Recessive Mutations in RYR1 Are a Common Cause of Congenital Fiber

ArticleinHuman Mutation 31(7):E1544-50 · July 2010with23 Reads
DOI: 10.1002/humu.21278 · Source: PubMed
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.
    • "YSCDB-2084; No. of Pages 12 recessive RYR1 mutations no dysregulation of Ca 2+ homeostasis was detected [55]. This result is puzzling since muscle biopsies from the same patients show significant depletion of RyR1 protein , which should lead to a pronounced reduction of the amount of Ca 2+ released following RyR1 activation [55][56][57]. In a recent study we addressed the pathophysiology of recessive RYR1 mutations and in particular the epigenetic mechanism(s) responsible for bringing about such a drastic decrease of RyR1 protein in the muscles of patients [55]. "
    [Show abstract] [Hide abstract] ABSTRACT: The physiological process by which Ca(2+) is released from the sarcoplasmic reticulum is called excitation-contraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca(2+)channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca(2+) release channel of the sarcoplasmic reticulum. The released Ca(2+) binds to troponin C, enabling contractile thick-thin filament interactions. The Ca(2+) is subsequently transported back into the sarcoplasmic reticulum by specialized Ca(2+) pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca(2+) channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca(2+) pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca(2+) homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca(2+) regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca(2+) regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca(2+) dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca(2+) homeostasis.
    Article · Jul 2016
    • "RYR1 mutations associated with MHS are typically heterozygous missense substi- tutions192021. Subsequently RYR1 mutations were described in the context of a variety of histological subtypes of congenital myopathies including central core disease, minicore/centronuclear myopathy with external ophthalmoplegia, centronuclear myopathy and congenital fibre-type disproportion222324. Both dominant and recessive forms of RYR1-related congenital myopathies have been described and genotype-phenotype correlations have provided insights into likely clinical-functional relationships . "
    [Show abstract] [Hide abstract] ABSTRACT: IntroductionFoetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes.ResultsAfter mapping a novel locus for FADS/LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/LMPS and 30 with EVMPS) revealed two additional homozygous mutations (in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/LMPS was 8.3%.Conclusions Our findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/LMPS even in the absence of specific histopathological indicators of RYR1-related disease.
    Full-text · Article · Dec 2014
    • "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]. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Aug 2013
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