We conclude that there is ample evidence to suggest that the cerebellum plays a role in some dystonias, including the early-onset primary torsion dystonia DYT1 and that further studies examining the role of this brain region and its interaction with the basal ganglia in dystonia are warranted.
We report that changes of phosphodiesterase-10A (PDE10A) can map widespread functional imbalance of basal ganglia circuits in a mouse model of DYT1dystonia overexpressing mutant torsinA.
Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a.
The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network.
Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes.
Here, we provide for the first time direct measurement of elevated striatal extracellular acetylcholine (ACh) in a knock-in mouse model of human DYT1dystonia (TorA<sup>∆E/+</sup> mice), confirming a striatal hypercholinergic state.
Our study suggests that there is an association between rs35153737 and dystonia in a southwestern Chinese population, and it may be caused by high linkage disequilibrium between this deletion and potential pathogenic variants in TOR1A.
TOR1A (torsinA, DYT1) is the leading cause of early-onset generalized dystonia, however, the associations between common TOR1A single nucleotide polymorphisms (SNPs) and primary adult-onset focal dystonia are controversial.
Together with previous findings in the motor cortex and the spinal cord, the brainstem may lie closer to the pathogenesis of dystonia than the motor cortex in DYT1 gene carriers.
Rodent models of DYT1dystonia, a motor disorder caused by a single gene mutation, demonstrate increased long-term potentiation and decreased long-term depression in corticostriatal synapses.
We screened the entire coding sequence and the 5'-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls.
To analyze contribution of rs3842225 and rs1182 single nucleotide polymorphisms (SNP) in TOR1A gene, the causative gene for the DYT1 form of hereditary early-onset generalized dystonia, to the development of focal and segmental dystonia in Russian patients.
This observation raises the possibility of genotype-phenotype correlations in DYT1 and indicates that the clinical spectrum of this type of dystonia might be broader then previous classic descriptions.
Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is early-onset torsion (DYT1) dystonia, a severe movement disorder.