Sequencing of genes involved in the movement of calcium across human skeletal muscle sarcoplasmic reticulum: continuing the search for genes associated with malignant hyperthermia.
The genetic basis of malignant hyperthermia (MH) is not fully characterised and likely involves more than just the currently classified mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) and the gene encoding the α1 subunit of the dihydropyridine receptor (CACNA1S). In this paper we sequence other genes involved in calcium trafficking within skeletal muscle in patients with positive in vitro contracture tests, searching for alternative genes associated with MH. We identified four rare variants in four different genes (CACNB1, CASQ1, SERCA1andCASQ2) encoding proteins involved in calcium handling in skeletal muscle in a cohort of 30 Australian MH susceptible probands in whom prior complete sequencing ofRYR1andCACNA1Shad yielded no rare variants. These four variants have very low minor allele frequencies and while it is tempting to speculate that they have a role in MH, they remain at present variants of unknown significance. Nevertheless they provide the basis for a new set of functional studies, which may indeed identify novel players in MH.
Senior Scientist, Malignant Hyperthermia Diagnostic Unit, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Anaesthesia, Perioperative and Pain Medicine Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victorian Clinical Genetics Service Molecular Genetics Laboratory, Murdoch Children's Research Institut.
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Bjorksten
Head, Malignant Hyperthermia Diagnostic Unit, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Anaesthesia, Perioperative and Pain Medicine Unit, University of Melbourne, Victoria.
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Gillies
Malignant Hyperthermia Diagnostic Unit, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Consultant Anaesthetist, Anaesthesia, Perioperative and Pain Medicine Unit, University of Melbourne, Victoria.
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Hockey
Research Affiliate/Head, Victorian Clinical Genetics Service Molecular Genetics Laboratory, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria.
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D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics; D020746:Calcium Channels, L-Type; D002155:Calsequestrin / Q000235:genetics; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics
C412223:CACNA1S protein, human; C443109:CASQ2 protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002155:Calsequestrin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D002118:Calcium
malignant hyperthermia, genetic variants