title: An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities.
abstract: Malignant hyperthermia is a potentially fatal hypermetabolic disorder triggered by halogenated anesthetics and the myorelaxant succinylcholine in genetically predisposed individuals. About 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms. RyR1 is predominantly found in skeletal muscle but also at lower amounts in immune and smooth muscle cells, suggesting that RYR1 mutations may have a wider range of effects than previously suspected. Mild bleeding abnormalities have been described in patients with malignant hyperthermia carrying gain-of-function RYR1 mutations. We sought to determine the frequency and molecular basis for this symptom. We found that some patients with specific RYR1 mutations had abnormally high bleeding scores, whereas their healthy relatives did not. Knock-in mice with the malignant hyperthermia susceptibility RYR1 mutation Y522S (MHS RYR1Y522S) had longer bleeding times than their wild-type littermates. Primary vascular smooth muscle cells from RYR1Y522S knock-in mice exhibited a higher frequency of subplasmalemmal Ca(2+) sparks, leading to a more negative resting membrane potential. The bleeding defect of RYR1Y522S mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca(2+) sparks in primary vascular smooth muscle cells from the MHS RYR1Y522S mice were blocked by ryanodine or dantrolene. Thus, RYR1 mutations may lead to prolonged bleeding by altering vascular smooth muscle cell function. The reversibility of the bleeding phenotype emphasizes the potential therapeutic value of dantrolene in the treatment of such bleeding disorders.
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Rubén J
authors.initials: RJ
authors.lastname: Lopez
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Byrne
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland. Department of Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Mirko
authors.initials: M
authors.lastname: Vukcevic
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Marijana
authors.initials: M
authors.lastname: Sekulic-Jablanovic
authors.affiliation: Department of Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Lifen
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
authors.forename: Marijke
authors.initials: M
authors.lastname: Brink
authors.affiliation: Department of Haematology, Evelina Children's Hospital, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Jay
authors.initials: J
authors.lastname: Alamelu
authors.affiliation: Department of Neurology, Radboud University Medical Centre, Nijmegen, Netherlands.
authors.forename: Nicol
authors.initials: N
authors.lastname: Voermans
authors.affiliation: National MH Investigation Unit, Department of Anesthesiology, Canisius Wilhelmina Hospital, 6532 Nijmegen, Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Snoeck
authors.affiliation: Department of Clinical Genetics, Guy's Hospital, London SE1 7EH, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Clement
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Neurology, The Royal London Hospital, London E1 1BB, UK.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radunovic
authors.affiliation: Department of Clinical Genetics, Guy's Hospital, London SE1 7EH, UK.
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wraige
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland. Department of Life Sciences, General Pathology Section, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
authors.affiliation: Departments of Biomedicine and Anesthesia, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland. Department of Life Sciences, General Pathology Section, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy.
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.affiliation: Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London SE1 7EH, UK. Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London SE1 1UL, UK. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 9RX, UK.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001778:Blood Coagulation Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020013:Calcium Signaling; D003620:Dantrolene / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; C000592747:ryanodine receptor 1, mouse; D003620:Dantrolene