Novel mutations in C-terminal channel region of the ryanodine receptor in malignant hyperthermia patients

Japanese Journal of Pharmacology
H OyamadaMasamitsu Iino

Abstract

Malignant hyperthermia (MH) is a pharmacogenetical complication of general anesthesia resulting from abnormal Ca2+-induced Ca2+ release (CICR) via the type 1 ryanodine receptor (RyR1) in skeletal muscles. In this study, we analyzed the genomic DNAs prepared for determination of all the 106 exons of the RyR1 gene from blood samples donated by two MH patients with extremely high CICR rates in their biopsied skeletal muscles and a clear history of MH incidence. Two novel point mutations were found in the exons 96 and 101 with alterations in the coded amino acids within the C-terminal channel region, i.e., Pro4668 to Ser and Leu4838 to Val. The latter mutation was found in both MH patients. Rabbit RyR1 channels carrying corresponding mutations were expressed in CHO cells for functional assay. It was found that the L to V but not the P to S mutation of the RyR1 resulted in enhanced Ca2+ release activity. These results indicate that the L4838V mutation is responsible for the MH incidence. The L4838V mutation is unique because it is the mutation first found within a hydrophobic transmembrane segment of the channel region and should provide further information on the function of the RyR1 as well as for genetic diagnosis of MH.

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Citations

Apr 2, 2011·Canadian Journal of Anaesthesia = Journal Canadien D'anesthésie·Natasha KraevaDavid H Maclennan
Nov 21, 2008·Pharmacogenomics·Kathryn M Stowell
Feb 5, 2009·Human Mutation·Soledad LevanoThierry Girard
Aug 19, 2006·Human Mutation·Rachel RobinsonPhilip Hopkins
Aug 24, 2005·Cell Calcium·Susan L Hamilton
Jul 19, 2015·British Journal of Anaesthesia·P M HopkinsUNKNOWN European Malignant Hyperthermia Group
Dec 16, 2010·The Korean journal of laboratory medicine·Ho LeeDal Sik Kim
Oct 1, 2009·Physiological Reviews·Makoto Endo
Jan 22, 2014·Anesthesia and Analgesia·Kathryn M Stowell
May 8, 2004·Clinical Chemistry·Alessia BagattinGian Antonio Danieli

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