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Recessive RYR1 mutations cause congenital myopathies including multiminicore disease, congenital fiber type disproportion and centronuclear myopathy. We created a mouse model knocked-in for the Q1970fsX16 + A4329D RYR1 mutations, which are isogenic with those identified in a severely affected child with multiminicore disease. During the first 20 weeks after birth the body weight and the spontaneous running distance of the mutant mice were 20% and 50% lower compared to WT littermates. Skeletal muscles from mutant mice contained 'cores' characterized by severe myofibrillar disorganization associated with misplacement of mitochondria. Furthermore, their muscles developed less force, and had smaller electrically evoked calcium transients. Mutant RyR1 channels incorporated into lipid bilayers were less sensitive to calcium and caffeine, but no change in single-channel conductance was observed. Our results demonstrate that the phenotype of the RyR1Q1970fsX16 + A4329D heterozygous mice recapitulates the clinical picture of multiminicore patients, and provide evidence of the molecular mechanisms responsible for skeletal muscle defects.

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Journal article


Hum Mol Genet

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