Ryanodine receptor mutations in malignant hyperthermia and central core disease

Abstract

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.

Using independent open-to-closed transitions to simplify aggregated Markov models of ion channel gating kinetics

“…They allow spatial and temporal control of calcium ions that regulate processes as diverse as fertilization, memory, muscle contraction (1), and immune response (2,3). Abnormal channel function is implicated in pathologies such as cystic fibrosis (4), ataxia (5), and overresponse to anesthesia (6).…”

Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

“…Nevertheless, additional clues about the possible functional effects of the RyR2 SCD mutations come from the observation that the CPVT/FPVT/ARVD2 mutations cluster in 3 regions of the channel, corresponding to malignant hyperthermia (MH) and central core disease (CCD) domains in RyR1. MH and CCD are diseases of skeletal muscle, 20 and their mutations may alter the Ca 2ϩ -dependent regulation of RyR1, 21-23 although there have been conflicting reports. 24,25 Single channel studies of mutant RyR1 channels isolated from MH pigs 26 (containing an R615C missense mutation) revealed an increased sensitivity to activation by Ca 2ϩ and a decreased sensitivity to inhibition by Mg 2ϩ .…”

Malignant Hyperthermia

“…Amongst these loci, mutations with a clear association with MH have been identified in only one gene, CACNA1S, encoding the alpha subunit of the dihydropyridine receptor, the voltage sensor of the skeletal muscle calcium release channel [29,42,43]. Early studies suggested that mutations cluster within three regions of RYR1 (reviewed in [19]) largely because many laboratories screen only these regions for the presence of mutations in MH susceptible patients. Complete screening of the entire coding regions of RYR1 has, however, revealed that mutations occur in almost all regions of the gene [17,41].…”