Disease relevance of Tor1a

• Early-onset torsion dystonia is a hyperkinetic movement disorder caused by a deletion of one glutamic acid residue in torsinA, a novel member of the AAA-family of ATPases [1].
• These data suggest that gene interaction between DQ1 and DQ2 (or alleles at associated loci), possibly from gene complementation of trans-associated surface molecules, influences the autoimmune response in primary Sjögren's syndrome [2].
• These membrane abnormalities develop in postmigratory embryonic neurons and subsequently worsen with further neuronal maturation, a finding evocative of the developmental dependence of DYT1 dystonia [3].
• Mutations in torsinA underlie early onset torsion dystonia, an autosomal dominant, neurologically based movement disorder [4].
• Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease [5].
• Overexpression of DeltaE-torsinA in neuroblastoma cells increases FM1-43 uptake [6].

Psychiatry related information on Tor1a

• However, mice overexpressing hMT, but not hWT, torsinA displayed a reduced ability to learn motor skills in an accelerating rotarod paradigm [7].
• Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability [8].
• Neurological damage includes visual disorders such as vertical supranuclear gaze palsy, movement disorders such as dystonia and ataxia, dementia, and seizures [9].
• PURPOSE OF REVIEW: Infantile spasms, mental retardation, autism, and dystonia represent disabling diseases for which little etiologic information is available [10].
• TH may be closely related to the pathogenesis of neurological diseases, such as dystonia and Parkinson's disease, psychiatric diseases, such as affective disorders and schizophrenia, as well as cardiovascular diseases [11].

High impact information on Tor1a

• Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse [12].
• This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA [13].
• A transgene containing lacZ inserted into the dystonia locus is expressed in neural tube [14].
• An analysis of all possible combinations at DQ has shown that the entire effect was due to heterozygotes expressing the DQ1 and DQ2 alleles [2].
• The similarity of the DQ8, DQ2 and I-A(g7) peptide-binding pockets suggests that diabetes is caused by the same antigen-presentation event(s) in humans and NOD mice [15].

Chemical compound and disease context of Tor1a

• The hph-1 ENU-mutant mouse provides a model of tetrahydrobiopterin deficiency for studying hyperphenylalaninaemia, dopa-response dystonia, and vascular dysfunction [16].

Biological context of Tor1a

• TorsinB is highly homologous to torsinA with its gene adjacent to that for torsinA on human chromosome 9q34 [4].
• The gene defect has incomplete penetrance, with approximately 30% of carriers developing clinically evident dystonia [7].
• In this issue of Neuron, Goodchild et al. show that torsinA knockout and knockin mice have similar phenotypes, which suggests that the mutant torsinA allele causes disease because it has decreased function [17].
• Several human inherited diseases have been localized to the Xq13.3 region of the human X chromosome (X-linked dystonia with Parkinsonism, sideroblastic anemia, SCID, Menkes disease and X-linked mental retardation loci) [18].
• Paying particular attention to the position of potential major histocompatibility complex (MHC) anchor residues, several were selected for testing in a DQ2-gamma-I-gliadin-restricted T-cell system [19].

Anatomical context of Tor1a

• Immunolocalization studies revealed that torsinA and torsinB were widely expressed throughout the mouse central nervous system [1].
• Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope [3].
• Immunoprecipitation studies in cultured cells and human brain tissue indicate that torsinA and torsinB are associated with each other in cells [4].
• Overexpression of both wild-type torsinB and mutant torsinA lead to enrichment of the protein in the nuclear envelope and formation of large cytoplasmic inclusions [4].
• Although functional significance of the patterns of torsinA and B expression in the developing brain remains to be established, our findings provide a basis for investigating the role of torsins in specific processes such as neurogenesis, neuronal migration, axon/dendrite development, and synaptogenesis [20].

Associations of Tor1a with chemical compounds

• The mutation removes a glutamic acid in the carboxy region of torsinA, a member of the Clp protease/heat shock protein family [21].
• TorsinA, the gene linked to early-onset dystonia, is upregulated by the dopaminergic toxin MPTP in mice [22].
• Thus, loss of BNIP-H function could render glutamate excitotoxicity or/and deregulated glutamatergic activation, leading to ataxia, dystonia or other neurological disorders [23].
• Botulinum toxin versus trihexyphenidyl in cervical dystonia: a prospective, randomized, double-blind controlled trial [24].
• The neurodegeneration induced by BoNT C1 may be significant in terms of its efficacy for the clinical treatment of dystonia and spasticity [25].

Other interactions of Tor1a

• In Western blot analysis of mouse brain homogenates, the antibodies specifically recognized 33 kDa endogenous torsinA and 52 kDa endogenous torsinB [1].
• Dyt1 DeltaGAG tissues also have ubiquitin- and torsinA-containing aggregates in neurons of the pontine nuclei [21].
• Cplx1-/- mice show pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia and resting tremor [26].
• Mutations in mouse Scn8a result in neurological disorders, including paralysis, ataxia, and dystonia [27].
• Mutations in GTP-cyclohydrolase I (GTP-CH) have been identified as causing a range of inborn errors of metabolism, including dopa-responsive dystonia [28].

Analytical, diagnostic and therapeutic context of Tor1a

• Molecular cloning and expression of rat torsinA in the normal and genetically dystonic (dt) rat [29].
• In situ hybridization reveals a widespread distribution of torsinA mRNA within brain [29].
• Overexpression of torsinA in mouse neural CAD cells followed by immunocytochemistry, revealed a dramatically different pattern of distribution for wild-type and mutant forms of the protein [30].
• To find out whether botulinum toxin alters the excitability of cortical motor areas, we studied intracortical inhibition with transcranial magnetic stimulation in patients with upper limb dystonia before, 1 month after, and 3 months after the injection of botulinum toxin type A in the affected muscles [31].
• The waddles (wdl) mouse is a unique animal model that exhibits ataxia and appendicular dystonia without pathological abnormalities of either the central or the peripheral nervous systems [32].

References