Characterization of the muscular and cardiac diseases of the DMSXL mouse model, a transgenic mouse model for Myotonic Dystrophy type 1
Résumé
Context of the study Myotonic Dystrophy type 1 (DM1) is an autosomal dominant, progressive, and multi-systemic genetic disorder affecting at least 900,000 individuals worldwide. It is primarily characterized by myotonia, muscular weakness, and muscle atrophy. Other clinical manifestations include cardiac conduction defects, cardio-respiratory problems, cataracts, endocrine dysfunction and frequent neurological manifestations. The disease is caused by unnaturally expanded repeats of CTG trinucleotide in the 3'-untranslated region of the DMPK (dystrophia myotonica protein kinase) gene. In DM1 patients, the number of CTG repeats within the mutant DMPK allele ranges from 50 to 5000. The number of repeats roughly correlates with disease onset, severity and life expectancy (more repeats correlated with earlier onset, more severe symptoms and shorter lifespan). CTG-containing mutant DMPK transcripts are toxic. They aggregate as nuclear foci and impact the expression and function of RNA-binding proteins (such as MBNL1 and CELF1), resulting in spliceopathy of downstream effector genes, which accounts for much of the disease phenotype. Several therapeutic approaches either pharmacological or gene-therapy based, are under investigation to address this unmet medical need. One current limitation for the efficient evaluation and development of therapeutic products is the lack of DM1 animal models that ideally recapitulate the symptoms and the complex pathophysiology of this disease. Among available animal models, one of the most relevant remains the DMSXL mouse model, which carries a 45-kb human genomic fragment including the DMPK gene with more than 1200 CTG repeats. The human DMPK transgene is under the control of its own promoter and has been shown to have an almost ubiquitous expression. Initial characterization studies demonstrated that homozygous DMSXL mice display several manifestations of the human DM1 pathology, including growth retardation, muscle defects, cognitive impairments, nuclear foci, and splicing abnormalities. After establishing a colony in our own facility, our goal was to define in our hands the most relevant and sensitive readouts that characterize this animal model, especially for its muscular and cardiac diseases, in both genders.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers produits par l'(les) auteur(s) |
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