Homo sapiens

Synonyms: DQ2, DYT1, Dystonia 1 protein, TA, TORA, ...
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Disease relevance of TOR1A


Psychiatry related information on TOR1A


High impact information on TOR1A

  • DQ2 or DQ8, but not other HLA molecules carried by patients, are the predominant restriction elements for these T cells [11].
  • DQ2 and DQ8 bind the epitopes so that the glutamic acid residues created by deamidation are accommodated in pockets that have a preference for negatively charged side chains [11].
  • After improvement in the first year, dystonia and dyskinesias recurred in 15 percent of the patients who received transplants, even after reduction or discontinuation of the dose of levodopa [12].
  • Some forms of dystonia respond to the intrathecal administration of baclofen, a specific gamma-aminobutyric acid-receptor (type B) agonist that inhibits sensory input to the neurons of the spinal cord [13].
  • In two women the spasms or restlessness of the legs decreased, without any change in the dystonia [13].

Chemical compound and disease context of TOR1A


Biological context of TOR1A

  • 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 predominantly focal sporadic dystonia [19].
  • Whereas clinical manifestations are related to cortical dysfunction, metabolic abnormalities in subcortical structures may represent trait features that are specific for individual dystonia genotypes [3].
  • This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease [4].
  • Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant [20].
  • DYT1 dystonia is a severe form of young-onset dystonia caused by a mutation in the gene that encodes for the protein torsinA, which is thought to play a role in protein transport and degradation [6].

Anatomical context of TOR1A


Associations of TOR1A with chemical compounds

  • BACKGROUND: The authors have previously used [18F]fluorodeoxyglucose (FDG) PET to identify a reproducible pattern of regional glucose metabolism that was expressed in both manifesting and nonmanifesting carriers of the DYT1 primary dystonia mutation [3].
  • Recent work has revealed that the causative mutation in most cases is deletion of a glutamate residue from the carboxy terminal of torsinA, a 332 amino acid protein encoded by the DYT1 gene [21].
  • However, both torsin A and DeltaE-torsin A were readily solubilized by nonionic detergents, were similarly accessible to proteases, and displayed equivalent migration patterns on sucrose gradients [22].
  • Regarding dystonia treatment, patients refractory to botulinum toxin type A can now be treated with botulinum toxin type B. Selective peripheral denervation remains an effective form of treatment for patients with secondary, but probably not with primary botulinum toxin treatment failure [23].
  • An understanding of the role of torsinA in cellular function and the impact of the mutation (deletion of a glutamic acid at residue 303) is likely to provide insights into the etiopathogenesis of primary dystonia [24].

Physical interactions of TOR1A

  • The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol [25].
  • We now report identification by sequencing, restriction endonuclease analyses, and clonal analyses of a heteroplasmic missense A to G base pair substitution at nucleotide position 3796 (A3796G) in the gene encoding the ND1 subunit of mitochondrial complex I in a patient with adult-onset dystonia, spasticity, and core-type myopathy [26].
  • VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET [27].
  • D2 receptor binding in dopa-responsive dystonia [28].
  • Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic paroxysmal dystonia [29].

Regulatory relationships of TOR1A

  • Previous serological analysis in this population had shown the presence of DQ2 in 95% of the patients (40% in controls) and a negative association with DQ1 haplotypes, suggesting the presence of other "permissive" or neutral alleles [30].
  • To evaluate the extent of this predicted diversity, DQ2 beta or DQ3.2 beta cDNA were introduced into a panel of homozygous B cell lines that expressed different DQ alpha alleles [31].
  • GTP cyclohydrolase I (GCH1) activity in phytohemaglutinin (PHA)-stimulated mononuclear blood cells (MBCs) is a useful clinical marker for diagnosis of tetrahydrobiopterin (BH4)-related genetic disorders such as recessively inherited GCH1 deficiency and dominantly inherited dopa-responsive dystonia (Segawa's disease) [32].
  • Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2 [33].
  • In comparison to stimulated control hamsters, a significantly lower prodynorphin expression was found in several limbic areas of stimulated mutant hamsters during the manifestation of dystonia, while preproenkephalin mRNA was significantly lower in the anterior and dorsal striatal subregions and in nucleus accumbens [34].

Other interactions of TOR1A

  • Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia [19].
  • Recently, a novel gene locus (DYT13) was detected in a family with segmental dystonia, and the gene causing myoclonus-dystonia was identified (SGCE) [23].
  • Three PTD loci (DYT1, DYT6 and DYT7) have been identified to date [35].
  • Adult onset idiopathic torsion dystonia is excluded from the DYT 1 region (9q34) in a Swedish family [36].
  • A genome-wide search performed in the family identified a novel PTD locus (DYT13) within a 22-cM interval on the short arm of chromosome 1, with a maximum lod score of 3.44 (theta = 0) between the disease and marker D1S2667 [35].

Analytical, diagnostic and therapeutic context of TOR1A

  • We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks [15].
  • Finally, a renaissance of functional surgical ablative procedures has taken place, with high frequency deep brain stimulation being introduced in dystonia treatment [23].
  • In Western blot analysis of normal human brain homogenates, the antibodies specifically recognized 38-kd endogenous torsin A and 62-kd endogenous torsin B [17].
  • One-Hz repetitive transcranial magnetic stimulation of the premotor cortex alters reciprocal inhibition in DYT1 dystonia [37].
  • We report on the second M-D family in which several clinically affected epsilon-sarcoglycan gene (SGCE) mutation carriers have seizures in addition to myoclonus and dystonia, adding to the evidence that epilepsy and EEG abnormalities may form part of the phenotypic spectrum of the condition [38].


  1. The TOR1A (DYT1) gene family and its role in early onset torsion dystonia. Ozelius, L.J., Page, C.E., Klein, C., Hewett, J.W., Mineta, M., Leung, J., Shalish, C., Bressman, S.B., de Leon, D., Brin, M.F., Fahn, S., Corey, D.P., Breakefield, X.O. Genomics (1999) [Pubmed]
  2. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Zimprich, A., Grabowski, M., Asmus, F., Naumann, M., Berg, D., Bertram, M., Scheidtmann, K., Kern, P., Winkelmann, J., Müller-Myhsok, B., Riedel, L., Bauer, M., Müller, T., Castro, M., Meitinger, T., Strom, T.M., Gasser, T. Nat. Genet. (2001) [Pubmed]
  3. Regional metabolism in primary torsion dystonia: effects of penetrance and genotype. Carbon, M., Su, S., Dhawan, V., Raymond, D., Bressman, S., Eidelberg, D. Neurology (2004) [Pubmed]
  4. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Ozelius, L.J., Hewett, J.W., Page, C.E., Bressman, S.B., Kramer, P.L., Shalish, C., de Leon, D., Brin, M.F., Raymond, D., Corey, D.P., Fahn, S., Risch, N.J., Buckler, A.J., Gusella, J.F., Breakefield, X.O. Nat. Genet. (1997) [Pubmed]
  5. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Goodchild, R.E., Dauer, W.T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Brainstem pathology in DYT1 primary torsion dystonia. McNaught, K.S., Kapustin, A., Jackson, T., Jengelley, T.A., Jnobaptiste, R., Shashidharan, P., Perl, D.P., Pasik, P., Olanow, C.W. Ann. Neurol. (2004) [Pubmed]
  7. Increased risk for recurrent major depression in DYT1 dystonia mutation carriers. Heiman, G.A., Ottman, R., Saunders-Pullman, R.J., Ozelius, L.J., Risch, N.J., Bressman, S.B. Neurology (2004) [Pubmed]
  8. Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence. Saunders-Pullman, R., Shriberg, J., Heiman, G., Raymond, D., Wendt, K., Kramer, P., Schilling, K., Kurlan, R., Klein, C., Ozelius, L.J., Risch, N.J., Bressman, S.B. Neurology (2002) [Pubmed]
  9. Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. Neumann, M., Adler, S., Schlüter, O., Kremmer, E., Benecke, R., Kretzschmar, H.A. Acta Neuropathol. (2000) [Pubmed]
  10. A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Jin, H., May, M., Tranebjaerg, L., Kendall, E., Fontán, G., Jackson, J., Subramony, S.H., Arena, F., Lubs, H., Smith, S., Stevenson, R., Schwartz, C., Vetrie, D. Nat. Genet. (1996) [Pubmed]
  11. Molecular basis of celiac disease. Sollid, L.M. Annu. Rev. Immunol. (2000) [Pubmed]
  12. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J.Q., Eidelberg, D., Fahn, S. N. Engl. J. Med. (2001) [Pubmed]
  13. Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. van Hilten, B.J., van de Beek, W.J., Hoff, J.I., Voormolen, J.H., Delhaas, E.M. N. Engl. J. Med. (2000) [Pubmed]
  14. Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells. Hewett, J., Gonzalez-Agosti, C., Slater, D., Ziefer, P., Li, S., Bergeron, D., Jacoby, D.J., Ozelius, L.J., Ramesh, V., Breakefield, X.O. Hum. Mol. Genet. (2000) [Pubmed]
  15. Impaired sequence learning in carriers of the DYT1 dystonia mutation. Ghilardi, M.F., Carbon, M., Silvestri, G., Dhawan, V., Tagliati, M., Bressman, S., Ghez, C., Eidelberg, D. Ann. Neurol. (2003) [Pubmed]
  16. Inhibition of N-linked glycosylation prevents inclusion formation by the dystonia-related mutant form of torsinA. Bragg, D.C., Kaufman, C.A., Kock, N., Breakefield, X.O. Mol. Cell. Neurosci. (2004) [Pubmed]
  17. Cellular distribution of torsin A and torsin B in normal human brain. Konakova, M., Huynh, D.P., Yong, W., Pulst, S.M. Arch. Neurol. (2001) [Pubmed]
  18. Perinuclear biogenesis of mutant torsin-A inclusions in cultured cells infected with tetracycline-regulated herpes simplex virus type 1 amplicon vectors. Bragg, D.C., Camp, S.M., Kaufman, C.A., Wilbur, J.D., Boston, H., Schuback, D.E., Hanson, P.I., Sena-Esteves, M., Breakefield, X.O. Neuroscience (2004) [Pubmed]
  19. Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia. Kamm, C., Asmus, F., Mueller, J., Mayer, P., Sharma, M., Muller, U.J., Beckert, S., Ehling, R., Illig, T., Wichmann, H.E., Poewe, W., Mueller, J.C., Gasser, T. Neurology (2006) [Pubmed]
  20. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated DeltaE-torsinA mutant. Torres, G.E., Sweeney, A.L., Beaulieu, J.M., Shashidharan, P., Caron, M.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. Expression of the early-onset torsion dystonia gene (DYT1) in human brain. Augood, S.J., Penney, J.B., Friberg, I.K., Breakefield, X.O., Young, A.B., Ozelius, L.J., Standaert, D.G. Ann. Neurol. (1998) [Pubmed]
  22. Torsin A and its torsion dystonia-associated mutant forms are lumenal glycoproteins that exhibit distinct subcellular localizations. Kustedjo, K., Bracey, M.H., Cravatt, B.F. J. Biol. Chem. (2000) [Pubmed]
  23. Dystonia: clinical features, genetics, and treatment. Klein, C., Ozelius, L.J. Curr. Opin. Neurol. (2002) [Pubmed]
  24. Immunohistochemical localization and distribution of torsinA in normal human and rat brain. Shashidharan, P., Kramer, B.C., Walker, R.H., Olanow, C.W., Brin, M.F. Brain Res. (2000) [Pubmed]
  25. Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy. Carelli, V., Ghelli, A., Bucchi, L., Montagna, P., De Negri, A., Leuzzi, V., Carducci, C., Lenaz, G., Lugaresi, E., Degli Esposti, M. Ann. Neurol. (1999) [Pubmed]
  26. A heteroplasmic mitochondrial complex I gene mutation in adult-onset dystonia. Simon, D.K., Friedman, J., Breakefield, X.O., Jankovic, J., Brin, M.F., Provias, J., Bressman, S.B., Charness, M.E., Tarsy, D., Johns, D.R., Tarnopolsky, M.A. Neurogenetics (2003) [Pubmed]
  27. VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET. De La Fuente-Fernández, R., Furtado, S., Guttman, M., Furukawa, Y., Lee, C.S., Calne, D.B., Ruth, T.J., Stoessl, A.J. Synapse (2003) [Pubmed]
  28. D2 receptor binding in dopa-responsive dystonia. Künig, G., Leenders, K.L., Antonini, A., Vontobel, P., Weindl, A., Meinck, H.M. Ann. Neurol. (1998) [Pubmed]
  29. Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic paroxysmal dystonia. Nobrega, J.N., Gernert, M., Löscher, W., Raymond, R., Belej, T., Richter, A. Neuroscience (1999) [Pubmed]
  30. Molecular characterization of HLA class II genes in celiac disease patients of Latin American Caucasian origin. Herrera, M., Theiler, G., Augustovski, F., Chertkoff, L., Fainboim, L., DeRosa, S., Cowan, E.P., Satz, M.L. Tissue Antigens (1994) [Pubmed]
  31. A genetically controlled pairing anomaly between HLA-DQ alpha and HLA-DQ beta chains. Kwok, W.W., Thurtle, P., Nepom, G.T. J. Immunol. (1989) [Pubmed]
  32. Normal values and age-dependent changes in GTP cyclohydrolase I activity in stimulated mononuclear blood cells measured by high-performance liquid chromatography. Hibiya, M., Ichinose, H., Ozaki, N., Fujita, K., Nishimoto, T., Yoshikawa, T., Asano, Y., Nagatsu, T. J. Chromatogr. B Biomed. Sci. Appl. (2000) [Pubmed]
  33. Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2. Guerrini, R., Bonanni, P., Nardocci, N., Parmeggiani, L., Piccirilli, M., De Fusco, M., Aridon, P., Ballabio, A., Carrozzo, R., Casari, G. Ann. Neurol. (1999) [Pubmed]
  34. Altered expression of preproenkephalin and prodynorphin mRNA in a genetic model of paroxysmal dystonia. Nobrega, J.N., Parkes, J.H., Wong, P., Raymond, R., Richter, A. Brain Res. (2004) [Pubmed]
  35. Identification of a novel primary torsion dystonia locus (DYT13) on chromosome 1p36 in an Italian family with cranial-cervical or upper limb onset. Valente, E.M., Bentivoglio, A.R., Cassetta, E., Dixon, P.H., Davis, M.B., Ferraris, A., Ialongo, T., Frontali, M., Wood, N.W., Albanese, A. Neurol. Sci. (2001) [Pubmed]
  36. Adult onset idiopathic torsion dystonia is excluded from the DYT 1 region (9q34) in a Swedish family. Holmgren, G., Ozelius, L., Forsgren, L., Almay, B.G., Holmberg, M., Kramer, P., Fahn, S., Breakefield, X.O. J. Neurol. Neurosurg. Psychiatr. (1995) [Pubmed]
  37. One-Hz repetitive transcranial magnetic stimulation of the premotor cortex alters reciprocal inhibition in DYT1 dystonia. Huang, Y.Z., Edwards, M.J., Bhatia, K.P., Rothwell, J.C. Mov. Disord. (2004) [Pubmed]
  38. Inherited myoclonus-dystonia and epilepsy: further evidence of an association? O'Riordan, S., Ozelius, L.J., de Carvalho Aguiar, P., Hutchinson, M., King, M., Lynch, T. Mov. Disord. (2004) [Pubmed]
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