Disease relevance of TOR1A

• The TOR1A (DYT1) gene family and its role in early onset torsion dystonia [1].
• Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease [2].
• CONCLUSIONS: Dystonia may be associated with abnormal movement preparation caused by defective sensorimotor integration [3].
• Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood [4].
• DYT1 dystonia appears to be a previously uncharacterized NE disease and the first, to our knowledge, to selectively affect CNS function [5].

Psychiatry related information on TOR1A

• The role of the pedunculopontine and cuneiform nuclei, and related brainstem brainstem structures, in mediating motor activity and controlling muscle tone suggests that alterations in these structures could underlie the pathophysiology of DYT1 dystonia [corrected][6]
• BACKGROUND: Prior studies suggest that dystonia is comorbid with affective disorders [7].
• Myoclonus dystonia: possible association with obsessive-compulsive disorder and alcohol dependence [8].
• We studied a 27-year-old woman who died after a 6-year history of progressive dementia, dystonia, ataxia, apraxia, spasticity, choreoathetosis, visual and auditory hallucinations, and optic atrophy [9].
• We now report small deletions in this candidate gene in the original DFN-1/MTS family, and in a family with deafness, dystonia and mental deficiency but not blindness [10].

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

• Early-onset torsion dystonia is a hereditary movement disorder thought to be caused by decreased release of dopamine into the basal ganglia, without apparent neuronal degeneration [14].
• Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism [15].
• Most cases of early-onset torsion dystonia are associated with a mutation in the DYT1 gene that results in the loss of a glutamic acid residue in the carboxy terminus of the encoded protein, torsinA [16].
• BACKGROUND: Early-onset torsion dystonia is a hyperkinetic movement disorder caused by a deletion of 1 glutamic acid residue in torsin A protein, a novel member of the AAA family of adenosine triphosphatases [17].
• Perinuclear biogenesis of mutant torsin-A inclusions in cultured cells infected with tetracycline-regulated herpes simplex virus type 1 amplicon vectors [18].

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

• By contrast, genotype-specific increases in metabolism were found in the putamen, anterior cingulate (BA 24/32), and cerebellar hemispheres of DYT1 carriers [3].
• DYT1 mRNA is highly enriched in the dopamine neurons of the substantia nigra pars compacta [21].
• During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum [15].
• This study supports the notion that DYT1 dystonia is associated with impaired protein handling and the nuclear envelope [6].
• We also noted tau/ubiquitin-immunoreactive aggregates in pigmented neurons of the substantia nigra pars compacta and locus coeruleus in all four DYT1 dystonia cases, but not in controls [6].

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].

References