ArticleHuman molecular genetics2015
A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 36 citations in OpenAlex.
- Validation of a torsinA cerebellar knockdown model of DYT1 dystonia.Dystonia (Lausanne, Switzerland) · 2026Article
- Transcriptomic profiling of DYT-TOR1A patient-derived iPSC reveals dysregulation in extracellular matrix, lipid metabolism, and Chr22q11.23.BMC medical genomics · 2025Article
- Altered Functional Brain Connectivity in Dyt1 Knock-in mouse models.Dystonia (Lausanne, Switzerland) · 2025Article
- Subtle changes in Purkinje cell firing in Purkinje cell-specificDystonia (Lausanne, Switzerland) · 2025Article
- Pathophysiology of Dyt1-Science translational medicine · 2023Article
- Motor deficit and lack of overt dystonia in Dlx conditional Dyt1 knockout mice.Behavioural brain research · 2023Article
- Dystonia-like behaviors and impaired sensory-motor integration following neurotoxic lesion of the pedunculopontine tegmental nucleus in mice.Frontiers in neurology · 2023Article
- p97/UBXD1 Generate Ubiquitylated Proteins That Are Sequestered into Nuclear Envelope Herniations in Torsin-Deficient Cells.International journal of molecular sciences · 2022Article
- Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of TOR1A dystonia.Neurobiology of disease · 2021Article
- TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia.The Journal of clinical investigation · 2021Article
- CNS critical periods: implications for dystonia and other neurodevelopmental disorders.JCI insight · 2021Review
- The abnormal firing of Purkinje cells in the knockin mouse model of DYT1 dystonia.Brain research bulletin · 2020Article
- Article
- Loss of the dystonia gene Thap1 leads to transcriptional deficits that converge on common pathogenic pathways in dystonic syndromes.Human molecular genetics · 2019Article
- Protective role of the lipid phosphatase Fig4 in the adult nervous system.Human molecular genetics · 2018Article
- TorsinA dysfunction causes persistent neuronal nuclear pore defects.Human molecular genetics · 2018Article
- Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia.Neurobiology of disease · 2017Article
- The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage.Developmental cell · 2017Article
- Heterozygous Gnal Mice Are a Novel Animal Model with Which to Study Dystonia Pathophysiology.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia.Cerebellum (London, England) · 2017Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
DYT1 dystonia, the most common inherited form of primary dystonia, is a neurodevelopmental disease caused by a dominant mutation in TOR1A. This mutation ('ΔE') removes a single glutamic acid from the encoded protein, torsinA. The effects of this mutation, at the molecular and circuit levels, and the reasons for its neurodevelopmental onset, remain incompletely understood. To uniquely address key questions of disease pathogenesis, we generated a conditional Tor1a knock-in allele that is converted from wild-type to DYT1 mutant ('induced' ΔE: Tor1a(i-ΔE)), following Cre recombination. We used this model to perform a gene dosage study exploring the effects of the ΔE mutation at the molecular, neuropathological and organismal levels. These analyses demonstrated that ΔE-torsinA is a hypomorphic allele and showed no evidence for any gain-of-function toxic properties. The unique capabilities of this model also enabled us to test a circuit-level hypothesis of DYT1 dystonia, which predicts that expression of the DYT1 genotype (Tor1a(ΔE/+)) selectively within hindbrain structures will produce an overtly dystonic animal. In contrast to this prediction, we find no effect of this anatomic-specific expression of the DYT1 genotype, a finding that has important implications for the interpretation of the human and mouse diffusion tensor-imaging studies upon which it is based. These studies advance understanding of the molecular effects of the ΔE mutation, challenge current concepts of the circuit dysfunction that characterize the disease and establish a powerful tool that will be valuable for future studies of disease pathophysiology.
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