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Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies

Abstract : The dominant tibial muscular dystrophy (TMD) and recessive limb-girdle muscular dystrophy 2J are allelicdisorders caused by mutations in the C-terminus of titin, a giant sarcomeric protein. Both clinical presentationswere initially identified in a large Finnish family and linked to a founder mutation (FINmaj). To furtherunderstand the physiopathology of these two diseases, we generated a mouse model carrying the FINmajmutation. In heterozygous mice, dystrophic myopathology appears late at 9 months of age in few distalmuscles. In homozygous (HO) mice, the first signs appear in the Soleus at 1 month of age and extend tomost muscles at 6 months of age. Interestingly, the heart is also severely affected in HO mice. The mutationleads to the loss of the very C-terminal end of titin and to a secondary deficiency of calpain 3, a partner oftitin. By crossing the FINmaj model with a calpain 3-deficient model, the TMD phenotype was corrected,demonstrating a participation of calpain 3 in the pathogenesis of this disease.
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https://hal-univ-evry.archives-ouvertes.fr/hal-02321460
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Submitted on : Monday, October 21, 2019 - 11:36:46 AM
Last modification on : Monday, June 29, 2020 - 4:32:12 PM

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Karine Charton, Nathalie Danièle, Anna Vihola, Carinne Roudaut, Evelyne Gicquel, et al.. Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies. Human Molecular Genetics, Oxford University Press (OUP), 2010, 19 (23), pp.4608-4624. ⟨10.1093/hmg/ddq388⟩. ⟨hal-02321460⟩

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