Recessive Mutations in RYR1 Are a Common Cause of Congenital Fiber

Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, Australia.
Human Mutation (Impact Factor: 5.14). 07/2010; 31(7):E1544-50. DOI: 10.1002/humu.21278
Source: PubMed

ABSTRACT The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion.

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    • "Both dominant and recessive mutations have been reported in RYR1. Dominant mutations have traditionally been associated with central core disease (CCD) and/or a susceptibility to malignant hyperthermia (MHS) [2], while recessive mutations predominate in patients with multiminicore disease (MmD), centronuclear myopathy (CNM), and congenital fiber type disproportion (CFTD) [4-6]. At this time, no specific treatments are available for any RYR1-related myopathy, though modifying oxidative stress may be one therapeutic avenue [7]. "
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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 · 3.36 Impact Factor
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    • "Several molecular mechanisms have been proposed explaining the mutations’ effect on RyR1 function (see [17], [26] for review): leaky channels and voltage sensor uncoupled channels for CCD [10], [26]–[30], hypersensitive channels for MHS [31], [32], low RyR1 expression/content for MmD [9], [33], [34], CFTD [21] and CNM [3], [20]. Interestingly, western blot analysis demonstrated a drastic reduction in the amount of RyR1 protein in these patients’ muscle biopsy. "
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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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    • "These findings emphasize the phenotypic variability of RYR1–related disorders. Mutations in RYR1 have been associated with different neuromuscular phenotypes including central core disease (CCD, MIM# 117000) [22], [23], multiminicore disease (MmD, MIM# 255320) [24], congenital myopathy with central or internalized nuclei [15], [16], congenital fiber-type disproportion (CFTD, MIM# 255310) [25], foetal akinesia [26], benign Samaritan congenital myopathy [27], and malignant hyperthermia susceptibility (MH, MIM# 145600) [28]. RYR1 codes for the skeletal muscle ryanodine receptor, a key player in skeletal muscle excitation-contraction coupling. "
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    ABSTRACT: Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient's access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity.
    PLoS ONE 06/2013; 8(6):e67527. DOI:10.1371/journal.pone.0067527 · 3.23 Impact Factor
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