Ryanodine receptor mutations in malignant hyperthermia and central core disease

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscl e 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 ryanodin e receptor (RYR1) gene encodes the key channel which mediates calcium relea se in skeletal muscle during excitation-contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in m ore than 50% of cases and in the majority of CCD cases. To date, 22 missens e 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 muta tions is associated with CCD, The majority of RYR1 mutations appear to be c lustered 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 mutat ion identified outside of these regions to date is a single mutation associ ated with a severe form of CCD in the highly conserved C-terminus of the ge ne. All of the RYR1 mutations result in amino acid substitutions in the myo plasmic portion of the protein, with the exception of the mutation in the C -terminus, which resides in the lumenal/transmembrane region. Functional an alysis shows that MHS and CCD mutations produce RYR1 abnormalities that alt er the channel kinetics for calcium inactivation and make the channel hyper - and hyposensitive to activating and inactivating ligands, respectively, T he likely deciding factors in determining whether a particular RYR1 mutatio n results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant p roteins to agonists; the level of abnormal channel-gating caused by the mut ation; the consequential decrease in the size of the releasable calcium sto re and increase in resting concentration of calcium; and the level of compe nsation achieved by the muscle with respect to maintaining calcium homeosta sis. From a diagnostic point of view the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Atta inment of this goal will require further detailed molecular genetic investi gations aimed at solving heterogeneity and discordance issues in MHS; new i nitiatives aimed at identifying modulating factors that influence the penet rance of clinical MH in MHS individuals; and detailed studies aimed at desc ribing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility, Hum Mutat 15:410-417, 2000. (C) 2000 Wiley-Liss, Inc.