ArticleHuman molecular genetics2019
Mouse model of severe recessive RYR1-related myopathy.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Actually, what is a gain-of-function mutation?Genetics · 2026Article
- Exacerbated Skeletal Muscle Phenotype in Mice with 'Homotypic' Expression of the Tubular Aggregate Myopathy ORAI1 G100S Mutation.Biomedicines · 2026Article
- Structural basis for simvastatin-induced skeletal muscle weakness associated with type 1 ryanodine receptor T4709M mutation.The Journal of clinical investigation · 2025Article
- Tamoxifen treatment fails to improve muscle dysfunction in a model of recessive RYR1-linked centronuclear myopathy.Disease models & mechanisms · 2025Article
- NADSkeletal muscle · 2025Article
- The RyR1 P3528S Substitution Alters Mouse Skeletal Muscle Contractile Properties and RyR1 Ion Channel Gating.International journal of molecular sciences · 2023Article
- Article
- Function of a mutant ryanodine receptor (T4709M) linked to congenital myopathy.Scientific reports · 2023Article
- RYR-1-Related Diseases International Research Workshop: From Mechanisms to Treatments Pittsburgh, PA, U.S.A., 21-22 July 2022.Journal of neuromuscular diseases · 2023Article
- Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies.The Journal of general physiology · 2022Review
- Postdevelopmental knockout of Orai1 improves muscle pathology in a mouse model of Duchenne muscular dystrophy.The Journal of general physiology · 2022Article
- X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition.Acta neuropathologica · 2022Article
- Ryanodine receptor RyR1-mediated elevation of CaJournal of animal science and biotechnology · 2022Article
- Correlation of Phenotype-Genotype and Protein Structure inFrontiers in neurology · 2022Article
- Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances.International journal of molecular sciences · 2021Review
- Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature.Skeletal muscle · 2020Review
- In vivo RyR1 reduction in muscle triggers a core-like myopathy.Acta neuropathologica communications · 2020Article
- Structural basis for diamide modulation of ryanodine receptor.Nature chemical biology · 2020Article
- Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990-2019.Orphanet journal of rare diseases · 2020Article
- From worms to fish to mice.eLife · 2020Article
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9 authors.
Funding
Abstract
Ryanodine receptor type I (RYR1)-related myopathies (RYR1 RM) are a clinically and histopathologically heterogeneous group of conditions that represent the most common subtype of childhood onset non-dystrophic muscle disorders. There are no treatments for this severe group of diseases. A major barrier to therapy development is the lack of an animal model that mirrors the clinical severity of pediatric cases of the disease. To address this, we used CRISPR/Cas9 gene editing to generate a novel recessive mouse model of RYR1 RM. This mouse (Ryr1TM/Indel) possesses a patient-relevant point mutation (T4706M) engineered into 1 allele and a 16 base pair frameshift deletion engineered into the second allele. Ryr1TM/Indel mice exhibit an overt phenotype beginning at 14 days of age that consists of reduced body/muscle mass and myofibre hypotrophy. Ryr1TM/Indel mice become progressively inactive from that point onward and die at a median age of 42 days. Histopathological assessment shows myofibre hypotrophy, increased central nuclei and decreased triad number but no clear evidence of metabolic cores. Biochemical analysis reveals a marked decrease in RYR1 protein levels (20% of normal) as compared to only a 50% decrease in transcript. Functional studies at end stage show significantly reduced electrically evoked Ca2+ release and force production. In summary, Ryr1TM/Indel mice exhibit a post-natal lethal recessive form of RYR1 RM that pheno-copies the severe congenital clinical presentation seen in a subgroup of RYR1 RM children. Thus, Ryr1TM/Indel mice represent a powerful model for both establishing the pathomechanisms of recessive RYR1 RM and pre-clinical testing of therapies for efficacy.
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