Quantitative RyR1 reduction and loss of calcium sensitivity of RyR1Q1970fsX16+A4329D cause cores and loss of muscle strength
| Autor: | Jan Eckhardt, Pawel Pelczar, Ahmed Alhussni, Thomas M. Humberstone, Christoph Bachmann, Susan Treves, Rebecca Sitsapesan, Alexis Ruiz, Abigail D. Wilson, Simona Boncompagni, Laura Pietrangelo, Elisa Venturi, Moran Elbaz, Francesco Zorzato, Chris Lindsay |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Myopathy Compound heterozygosity Mice 0302 clinical medicine Myopathy Central Core Genetics (clinical) Mice Knockout Ryanodine receptor Skeletal General Medicine Phenotype medicine.anatomical_structure Muscle medicine.symptom Heterozygote medicine.medical_specialty Knockout chemistry.chemical_element Motor Activity Biology Calcium NO 03 medical and health sciences Internal medicine Genetics medicine Animals Genetic Predisposition to Disease Calcium Signaling Muscle Strength Centronuclear myopathy Muscle Skeletal Molecular Biology Alleles Genetic Association Studies Calcium metabolism RYR1 Alleles Animals Calcium Calcium Signaling Disease Models Animal Genetic Association Studies Genetic Predisposition to Disease Heterozygote Male Mice Knockout Motor Activity Muscle Strength Muscle Skeletal Myopathy Central Core Phenotype Ryanodine Receptor Calcium Release Channel Mutation Animal Skeletal muscle Ryanodine Receptor Calcium Release Channel medicine.disease Disease Models Animal 030104 developmental biology Endocrinology chemistry Disease Models Mutation Central Core 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics. 28:2987-2999 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddz092 |
| Popis: | Recessive ryanodine receptor 1 (RYR1) mutations cause congenital myopathies including multiminicore disease (MmD), 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 MmD. 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 wild-type 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 compound heterozygous mice recapitulates the clinical picture of multiminicore patients and provide evidence of the molecular mechanisms responsible for skeletal muscle defects. |
| Databáze: | OpenAIRE |
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