Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm
Introduction
Although five decades of research into the mechanisms involved in cytosolic Ca2+ regulation have advanced our understanding of fundamental cellular processes ranging from muscle contraction to gene expression [1], the precise impact of altered Ca2+ signalling on human disease has remained elusive for a long time. The discovery of genes encoding key proteins involved in Ca2+ homeostasis was fundamental in bridging the gap between understanding the role of Ca2+ in basic physiological processes and the pathophysiology of human diseases. The identification of the Ca2+ release channel protein (ryanodine receptor, RyR1) of striated muscle [2] and the identification of mutations in its gene, RYR1 [3], allowed for the first time a direct correlation between altered Ca2+ homeostasis and muscle disease (Figure 1), in particular malignant hyperthermia (MH) [4, 5, 6], central core disease (CDD) [7], specific forms of multi-minicore disease (MmD) [8, 9, 10] and centronuclear myopathy (CNM) [11] (Table 1). The overall population frequency of RYR1 mutations (about 1:50,000) is likely to have been underestimated as suggested by the finding of compound heterozygosity or homozygosity for RYR1 mutations in some patients within extensively analyzed MH and CCD pedigrees and other rare disorders including MmD [8, 9, 10], exercise-induced rhabdomyolysis [12], and some forms of exercise-induced hyperthermia [13].
Section snippets
The ryanodine receptor calcium channels
Ryanodine receptors are members of a family of intracellular Ca2+ release channel proteins present on ER/SR membranes [14]. Type 1 RyR is encoded by a gene on human chromosome 19q13.1 [15], and is mainly expressed in skeletal muscle and to a lower level in Purkinje cells [16], human B-lymphocytes [17, 18], and dendritic cells [19, 20, 21, 22]; this implies that mutations in the RYR1 might affect not only excitable cells but also the immune system and other tissues. The functional calcium
Conclusions
During the last few years the general understanding of congenital muscle disorders has greatly improved thanks to the identification of causative mutations in the RYR1 gene. However, the development of therapeutic treatments for affected patients has been hampered by the poor understanding of the molecular pathological mechanisms of the RyR1 defects. Understanding the mechanism(s) responsible for RYR1 allele silencing, discriminating between Ca2+ leak and EC uncoupling are important not only to
Acknowledgements
This work was supported by grants from Association Francaise contre les myopathies, PRIN, Swiss muscle foundation, S.N.F.N°3200B0114597, M.A.E.
References (68)
- et al.
Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene
Neuromuscul Disord
(2007) - et al.
Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees
Br J Anaesth
(2002) Ryanodine receptors
Cell Calcium
(2005)- et al.
The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene
Genomics
(1996) - et al.
Skeletal muscle type ryanodine receptor is involved in calcium signaling in human B lymphocytes
J Biol Chem
(1999) - et al.
B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators
J Biol Chem
(2001) - et al.
Identification of functional type 1 ryanodine receptors in mouse dendritic cells
FEBS Lett
(2002) - et al.
Identification of functional type 1 ryanodine receptors in human dendritic cells
Biochem Biophys Res Commun
(2007) - et al.
The pore structure of the closed RyR1 channel
Structure
(2005) - et al.
Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders
Neuromuscul Disord
(2005)
Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1
Biophys J
Selenium compounds modulate the calcium release channel/ryanodine receptor of rabbit skeletal muscle by oxidizing functional thiols
Biochemical Pharmacol
Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations
Neuromuscul Disord
Epigenetic allele silencing unveils recessive RYR1 mutations in core myopathies
Am J Hum Gen
Subtle central and peripheral nervous system abnormalities in a family with centronuclear myopathy and a novel dynamin 2 gene mutation
Neuromuscul Disord
Identification of a region of RyR1 that participates in allosteric coupling with the alpha(1S) (Cav1.1) II–III loop
J Biol Chem
Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multi-minicore disease: reassessing the nosology of early-onset myopathies
Am J Hum Genet
The phenotype and long term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy
Eur J Paediat Neurol
Early onset myopathy with a novel mutation in the selenoprotein N gene
Neuromuscul Disord
Unlocking the secrets of cell signalling
Annu Rev Physiol
Purification and reconstitution of the calcium release channel from skeletal muscle
Nature
Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia
Science
Malignant hyperthermia orphanet
J Rare Dis
Mutations in RYR1 in malignant hyperthermia and central core disease
Hum Mutat
Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically linked myopathies
J Muscle Res Cell Motil
Central core disease orphanet
J Rare Dis
Multi-minicore disease orphanet
J Rare Dis
Multiminicore myopathy, central core disease, malignant hyperthermia susceptibility, and RYR1 mutations: one disease with many faces?
Arch Neurol
Functional effects of mutations identified in patients with multiminicore disease
IUBMB Life
Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis
Anesthesiology
Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity
EMBO J
Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal
Environ Health Perspect
Ca2+ signaling through ryanodine receptor 1 enhances maturation and activation of human dendritic cells
J Cell Sci
Internal structure and visualization of transmembrane domains of the RyR1 calcium release channel by cryo-EM
Nat Struct Molec Biol
Cited by (129)
Drug development for the treatment of RyR1-related skeletal muscle diseases
2023, Current Opinion in PharmacologyCalcium channels linked to altered cellular function and disease
2020, Current Opinion in PhysiologyBi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice
2020, Journal of Biological ChemistryStructural development of a type-1 ryanodine receptor (RyR1) Ca<sup>2+</sup>-release channel inhibitor guided by endoplasmic reticulum Ca<sup>2+</sup> assay
2019, European Journal of Medicinal ChemistryCitation Excerpt :The resulting increase of cytoplasmic Ca2+ level induces skeletal muscle contraction. Genetic mutations of RyR1 are known to be associated with several muscle diseases, such as malignant hyperthermia (MH) and central core diseases (CCD) [5,6], in which over-activation of the mutated RyR1 channel causes leakage of Ca2+ from the SR store. In addition, the symptoms of several diseases, such as muscular dystrophy [7] and Alzheimer disease [8], are thought to be caused, at least in part, by over-activation of non-mutated RyR1 induced by external factors.
Interactions among ryanodine receptor isotypes contribute to muscle fiber type development and function
2020, DMM Disease Models and Mechanisms