A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course
Valérie BiancalanaJohn RenduAnnabelle ChaussenotHelen MeciliÉric BiethMélanie FradinSandra MercierMaud MichaudMarie‐Christine NouguèsLaurent PasquierSabrina SacconiNorma B. RomeroPascale MarcorellesFrançois‐Jérôme AuthierAntoinette Gelot BernabeEmmanuelle Uro‐CosteClaude CancèsBertrand IsidorArmelle MagotMarie-Christine Minot-MyhiéYann PéréonJulie Perrier-BoeswillwaldG. BretaudeauNicolas DondaineAlison BouzenardMégane PizzimentiB. EymardAna FerreiroJocelyn LaporteJulien FauréJohann Böhm
5
Citation
38
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca 2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca 2+ -dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1 -related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1 -typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.Keywords:
Central core disease
Congenital myopathy
Malignant hyperthermia
Muscle disorder
This PhD thesis has been focused on the identification and functional characterization of sequence variants in the RYR1 gene, associated with Malignant hyperthermia (MH) and some congenital myopathies (CMs). MH is an autosomal dominant pharmacogenetic disorder caused by an altered intracellular Ca2+ homeostasis. This pathology shows a life treatening hypermetabolic crisis after administration of anaesthetics and/or depolarizing muscle relaxants. MH is syntomatologic silent and until now the only sensitive and specific test for the diagnosis of MH is the in vitro contracture test (IVCT), carried out on muscle byopsies. MH presents wide genetic heterogeneity: six genetic loci associated with the MH suscettible phenotype (MHS) have been identified. In more than 70% of MHS patients the locus segregating with the pathology is MHS-1, where the RYR1 gene maps. The RYR1 gene codifies for the ryanodine receptor type 1 (RYR1), a calcium release channel localised in the sarco/endoplasmic reticulum (SR/ER) membrane of skeletal muscle and B-lymphocytes. CMs are a heterogeneous group of inherited neuromuscular disorders characterized by hypotonia and muscle weakness, that usually present at birth or early childhood or rarely adulthood. Myophathies linked to RYR1 mutations are differentiated on the basis of the histopathological features in: core myopathies (central core disease, multiminicore disease, nemaline rod myopathy, and centronuclear myopathy), characterized histologically by central cores, multi-minicores, nemaline rods, central nuclei in muscle fibers, respectively; and others myopathies (congenital neuromuscular disease with uniform Type 1 fibers, and congenital fiber-type disproportion myopathy) characterized histologically by the almost exclusive presence of Type 1 muscle fiber and relative hypotrophy of type 1 muscle fibers, respectively. Great phenotypic and histopathological overlap and marked phenotypic variability are present in different myopathies. So far more than 200 sequence variants have been identified in the RYR1 gene, but only 28 variants have been investigated for their functional effect and included in the guidelines for molecular genetic detection of MH susceptibility (www.emhg.org).
In this study, the mutation analysis of the RYR1 gene was performed by Denaturing High Performance Liquid Chromatography (dHPLC) and automatic sequencing in 24 MHS subjects, one CCD patient and one with minicores. 14 RYR1 gene sequence variants, an in-frame insertion variant and several known and novel polymorphisms have been identified. We characterized the effect of nine RYR1 variants on the channel function. The functional characterization was performed by two in vitro assays, proton and calcium release assays, on Epstein-Barr virus immortalized B-lymphocytes from patients carrying the sequence variants. The results showed alterations in the functional activity of the RYR1 mutated channel.
Central core disease
Malignant hyperthermia
Congenital myopathy
Nemaline myopathy
Muscle disorder
Compound heterozygosity
Cite
Citations (0)
Central core disease
Malignant hyperthermia
Congenital myopathy
Cite
Citations (132)
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation–contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility. Hum Mutat 15:410–417, 2000. © 2000 Wiley-Liss, Inc.
Malignant hyperthermia
Central core disease
Congenital myopathy
Cite
Citations (341)
Central core disease
Malignant hyperthermia
Congenital myopathy
Pedigree chart
Muscle disorder
Cite
Citations (116)
Malignant hyperthermia
Central core disease
Congenital myopathy
Compound heterozygosity
Cite
Citations (34)
Abstract Two likely causative mutations in the RYR1 gene were identified in two patients with myopathy with tubular aggregates, but no evidence of cores or core‐like pathology on muscle biopsy. These patients were clinically evaluated and underwent routine laboratory investigations, electrophysiologic tests, muscle biopsy and muscle magnetic resonance imaging (MRI). They reported stiffness of the muscles following sustained activity or cold exposure and had serum creatine kinase elevation. The identified RYR1 mutations (p.Thr2206Met or p.Gly2434Arg, in patient 1 and patient 2, respectively) were previously identified in individuals with malignant hyperthermia susceptibility and are reported as causative according to the European Malignant Hyperthermia Group rules. To our knowledge, these data represent the first identification of causative mutations in the RYR1 gene in patients with tubular aggregate myopathy and extend the spectrum of histological alterations caused by mutation in the RYR1 gene.
Malignant hyperthermia
Central core disease
Congenital myopathy
Creatine kinase
Cite
Citations (10)
Recent advances of research on malignant hyperthermia(MH) were reviewed. The rate of Ca-induced Ca release(CICR) from the sarcoplasmic reticulum(SR) was measured on the skinned muscle fiber preparation of porcine and human MH. The rate of CICR was significantly increased both in porcine and human MH. These observations supported conclusion obtained by genetical studies that the ryanodine receptor (RYR1) was site of abnormality in most of porcine and part of human MH. The RYR1 is Ca release channel of skeletal muscle SR and CICR is one of main function of the channel. Subsequently, point mutation of RYR1 gene was found in the foot domain of the molecule. Heretofore, 9 kind of mutations were described in association of MH-susceptible(MHS) trait. 4 of them were accompanied by a form of congenital myopathy, central core disease(CCD). CCD is considered as an allelic disease of MH. But pathogenesis of peculiar morphological abnormality of CCD is mostly unknown. Mutations are identified only in half of familial MH cases, suggesting MH is heterogeneous. Recently, it was reported that mutation of the dihydropyridine receptor gene was associated with MHS in a french family. The dihydropyridine receptor is distributed on the transverse tubule membrane and constitutes the triad structure with RYR1.
Central core disease
Malignant hyperthermia
Congenital myopathy
Cite
Citations (0)
Malignant hyperthermia
Central core disease
Proband
Congenital myopathy
Cite
Citations (50)
Malignant hyperthermia
Congenital myopathy
Central core disease
Compound heterozygosity
Cite
Citations (15)
Summary The core myopathies are a subset of myopathies that present in infancy with hypotonia and muscle weakness. They were formerly considered a rare type of congenital myopathy but are now recognized as being more prevalent. Due to their genetic linkage to mutations in the ryanodine receptor gene ( RYR 1 ), core myopathies (in particular, central core disease) carry a high risk of malignant hyperthermia susceptibility. In this review article, we describe the phenotypical, genetic, and histopathological characteristics of core myopathies and further describe the currently understood nature of their risk of malignant hyperthermia. We also review the level of suspicion a clinician should exhibit with a child who has a possible core myopathy or other congenital myopathy presenting for an anesthetic prior to a definitive genetic analysis. For this review article, we performed literature searches using the key words anesthesiology, core myopathies, pediatric neurology, malignant hyperthermia, genetics, ryanodine receptor, and molecular biology. We also relied on literature accumulated by the two authors, who served as hotline consultants for the M alignant H yperthermia H otline of the M alignant H yperthermia A ssociation of the U nited S tates ( MHAUS ) for the past 12 years.
Malignant hyperthermia
Cite
Citations (59)