Dataset Information

Mouse model of severe recessive RYR1-related myopathy.

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.

SUBMITTER: Brennan S

PROVIDER: S-EPMC6737254 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mouse model of severe recessive RYR1-related myopathy.

Brennan Stephanie S Garcia-Castañeda Maricela M Michelucci Antonio A Sabha Nesrin N Malik Sundeep S Groom Linda L Wei LaPierre Lan L Dowling James J JJ Dirksen Robert T RT

Human molecular genetics 20190901 18

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 rec ...[more]

PMID: 31107960

Similar Datasets

Project description:RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n?=?14) and previously reported (n?=?92) recessive RYR1 cases.Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.

Project description:ObjectiveTo report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients.MethodsEleven patients evaluated in the neonatal period with severe neonatal-onset RYR1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed.ResultsClinical features associated with the severe neonatal presentation of RYR1-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype-findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores.ConclusionsThis series confirms and expands the clinical and histologic variability associated with severe congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated myopathy in the appropriate clinical context.

Dataset Information

Mouse model of severe recessive RYR1-related myopathy.

Publications

Mouse model of severe recessive RYR1-related myopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets