title: Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia.
abstract: A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, Indiana; and.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Beam
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Ohio Northern University, College of Pharmacy, Ada, Ohio.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Loudermilk
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, Indiana; and dfkisor@manchester.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Kisor
mesh_terms: D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type; D020022:Genetic Predisposition to Disease; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics*; D010597:Pharmacogenetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel
keywords: CACNA1S; malignant hyperthermia; pharmacogenetics