ArticleMolecular therapy. Nucleic acids2020
Mutant Allele-Specific CRISPR Disruption in DYT1 Dystonia Fibroblasts Restores Cell Function.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Non-invasive detection of allele-specific CRISPR-SaCas9-KKH disruption ofMolecular therapy. Nucleic acids · 2025Article
- The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.Brain : a journal of neurology · 2023Article
- Massively parallel evaluation and computational prediction of the activities and specificities of 17 small Cas9s.Nature methods · 2023Article
- DYT-Frontiers in neuroscience · 2023Review
- DYT-TOR1A genotype alters extracellular vesicle composition in murine cell model and shows potential for biomarker discovery.Dystonia (Lausanne, Switzerland) · 2023Article
- TorsinA folding and N-linked glycosylation are sensitive to redox homeostasis.Biochimica et biophysica acta. Molecular cell research · 2021Article
- Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice.Neurobiology of disease · 2021Article
- Targeting Long Non-coding RNA to Therapeutically Regulate Gene Expression in Cancer.Molecular therapy. Nucleic acids · 2020Review
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 4 countries.
Funding
Abstract
Most individuals affected with DYT1 dystonia have a heterozygous 3-bp deletion in the TOR1A gene (c.907_909delGAG). The mutation appears to act through a dominant-negative mechanism compromising normal torsinA function, and it is proposed that reducing mutant torsinA may normalize torsinA activity. In this study, we used an engineered Cas9 variant from Streptococcus pyogenes (SpCas9-VRQR) to target the mutation in the TOR1A gene in order to disrupt mutant torsinA in DYT1 patient fibroblasts. Selective targeting of the DYT1 allele was highly efficient with most common non-homologous end joining (NHEJ) edits, leading to a predicted premature stop codon with loss of the torsinA C terminus (delta 302-332 aa). Structural analysis predicted a functionally inactive status of this truncated torsinA due to the loss of residues associated with ATPase activity and binding to LULL1. Immunoblotting showed a reduction of the torsinA protein level in Cas9-edited DYT1 fibroblasts, and a functional assay using HSV infection indicated a phenotypic recovery toward that observed in control fibroblasts. These findings suggest that the selective disruption of the mutant TOR1A allele using CRISPR-Cas9 inactivates mutant torsinA, allowing the remaining wild-type torsinA to exert normal function.
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Registered trials
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