Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients.
Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known DeltaGAG DYT1 dystonia and 88 subjects with DeltaGAG-negative dystonia.
We have used a transgenic mouse model of DYT1dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function.
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.
In conclusion, multiple cell types appear to utilize torsin AAA+ proteins and differential expression of torsinB may contribute to both the neuronal specific importance of torsinA and the symptom specificity of DYT1dystonia.
Abnormal anatomical connectivity of the supplementary motor area may contribute to the susceptibility of DYT1 carriers to develop clinical manifestations of dystonia.
Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress.
These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1dystonia and persists along development, representing a susceptibility factor for symptom generation.
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.
Interestingly, mutations in the TOR1A gene (the gene encoding torsinA) are associated with DYT1dystonia and with the preferential localization of mutated torsinA at the NE, where it is associated with lamina-associated polypeptide 1.
We conclude that marked phenotypic heterogeneity characterizes some families with DYT1dystonia, suggesting a role for genetic, environmental, or other modifiers.
Breakthroughs include the discovery of a genetic modifier that protects against clinical expression in DYT1dystonia and the identification of the gene causing DYT6, THAP1.
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.