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Heinz Jungbluth - One of the best experts on this subject based on the ideXlab platform.
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congenital myopathies disorders of excitation contraction coupling and muscle contraction
Nature Reviews Neurology, 2018Co-Authors: Francesco Zorzato, Heinz Jungbluth, Susan Treves, Anna Sarkozy, Julien Ochala, C SewryAbstract:The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central Core Disease (CCD), multi-miniCore Disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.
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late onset axial myopathy with Cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor ryr1 gene
Neuromuscular Disorders, 2009Co-Authors: Heinz Jungbluth, C Sewry, S Lillis, Haiyan Zhou, S Abbs, Michael Swash, Francesco MuntoniAbstract:Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wide range of phenotypes including the malignant hyperthermia (MH) susceptibility trait, Central Core Disease (CCD) and other congenital myopathies characterized by early onset and predominant proximal weakness. We report a patient presenting at 77 years with a predominant axial myopathy associated with prominent involvement of spine extensors, confirmed on MRI and muscle biopsy, compatible with a Core myopathy. RYR1 mutational analysis revealed a novel heterozygous missense mutation (c.119G>T; p.Gly40Val) affecting the RYR1 N-terminus, previously predominantly associated with MH susceptibility. This case expands the spectrum of RYR1-related phenotypes and suggests that MH-related RYR1 mutations may give rise to overt neuromuscular symptoms later in life, with clinical features not typically found in CCD due to C-terminal hotspot mutations. Late-onset congenital myopathies may be under-recognised and diagnosis requires a high degree of clinical suspicion.
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Congenital muscle disorders with Cores: the ryanodine receptor calcium channel paradigm.
2009Co-Authors: Treves S., Heinz Jungbluth, Muntoni H. F., Zorzato F.Abstract:Dysregulation of calcium signals due to defects of skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), Central Core Disease (CCD; MIM #11700), MultiminiCore Disease (MmD; MIM # 255320) and Centronuclear myopathy (CNM). Experimental data have show that RYR1 mutations result mainly in four types of channel defects. One class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to a depletion of Ca2+ from the SR store. A third class of RYR1 mutations linked to CCD causes excitation-contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR store. The forth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels to be expressed in SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes
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mri in dnm2 related centronuclear myopathy evidence for highly selective muscle involvement
Neuromuscular Disorders, 2007Co-Authors: J Schessl, Heinz Jungbluth, Livija Medne, Y Zou, Mark J Brown, Jason T Huse, Drew A Torigian, Hans H Goebel, Carsten G BonnemannAbstract:Dynamin 2 has recently been recognized as a causative gene for the autosomal dominant form of centronuclear myopathy (dominant centronuclear myopathy). Here we report an affected father and daughter with dynamin 2 related AD CNM with predominantly distal onset of weakness. In addition to the diagnostic Central location of myonuclei the muscle biopsy also showed Core-like structures. Muscle MRI in the lower leg revealed prominent involvement of the soleus, but also of the gastrocnemius and the tibialis anterior whereas in the thigh there was a consistent pattern of selective involvement of adductor longus, semimembranosus, biceps femoris, rectus femoris, and vastus intermedius with relative sparing of vastus lateralis and medialis, sartorius, gracilis, and partly of the semitendinosus. These characteristic findings on muscle MRI confirm similar findings reported for CT imaging in dynamin 2 related dominant centronuclear myopathy and may help to differentiate this disorder from Central Core Disease and other myopathies.
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functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi miniCore Disease and Central Core Disease expressed in immortalized lymphocytes
Biochemical Journal, 2006Co-Authors: Sylvie Ducreux, Francesco Zorzato, Heinz Jungbluth, Francesco Muntoni, Susan Treves, Nicole Monnier, Ana Ferreiro, C R MullerAbstract:More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and Central Core Disease, and with recessive forms of multi-miniCore Disease. Studies on the functional effects of pathogenic dominant mutations have shown that they mostly affect intracellular Ca2+ homoeostasis, either by rendering the channel hypersensitive to activation (malignant hyperthermia) or by altering the amount of Ca2+ released subsequent to physiological or pharmacological activation (Central Core Disease). In the present paper, we show, for the first time, data on the functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-miniCore Disease. We studied the intracellular Ca2+ homoeostasis of EBV (Epstein–Barr virus)-transformed lymphoblastoid cells from the affected patients, their healthy relatives and control individuals. Our results show that the P3527S substitution in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-chloro-m-cresol and caffeine, but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on either the size of the intracellular Ca2+ stores, or on the amount of Ca2+ released after ryanodine receptor activation; however, both the P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration.
David H. Maclennan - One of the best experts on this subject based on the ideXlab platform.
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reduced threshold for store overload induced ca2 release is a common defect of ryr1 mutations associated with malignant hyperthermia and Central Core Disease
Biochemical Journal, 2017Co-Authors: Wenqian Chen, Ruiwu Wang, Andrea Koop, Robert T. Dirksen, David H. Maclennan, Yingjie Liu, Wenting Guo, Jinhong Wei, Sui Rong Wayne ChenAbstract:Mutations in the skeletal muscle ryanodine receptor (RyR1) cause malignant hyperthermia (MH) and Central Core Disease (CCD), whereas mutations in the cardiac ryanodine receptor (RyR2) lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most Disease-associated RyR1 and RyR2 mutations are located in the N-terminal, Central, and C-terminal regions of the corresponding ryanodine receptor (RyR) isoform. An increasing body of evidence demonstrates that CPVT-associated RyR2 mutations enhance the propensity for spontaneous Ca2+ release during store Ca2+ overload, a process known as store overload-induced Ca2+ release (SOICR). Considering the similar locations of Disease-associated RyR1 and RyR2 mutations in the RyR structure, we hypothesize that like CPVT-associated RyR2 mutations, MH/CCD-associated RyR1 mutations also enhance SOICR. To test this hypothesis, we determined the impact on SOICR of 12 MH/CCD-associated RyR1 mutations E2347-del, R2163H, G2434R, R2435L, R2435H, and R2454H located in the Central region, and Y4796C, T4826I, L4838V, A4940T, G4943V, and P4973L located in the C-terminal region of the channel. We found that all these RyR1 mutations reduced the threshold for SOICR. Dantrolene, an acute treatment for MH, suppressed SOICR in HEK293 cells expressing the RyR1 mutants R164C, Y523S, R2136H, R2435H, and Y4796C. Interestingly, carvedilol, a commonly used β-blocker that suppresses RyR2-mediated SOICR, also inhibits SOICR in these RyR1 mutant HEK293 cells. Therefore, these results indicate that a reduced SOICR threshold is a common defect of MH/CCD-associated RyR1 mutations, and that carvedilol, like dantrolene, can suppress RyR1-mediated SOICR. Clinical studies of the effectiveness of carvedilol as a long-term treatment for MH/CCD or other RyR1-associated disorders may be warranted.
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type 1 ryanodine receptor knock in mutation causing Central Core Disease of skeletal muscle also displays a neuronal phenotype
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Valerie De Crescenzo, David H. Maclennan, Elena Zvaritch, Kevin E Fogarty, Jason J Lefkowitz, Karl D Bellve, John V WalshAbstract:The type 1 ryanodine receptor (RyR1) is expressed widely in the brain, with high levels in the cerebellum, hippocampus, and hypothalamus. We have shown that L-type Ca2+ channels in terminals of hypothalamic magnocellular neurons are coupled to RyRs, as they are in skeletal muscle, allowing voltage-induced Ca2+ release (VICaR) from internal Ca2+ stores without Ca2+ influx. Here we demonstrate that RyR1 plays a role in VICaR in nerve terminals. Furthermore, in heterozygotes from the Ryr1I4895T/WT (IT/+) mouse line, carrying a knock-in mutation corresponding to one that causes a severe form of human Central Core Disease, VICaR is absent, demonstrating that type 1 RyR mediates VICaR and that these mice have a neuronal phenotype. The absence of VICaR was shown in two ways: first, depolarization in the absence of Ca2+ influx elicited Ca2+syntillas (scintilla, spark, in a nerve terminal, a SYNaptic structure) in WT, but not in mutant terminals; second, in the presence of extracellular Ca2+, IT/+ terminals showed a twofold decrease in global Ca2+ transients, with no change in plasmalemmal Ca2+ current. From these studies we draw two conclusions: (i) RyR1 plays a role in VICaR in hypothalamic nerve terminals; and (ii) a neuronal alteration accompanies the myopathy in IT/+ mice, and, possibly in humans carrying the corresponding RyR1 mutation.
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mechanistic models for muscle Diseases and disorders originating in the sarcoplasmic reticulum
Biochimica et Biophysica Acta, 2011Co-Authors: David H. Maclennan, Elena ZvaritchAbstract:Abstract This review focuses on muscle disorders and Diseases caused by defects in the Ca2+ release channels of the sarcoplasmic reticulum, the ryanodine receptors, and in the luminal, low affinity, high capacity Ca2+-binding proteins, calsequestrins. It provides a time line over the past half century of the highlights of research on malignant hyperthermia (MH), Central Core Disease (CCD) and catecholaminergic polymorphic ventricular tachycardia (CPVT), that resulted in the identification of the ryanodine receptor (RYR), calsequestrin (CASQ) and dihydropyridine receptor (CACNA1S) genes as sites of Disease-causing mutations. This is followed by a description of approaches to functional analysis of the effects of Disease-causing mutations on protein function, focusing on studies of how mutations affect spontaneous (store overload-induced) Ca2+-release from the sarcoplasmic reticulum, the underlying cause of MH and CPVT. Subsequent sections describe results obtained by analysis of knockin mouse lines carrying MH- and CCD-causing mutations, including a Casq1 knockout. The review concludes with the presentation of two mechanistic models. The first shows how dysregulation of Ca2+ homeostasis can lead to muscle Diseases involving both RyR and Casq proteins. The second describes a theory of Central Core formation wherein non-uniformity of Ca2+ release, resulting in non-uniformity of muscle contraction, is presented as an intrinsic property of the specific tertiary structure of mutant heterotetrameric ryanodine receptors and as the underlying cause of Core formation in skeletal muscle. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
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crystal structure of type i ryanodine receptor amino terminal beta trefoil domain reveals a Disease associated mutation hot spot loop
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Fernando J Amador, David H. Maclennan, Shuang Liu, Noboru Ishiyama, Michael J Plevin, Aaron D Wilson, Mitsuhiko IkuraAbstract:Muscle contraction and relaxation is regulated by transient elevations of myoplasmic Ca(2+). Ca(2+) is released from stores in the lumen of the sarco(endo)plasmic reticulum (SER) to initiate formation of the Ca(2+) transient by activation of a class of Ca(2+) release channels referred to as ryanodine receptors (RyRs) and is pumped back into the SER lumen by Ca(2+)-ATPases (SERCAs) to terminate the Ca(2+) transient. Mutations in the type 1 ryanodine receptor gene, RYR1, are associated with 2 skeletal muscle disorders, malignant hyperthermia (MH), and Central Core Disease (CCD). The evaluation of proposed mechanisms by which RyR1 mutations cause MH and CCD is hindered by the lack of high-resolution structural information. Here, we report the crystal structure of the N-terminal 210 residues of RyR1 (RyR(NTD)) at 2.5 A. The RyR(NTD) structure is similar to that of the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor (IP(3)Rsup), but lacks most of the long helix-turn-helix segment of the "arm" domain in IP(3)Rsup. The N-terminal beta-trefoil fold, found in both RyR and IP(3)R, is likely to play a critical role in regulatory mechanisms in this channel family. A Disease-associated mutation "hot spot" loop was identified between strands 8 and 9 in a highly basic region of RyR1. Biophysical studies showed that 3 MH-associated mutations (C36R, R164C, and R178C) do not adversely affect the global stability or fold of RyR(NTD), supporting previously described mechanisms whereby mutations perturb protein-protein interactions.
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ca2 signaling in hek 293 and skeletal muscle cells expressing recombinant ryanodine receptors harboring malignant hyperthermia and Central Core Disease mutations
Journal of Biological Chemistry, 2005Co-Authors: Marisa Brini, David H. Maclennan, Sabrina Manni, Nicola Pierobon, Parveen Sharma, Ernesto CarafoliAbstract:Abstract Malignant hyperthermia (MH) and Central Core Disease (CCD) are caused by mutations in the RYR1 gene encoding the skeletal muscle isoform of the ryanodine receptor (RyR1), a homotetrameric Ca2+ release channel. Rabbit RyR1 mutant cDNAs carrying mutations corresponding to those in human RyR1 that cause MH and CCD were expressed in HEK-293 cells, which do not have endogenous RyR, and in primary cultures of rat skeletal muscle, which express rat RyR1. Analysis of intracellular Ca2+ pools was performed using aequorin probes targeted to the lumen of the endo/sarcoplasmic reticulum (ER/SR), to the mitochondrial matrix, or to the cytosol. Mutations associated with MH caused alterations in intracellular Ca2+ homeostasis different from those associated with CCD. Measurements of luminal ER/SR Ca2+ revealed that the mutations generated leaky channels in all cases, but the leak was particularly pronounced in CCD mutants. Cytosolic and mitochondrial Ca2+ transients induced by caffeine stimulation were drastically augmented in the MH mutant, slightly reduced in one CCD mutant (Y523S) and completely abolished in another (I4898T). The results suggest that local Ca2+ derangements of different degrees account for the specific cellular phenotypes of the two disorders.
Francesco Muntoni - One of the best experts on this subject based on the ideXlab platform.
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adenovirus mediated expression of myogenic differentiation factor 1 myod in equine and human dermal fibroblasts enables their conversion to caffeine sensitive myotubes
Neuromuscular Disorders, 2014Co-Authors: M Fernandezfuente, G Vassaux, Cesare M. Terracciano, Francesco Muntoni, Susan C. Brown, Pilar Martinduque, Richard J. PiercyAbstract:Several human and animal myopathies, such as malignant hyperthermia (MH), Central Core Disease and equine recurrent exertional rhabdomyolysis (RER) are confirmed or thought to be associated with dysfunction of skeletal muscle calcium regulation. For some patients in whom the genetic cause is unknown, or when mutational analysis reveals genetic variants with unclear pathogenicity, defects are further studied through use of muscle histopathology and in vitro contraction tests, the latter in particular, when assessing responses to ryanodine receptor agonists, such as caffeine. However, since muscle biopsy is not always suitable, researchers have used cultured cells to model these Diseases, by examining calcium regulation in myotubes derived from skin, following forced expression of muscle-specific transcription factors. Here we describe a novel adenoviral vector that we used to express equine MyoD in dermal fibroblasts. In permissive conditions, transduced equine and human fibroblasts differentiated into multinucleated myotubes. We demonstrate that these cells have a functional excitation-calcium release mechanism and, similarly to primary muscle-derived myotubes, respond in a dose-dependent manner to increasing concentrations of caffeine. MyoD-induced conversion of equine skin-derived fibroblasts offers an attractive method for evaluating calcium homeostasis defects in vitro without the need for invasive muscle biopsy.
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late onset axial myopathy with Cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor ryr1 gene
Neuromuscular Disorders, 2009Co-Authors: Heinz Jungbluth, C Sewry, S Lillis, Haiyan Zhou, S Abbs, Michael Swash, Francesco MuntoniAbstract:Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wide range of phenotypes including the malignant hyperthermia (MH) susceptibility trait, Central Core Disease (CCD) and other congenital myopathies characterized by early onset and predominant proximal weakness. We report a patient presenting at 77 years with a predominant axial myopathy associated with prominent involvement of spine extensors, confirmed on MRI and muscle biopsy, compatible with a Core myopathy. RYR1 mutational analysis revealed a novel heterozygous missense mutation (c.119G>T; p.Gly40Val) affecting the RYR1 N-terminus, previously predominantly associated with MH susceptibility. This case expands the spectrum of RYR1-related phenotypes and suggests that MH-related RYR1 mutations may give rise to overt neuromuscular symptoms later in life, with clinical features not typically found in CCD due to C-terminal hotspot mutations. Late-onset congenital myopathies may be under-recognised and diagnosis requires a high degree of clinical suspicion.
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functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi miniCore Disease and Central Core Disease expressed in immortalized lymphocytes
Biochemical Journal, 2006Co-Authors: Sylvie Ducreux, Francesco Zorzato, Heinz Jungbluth, Francesco Muntoni, Susan Treves, Nicole Monnier, Ana Ferreiro, C R MullerAbstract:More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and Central Core Disease, and with recessive forms of multi-miniCore Disease. Studies on the functional effects of pathogenic dominant mutations have shown that they mostly affect intracellular Ca2+ homoeostasis, either by rendering the channel hypersensitive to activation (malignant hyperthermia) or by altering the amount of Ca2+ released subsequent to physiological or pharmacological activation (Central Core Disease). In the present paper, we show, for the first time, data on the functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-miniCore Disease. We studied the intracellular Ca2+ homoeostasis of EBV (Epstein–Barr virus)-transformed lymphoblastoid cells from the affected patients, their healthy relatives and control individuals. Our results show that the P3527S substitution in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-chloro-m-cresol and caffeine, but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on either the size of the intracellular Ca2+ stores, or on the amount of Ca2+ released after ryanodine receptor activation; however, both the P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration.
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principal mutation hotspot for Central Core Disease and related myopathies in the c terminal transmembrane region of the ryr1 gene
Neuromuscular Disorders, 2003Co-Authors: M Davis, Eric Haan, Heinz Jungbluth, Francesco Muntoni, C Sewry, Kathryn N North, Thierry Kuntzer, Phillipa J Lamont, Agnes Bankier, P TomlinsonAbstract:The congenital myopathies are a group of disorders characterised by the predominance of specific histological features observed in biopsied muscle. Central Core Disease and nemaline myopathy are examples of congenital myopathies that have specific histological characteristics but significantly overlapping clinical pictures. Central Core Disease is an autosomal dominant disorder with variable penetrance which has been linked principally to the gene for the skeletal muscle calcium release channel (RYR1). Two recent reports have identified the 3' transmembrane domain of this gene as a common site for mutations. Two other studies have reported single families that have features of both Central Core Disease and nemaline myopathy (Core/rod Disease) caused by mutations in RYR1. Screening of the 3' region (exons 93-105) of the RYR1 gene for mutations in 27 apparently unrelated patients with either Central Core Disease or Core/rod Disease by single strand conformation polymorphism analysis and DNA sequencing identified three described and nine novel mutations in 15 patients.
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identification of four novel mutations in the c terminal membrane spanning domain of the ryanodine receptor 1 association with Central Core Disease and alteration of calcium homeostasis
Human Molecular Genetics, 2001Co-Authors: Nikola Tilgen, Francesco Zorzato, Francesco Muntoni, Caroline Sewry, Frank Lehmannhorn, Birgit Halligerkeller, Laura M Palmucci, Christiane Schneider, Erwin Hauser, C R MullerAbstract:The skeletal muscle ryanodine receptor gene (RYR1; OMIM 180901) on chromosome 19q13.1 encodes the skeletal muscle calcium release channel. To date, more than 25 missense mutations have been identified in RYR1 and are associated with Central Core Disease (CCD; OMIM 117000) and/or the malignant hyperthermia susceptibility phenotype (MHS1; OMIM 145600). The majority of RYR1 mutations are clustered in the N-terminal hydrophilic domain of the protein. Only four mutations have been identified so far in the highly conserved C-terminal region encoding the luminal/transmembrane domain of the protein which forms the ion pore. Three of these mutations have been found to segregate with pure or mixed forms of CCD. We have screened the C-terminal domain of the RYR1 gene for mutations in 50 European patients, diagnosed clinically and/or histologically as having CCD. We have identified five missense mutations (four of them novel) in 13 index patients. The mutations cluster in exons 101 and 102 and replace amino acids which are conserved in all known vertebrate RYR genes. In order to study the functional effect of these mutations, we have immortalized B-lymphocytes from some of the patients and studied their [Ca2+] i homeostasis. We show that lymphoblasts carrying the newly identified RYR1 mutations exhibit: (i) a release of calcium from intracellular stores in the absence of any pharmacological activators of RYR; (ii) significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals; and (iii) a normal sensitivity of the calcium release to the RYR inhibitor dantrolene. Our data suggest the C-terminal domain of RYR1 as a hot spot for mutations leading to the CCD phenotype. If the functional alterations of mutated RYR channels observed in lymphoblastoid cells are also present in skeletal muscles this could explain the predominant symptom of CCD, i.e. chronic muscle weakness. Finally, the study of calcium homeostasis in lymphoblastoid cells naturally expressing RYR1 mutations offers a novel non-invasive approach to gain insights into the pathogenesis of MH and CCD.
Francesco Zorzato - One of the best experts on this subject based on the ideXlab platform.
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congenital myopathies disorders of excitation contraction coupling and muscle contraction
Nature Reviews Neurology, 2018Co-Authors: Francesco Zorzato, Heinz Jungbluth, Susan Treves, Anna Sarkozy, Julien Ochala, C SewryAbstract:The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central Core Disease (CCD), multi-miniCore Disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.
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Congenital muscle disorders with Cores: the ryanodine receptor calcium channel paradigm
CURR OPIN PHARMACOL, 2008Co-Authors: Francesco ZorzatoAbstract:Dysregulation of calcium signals because of 0 defects of the skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), Central Core Disease (CCD; MIM #11700), specific forms of multi-miniCore Disease (MmD; MIM # 255320) and centronuclear myopathy (CNM). Experimental data have shown that RYR1 mutations result mainly in four types of channel defects: one class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to depletion of Ca2+ from SR stores. A third class of RYR1 mutations linked to CCD causes excitation-contract ion uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR. The fourth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels expression on SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes.
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functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi miniCore Disease and Central Core Disease expressed in immortalized lymphocytes
Biochemical Journal, 2006Co-Authors: Sylvie Ducreux, Francesco Zorzato, Heinz Jungbluth, Francesco Muntoni, Susan Treves, Nicole Monnier, Ana Ferreiro, C R MullerAbstract:More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and Central Core Disease, and with recessive forms of multi-miniCore Disease. Studies on the functional effects of pathogenic dominant mutations have shown that they mostly affect intracellular Ca2+ homoeostasis, either by rendering the channel hypersensitive to activation (malignant hyperthermia) or by altering the amount of Ca2+ released subsequent to physiological or pharmacological activation (Central Core Disease). In the present paper, we show, for the first time, data on the functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-miniCore Disease. We studied the intracellular Ca2+ homoeostasis of EBV (Epstein–Barr virus)-transformed lymphoblastoid cells from the affected patients, their healthy relatives and control individuals. Our results show that the P3527S substitution in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-chloro-m-cresol and caffeine, but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on either the size of the intracellular Ca2+ stores, or on the amount of Ca2+ released after ryanodine receptor activation; however, both the P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration.
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Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders.
Neuromuscular disorders : NMD, 2005Co-Authors: Susan Treves, Ayuk A Anderson, Sylvie Ducreux, Alexandra Divet, Christophe Bleunven, Cristiano Grasso, Silvia Paesante, Francesco ZorzatoAbstract:The skeletal muscle ryanodine receptor is an intracellular calcium release channel which plays a Central role in excitation contraction coupling. At least 80 mutations have been identified in the gene encoding the skeletal muscle ryanodine receptor and linked to several neuromuscular disorders, whose common feature appears to be a dysregulation of calcium homeostasis. A decade of research into the functional consequences of how these mutations affect the functional properties of the ryanodine receptor and their impact on Disease, have significantly advanced our understanding of Malignant Hyperthermia, Central Core Disease and MultiminiCore Disease. This review gives an overview of the important findings in the field of calcium homeostasis in skeletal muscle and describes how mutations in the ryanodine receptor gene might affect the function of this intracellular calcium release channel and lead to neuromuscular disorders.
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identification of four novel mutations in the c terminal membrane spanning domain of the ryanodine receptor 1 association with Central Core Disease and alteration of calcium homeostasis
Human Molecular Genetics, 2001Co-Authors: Nikola Tilgen, Francesco Zorzato, Francesco Muntoni, Caroline Sewry, Frank Lehmannhorn, Birgit Halligerkeller, Laura M Palmucci, Christiane Schneider, Erwin Hauser, C R MullerAbstract:The skeletal muscle ryanodine receptor gene (RYR1; OMIM 180901) on chromosome 19q13.1 encodes the skeletal muscle calcium release channel. To date, more than 25 missense mutations have been identified in RYR1 and are associated with Central Core Disease (CCD; OMIM 117000) and/or the malignant hyperthermia susceptibility phenotype (MHS1; OMIM 145600). The majority of RYR1 mutations are clustered in the N-terminal hydrophilic domain of the protein. Only four mutations have been identified so far in the highly conserved C-terminal region encoding the luminal/transmembrane domain of the protein which forms the ion pore. Three of these mutations have been found to segregate with pure or mixed forms of CCD. We have screened the C-terminal domain of the RYR1 gene for mutations in 50 European patients, diagnosed clinically and/or histologically as having CCD. We have identified five missense mutations (four of them novel) in 13 index patients. The mutations cluster in exons 101 and 102 and replace amino acids which are conserved in all known vertebrate RYR genes. In order to study the functional effect of these mutations, we have immortalized B-lymphocytes from some of the patients and studied their [Ca2+] i homeostasis. We show that lymphoblasts carrying the newly identified RYR1 mutations exhibit: (i) a release of calcium from intracellular stores in the absence of any pharmacological activators of RYR; (ii) significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals; and (iii) a normal sensitivity of the calcium release to the RYR inhibitor dantrolene. Our data suggest the C-terminal domain of RYR1 as a hot spot for mutations leading to the CCD phenotype. If the functional alterations of mutated RYR channels observed in lymphoblastoid cells are also present in skeletal muscles this could explain the predominant symptom of CCD, i.e. chronic muscle weakness. Finally, the study of calcium homeostasis in lymphoblastoid cells naturally expressing RYR1 mutations offers a novel non-invasive approach to gain insights into the pathogenesis of MH and CCD.
Paivi Laitinen - One of the best experts on this subject based on the ideXlab platform.
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involvement of the cardiac ryanodine receptor calcium release channel in catecholaminergic polymorphic ventricular tachycardia
Journal of Cellular Physiology, 2002Co-Authors: Andrew R. Marks, Silvia G Priori, Mirella Memmi, Kimmo Kontula, Paivi LaitinenAbstract:The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these Diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/Central Core Disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in “leaky” channels. SR calcium leak during diastole can generate “delayed after depolarizations” that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation. J. Cell. Physiol. 190: 1–6, 2002. © 2002 Wiley-Liss, Inc.
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involvement of the cardiac ryanodine receptor calcium release channel in catecholaminergic polymorphic ventricular tachycardia
Journal of Cellular Physiology, 2002Co-Authors: Andrew R. Marks, Silvia G Priori, Mirella Memmi, Kimmo Kontula, Paivi LaitinenAbstract:The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these Diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/Central Core Disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in "leaky" channels. SR calcium leak during diastole can generate "delayed after depolarizations" that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation.