Article

Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies

Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London W12 0NN.
Brain (Impact Factor: 10.23). 09/2007; 130(Pt 8):2024-36. DOI: 10.1093/brain/awm096
Source: PubMed

ABSTRACT Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel.

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    • "There is no clear division between MH and CCD and some RyR1 mutations have been linked to a combined MH and CCD phenotype [178]. Notably, most MH mutations in RyR1 gene lead to a gain-of-function effect, with increased sensitivity to channel agonists, causing a leak in RyR1 channels, whereas most CCD-related mutations have been associated with channels displaying reduced conductance [179]. "
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    ABSTRACT: Calcium (Ca2+) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs) and inositol 1,4,5--trisphosphate receptors (IP3Rs) are the majorCa2+ release channels (CRCs) on the endo/sarcoplasmic reticulum(ER/SR).RyR1 and RyR2 are the key isoforms in skeletal and cardiac muscle and are essential role in excitation--contraction(E--C) coupling. IP3R1 and IP3R2 are required for muscle and neuronal function. RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca2+ release. This review focuses on the roles of CRCs in heart, skeletal muscle, brain, and aging.
    Current Molecular Pharmacology 05/2015;
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    • "A smaller study from Zhou and colleagues (2007) observed that recessive RYR1 mutations are located throughout the gene and are associated with variable histological patterns and symptoms. An additional finding, from this and from other existing studies, is that many recessive RYR1 mutations are hypomorphic sequence changes that lead to markedly reduced or absent protein expression [1,10]. "
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    ABSTRACT: 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. 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 hough, 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.
    Orphanet Journal of Rare Diseases 08/2013; 8(1):117. DOI:10.1186/1750-1172-8-117 · 3.96 Impact Factor
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    • "Interestingly, many dominant mutations linked to MH appear to cluster in the cytoplasmic N-terminal and central region (commonly called hot spot region 1 & 2 respectively) while mutations found in patients with CCD are predominantly localized to the C-terminal hydrophobic region (hot spot 3). On the contrary, recessive MmD mutations are spread all over the gene [9]. These observations emphasize one aspect of the complex genotype-phenotype correlations associated with RYR1 mutations. "
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    ABSTRACT: We describe an autosomal recessive heterogeneous congenital myopathy in a large consanguineous family. The disease is characterized by variable severity, progressive course in 3 of 4 patients, myopathic face without ophthalmoplegia and proximal muscle weakness. Absence of cores was noted in all patients. Genome wide linkage analysis revealed a single locus on chromosome 19q13 with Zmax = 3.86 at θ = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Direct sequencing of the main candidate gene within the candidate region, RYR1, was performed. A novel homozygous A to G nucleotide substitution (p.Y3016C) within exon 60 of the RYR1 gene was found in patients. ARMS PCR was used to screen for the mutation in all available family members and in an additional 150 healthy individuals. This procedure confirmed sequence analysis and did not reveal the A to G mutation (p.Y3016C) in 300 chromosomes from healthy individuals. Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca(2+) stores. Western blot analysis demonstrated a significant reduction of the RyR1 protein in the patient's muscle concomitant with a reduction of the DHPRα1.1 protein. This novel mutation resulting in RyR1 protein decrease causes heterogeneous clinical presentation, including slow progression course and absence of centrally localized cores on muscle biopsy. We suggest that RYR1 related myopathy should be considered in a wide variety of clinical and pathological presentation in childhood myopathies.
    PLoS ONE 07/2013; 8(7):e69296. DOI:10.1371/journal.pone.0069296 · 3.23 Impact Factor
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