{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:21:42Z","timestamp":1789986102012,"version":"4.0.1"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background:<\/jats:title><jats:p>Mutations within the gene encoding the skeletal muscle calcium channel ryanodine receptor can result in malignant hyperthermia. Although it is important to characterize the functional effects of candidate mutations to establish a genetic test for diagnosis, ex vivo methods are limited because of the low incidence of the disorder and sample unavailability. More than 250 candidate mutations have been identified, but only a few mutations have been functionally characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>The human skeletal muscle ryanodine receptor complementary DNA was cloned with or without a disease-related variant. Wild-type and mutant calcium channel proteins were transiently expressed in human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40, and functional analysis was carried out using calcium imaging with fura-2 AM. Six human malignant hyperthermia-related mutants such as R44C, R163C, R401C, R533C, R533H, and H4833Y were analyzed. Cells were stimulated with a specific ryanodine receptor agonist 4-chloro-m-cresol, and intracellular calcium mobility was analyzed to determine the functional aspects of mutant channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Mutant proteins that contained a variant linked to malignant hyperthermia showed higher sensitivity to the agonist. Compared with the wild type (EC50 = 453.2 \u00b5m, n = 18), all six mutants showed a lower EC50 (21.2\u2013170.4 \u00b5m, n = 12\u201323), indicating susceptibility against triggering agents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>These six mutations cause functional abnormality of the calcium channel, leading to higher sensitivity to a specific agonist, and therefore could be considered potentially causative of malignant hyperthermia reactions.<\/jats:p><\/jats:sec>","DOI":"10.1097\/aln.0b013e31828cebfe","type":"journal-article","created":{"date-parts":[[2013,3,2]],"date-time":"2013-03-02T14:37:10Z","timestamp":1362235030000},"page":"111-118","source":"Crossref","is-referenced-by-count":21,"title":["Skeletal Muscle Ryanodine Receptor Mutations Associated with Malignant Hyperthermia Showed Enhanced Intensity and Sensitivity to Triggering Drugs when Expressed in Human Embryonic Kidney Cells"],"prefix":"10.1097","volume":"119","author":[{"given":"Keisaku","family":"Sato","sequence":"first","affiliation":[{"name":"Postdoctoral Associate, Department of Medicine, University of Florida, Gainesville, Florida."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia","family":"Roesl","sequence":"additional","affiliation":[{"name":"Ph.D. Candidate"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Pollock","sequence":"additional","affiliation":[{"name":"Consultant Anesthetist, Department of Anesthesia and Intensive Care, Palmerston North Hospital, Palmerston North, New Zealand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn M.","family":"Stowell","sequence":"additional","affiliation":[{"name":"Associate Professor, Institute of Fundamental Sciences, Massey University, Palmerston North, New Zealand."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"2021031821154781200_R1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1172-2-21","article-title":"Malignant hyperthermia.","volume":"2","year":"2007","journal-title":"Orphanet J Rare Dis"},{"key":"2021031821154781200_R2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1750-1172-2-25","article-title":"Central core disease.","volume":"2","year":"2007","journal-title":"Orphanet J Rare Dis"},{"key":"2021031821154781200_R3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1750-1172-2-31","article-title":"Multi-minicore disease.","volume":"2","year":"2007","journal-title":"Orphanet J Rare Dis"},{"key":"2021031821154781200_R4","doi-asserted-by":"crossref","first-page":"25722","DOI":"10.1074\/jbc.M302165200","article-title":"Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling.","volume":"278","year":"2003","journal-title":"J Biol Chem"},{"key":"2021031821154781200_R5","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1124\/mol.110.067959","article-title":"Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice.","volume":"79","year":"2011","journal-title":"Mol Pharmacol"},{"key":"2021031821154781200_R6","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1096\/fj.11-197582","article-title":"Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage.","volume":"26","year":"2012","journal-title":"FASEB J"},{"key":"2021031821154781200_R7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1085\/jgp.201010523","article-title":"Muscle weakness in Ryr1I4895T\/WT knock-in mice as a result of reduced ryanodine receptor Ca2+ ion permeation and release from the sarcoplasmic reticulum.","volume":"137","year":"2011","journal-title":"J Gen Physiol"},{"key":"2021031821154781200_R8","doi-asserted-by":"crossref","first-page":"18537","DOI":"10.1073\/pnas.0709312104","article-title":"An Ryr1I4895T mutation abolishes Ca2+ release channel function and delays development in homozygous offspring of a mutant mouse line.","volume":"104","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021031821154781200_R9","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1093\/bja\/56.11.1267","article-title":"A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility.","volume":"56","author":"European Malignant Hyperpyrexia Group","year":"1984","journal-title":"Br J Anaesth"},{"key":"2021031821154781200_R10","first-page":"511","article-title":"Standardization of the caffeine halothane muscle contracture test. 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