title: Functional analysis ofRYR1variants linked to malignant hyperthermia.
abstract: Malignant hyperthermia manifests as a rapid and sustained rise in temperature in response to pharmacological triggering agents, e.g. inhalational anesthetics and the muscle relaxant suxamethonium. Other clinical signs include an increase in end-tidal CO2, increased O2consumption, as well as tachycardia, and if untreated a malignant hyperthermia episode can result in death. The metabolic changes are caused by dysregulation of skeletal muscle Ca2+homeostasis, resulting from a defective ryanodine receptor Ca2+channel, which resides in the sarcoplasmic reticulum and controls the flux of Ca2+ions from intracellular stores to the cytoplasm. Most genetic variants associated with susceptibility to malignant hyperthermia occur in theRYR1gene encoding the ryanodine receptor type 1. While malignant hyperthermia susceptibility can be diagnosed byin vitrocontracture testing of skeletal muscle biopsy tissue, it is advantageous to use DNA testing. Currently only 35 of over 400 potential variants inRYR1have been classed as functionally causative of malignant hyperthermia and thus can be used for DNA diagnostic tests. Here we describe functional analysis of 2RYR1variants (c. 7042_7044delCAG, p.ΔGlu2348 and c.641C>T, p.Thr214Met) that occur in the same malignant hyperthermia susceptible family. The p.Glu2348 deletion, causes hypersensitivity to ryanodine receptor agonists usingin vitroanalysis of cloned humanRYR1cDNA expressed in HEK293T cells, while the Thr214Met substitution, does not appear to significantly alter sensitivity to agonist in the same system. We suggest that the c. 7042_7044delCAG, p.ΔGlu2348RYR1variant could be added to the list of diagnostic mutations for susceptibility to malignant hyperthermia.
authors.affiliation: Institute of Fundamental Sciences, Massey University , Palmerston North, New Zealand.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stephens
authors.affiliation: Institute of Fundamental Sciences, Massey University , Palmerston North, New Zealand.
authors.forename: Anja H
authors.initials: AH
authors.lastname: Schiemann
authors.affiliation: Centre for Integrative Physiology, The University of Edinburgh , Edinburgh, United Kingdom.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Roesl
authors.affiliation: UK Malignant Hyperthermia Investigation Unit, Leeds Institute of Biomedical & Clinical Sciences, School of Medicine, University of Leeds, St. James's University Hospital , Leeds, United Kingdom.
authors.forename: Dorota
authors.initials: D
authors.lastname: Miller
authors.affiliation: Institute of Fundamental Sciences, Massey University , Palmerston North, New Zealand.
authors.forename: Sean
authors.initials: S
authors.lastname: Massey
authors.affiliation: Anaesthetic Department, Palmerston North Hospital , Palmerston North, New Zealand.
authors.forename: Neil
authors.initials: N
authors.lastname: Pollock
authors.affiliation: Anaesthetic Department, Palmerston North Hospital , Palmerston North, New Zealand.
authors.forename: Terasa
authors.initials: T
authors.lastname: Bulger
authors.affiliation: Institute of Fundamental Sciences, Massey University , Palmerston North, New Zealand.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stowell
keywords: anesthesia; calcium channel; malignant hyperthermia; ryanodine receptor; skeletal muscle