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Poster De Conférence Année : 2022

Development of a new mouse model for Myotonic Dystrophy type 1

Résumé

"Introduction The autosomal dominant Myotonic Dystrophy type 1 (DM1) disease, one of the most frequent neuromuscular diseases in adult displays muscular and non-muscular symptoms including myotonia, muscle weakness and atrophy as well as heart defects and cognitive impairments. DM1 is a triplet repeat disorder resulting from expansion of CTG repeats in the 3’untranslated region of the DMPK gene. The CTG tract ranges from 50 to thousands of repeats in patients whereas normal individuals have no more than 37 repeats. As a consequence, mutant DMPK mRNAs harboring triplet expansions are no longer exported to the cytoplasm, form nuclear aggregates that sequester and alter the function of RNA binding proteins such as MBNL, which are involved in alternative splicing control during development. Misregulation of splicing events leading to the re-expression of fetal isoforms in adults’ tissues that cannot fulfil the function of adult isoforms were associated with clinical symptoms making DM1 the archetype of spliceopathy. However, additional mechanisms are involved in the complex pathophysiology of this multisystemic disease. Results Characterization of the molecular and cellular mechanisms involved in DM1 pathogenesis but also assessment of therapeutic approaches, require models that phenocopy as much as possible the disease features observed in patients. Some DM1 mouse models currently exist and have led to numerous discoveries. However due to several drawbacks including the size and/or the purity of the CUG repeats as well as the level of CUGexp-RNA expression or its tissue expression profile, these models reproduce only part of the DM1 symptoms. Here, we aim to develop a model expressing the DMPK gene with large and pure CTG repeats in a tissue-specific and dose-dependent manner. For this purpose, we engineered a new model from the well-established transgenic DMSXL mouse model carrying the human DMPK gene with more than 1000 CTG. By using the CRISPR-Cas9 technology, we exchanged the DMPK promoter for a robust and inducible TRE3G promoter. Then, these mice were crossed with transgenic mice expressing the rtTA activator under the control of the HSA promoter allowing expression in skeletal muscles. Resulting HSArtTA- iDMSXL adult mice were given doxycycline to express CUGexp-DMPK transcripts and display DM1 molecular features such RNA foci and splicing defects. Conclusion Dosage effects, longitudinal studies, muscle function and histology are currently under investigation and will be discussed"
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Dates et versions

hal-04002540 , version 1 (23-02-2023)

Identifiants

  • HAL Id : hal-04002540 , version 1

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Alain Sureau, Aline Huguet, Ludovic Arandel, Aurélien Cordier, Pauline Megalli, et al.. Development of a new mouse model for Myotonic Dystrophy type 1. 7th International Myology Congress, Sep 2022, Nice, France. ⟨hal-04002540⟩
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