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A dog model for centronuclear myopathy (CNM) carrying the most common DNM2 mutation

Abstract : Mutations in DNM2 cause autosomal dominant centronuclear myopathy (ADCNM), a rare disease characterized by skeletal muscle weakness and structural anomalies of the myofibres including nuclear centralization and mitochondrial mispositioning. Following the clinical report of a Border Collie male with exercise intolerance and histopathological hallmarks of CNM on the muscle biopsy, we identified the c.1393C>T (R465W) mutation in DNM2, corresponding to the most common ADCNM mutation in humans. In order to establish a large animal model for longitudinal and preclinical studies on the muscle disorder, we collected sperm samples from the Border Collie male and generated a dog cohort for subsequent clinical, genetic, and histological investigations. Four of the five offspring carried the DNM2 mutation and showed muscle atrophy and a mildly impaired gait. Morphological examinations of transverse muscle sections revealed CNM-typical fibres with centralized nuclei and remodelling of the mitochondrial network. Overall, the DNM2-CNM dog represents a faithful animal model for the human disorder, allows the investigation of ADCNM disease progression, and constitutes a valuable complementary tool to validate innovative therapies established in mice.
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Submitted on : Friday, March 18, 2022 - 1:18:10 PM
Last modification on : Monday, October 3, 2022 - 12:54:07 PM

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Johann Böhm, Inès Barthélémy, Charlène Landwerlin, Nicolas Blanchard-Gutton, Frédéric Relaix, et al.. A dog model for centronuclear myopathy (CNM) carrying the most common DNM2 mutation. Disease Models & Mechanisms, In press, ⟨10.1242/dmm.049219⟩. ⟨hal-03613313⟩



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