title: Functional characterization of the RYR1 mutation p.Arg4737Trp associated with susceptibility to malignant hyperthermia.
abstract: Aside from the in vitro contracture test, genetic screening for causative RYR1 mutations is the established procedure to diagnose susceptibility to malignant hyperthermia (MH). However, currently only 34 out of more than 300 known RYR1 mutations have been confirmed to be causative for MH by experimental studies addressing their functional impact on intracellular calcium homeostasis. The RYR1 mutation p.Arg4737Trp has been recently detected in a German MH family. To evaluate the effects of that mutation on intracellular calcium handling, the response after stimulation with the RYR1 agonist 4-chloro-m-cresol was investigated in immortalized B lymphocytes containing the p.Arg4737Trp mutation and compared to the response of wild type RYR1 from unaffected family members and unrelated controls. Intracellular resting calcium was slightly but significantly elevated in mutation positive cells. Calcium release following stimulation with 4-chloro-m-cresol was significantly increased in B lymphocytes carrying the p.Arg4737Trp mutation compared to mutation negative controls. Hence, the functional properties of the RYR1 mutation p.Arg4737Trp are consistent with susceptibility to MH. Together with previously published data, the mutation has now been reported in three independent MH positive families.
authors.affiliation: Department of Anaesthesia and Critical Care, University of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Johannsen
authors.affiliation: Department of Anesthesia and Biomedicine, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.affiliation: Department of Human Genetics, University of Wuerzburg, Biozentrum, Am Hubland, 97074 Wuerzburg, Germany.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Müller
authors.affiliation: Department of Anaesthesia and Critical Care, University of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mögele
authors.affiliation: Department of Anaesthesia and Critical Care, University of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schneiderbanger
authors.affiliation: Department of Anaesthesia and Critical Care, University of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Roewer
authors.affiliation: Department of Anaesthesia and Critical Care, University of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany. Electronic address: Schuster_F@ukw.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Schuster
mesh_terms: D000777:Anesthetics / Q000494:pharmacology; D001120:Arginine / Q000235:genetics*; D001402:B-Lymphocytes / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002461:Cell Line, Transformed; D003408:Cresols / Q000494:pharmacology; D005192:Family Health; D005260:Female; D005659:Fungicides, Industrial / Q000494:pharmacology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005858:Germany; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000473:pathology; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics*
chemical_list: D000777:Anesthetics; D003408:Cresols; D005659:Fungicides, Industrial; D010726:Phosphodiesterase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol; D002110:Caffeine; D014364:Tryptophan; D001120:Arginine; D006221:Halothane
keywords: Calcium release, 4-chloro-m-cresol; In vitro contracture test; Malignant hyperthermia; Mutation; Ryanodine receptor