Wehner M, Rueffert H, Koenig F, Olthoff D
Department of Anaesthesiology and Intensive Care, Leipzig University Hospital, Liebigstrasse 20a, 04103 Leipzig, Germany.
Genet Test. 2003 Fall;7(3):203-11. doi: 10.1089/109065703322537214.
Malignant hyperthermia (MH) is caused by increased calcium release from sarcoplasmic reticulum, triggered by volatile anesthetics or depolarizing muscle relaxants. Numerous mutations associated with MH have been detected in the skeletal muscle type ryanodine receptor gene (RyR1), but so far facilitated calcium release has only been demonstrated for a few of them. This is a prerequisite for confirming the causative role of an RyR1 mutation for MH. Calcium release from sarcoplasmic reticulum induced by 4-chloro-m-cresol (4CmC), caffeine, and halothane was determined in human myotubes by calcium imaging. The RyR1 Ile2182Phe mutation and the RyR1 Gly2375Ala mutation have been identified in individuals susceptible to MH. In myotubes of individuals carrying the RyR1 Ile2182Phe or the RyR1 Gly2375Ala mutation, the EC(50) for caffeine and halothane was reduced; in the Ile2182Phe myotubes, the EC(50) for 4CmC was also reduced, all consistent with facilitated calcium release from the sarcoplasmic reticulum. From these data we conclude that both mutations are pathogenic for MH.
恶性高热（MH）是由挥发性麻醉剂或去极化肌松药引发的肌浆网钙释放增加所致。在骨骼肌型兰尼碱受体基因（RyR1）中已检测到许多与MH相关的突变，但迄今为止，仅对其中少数突变证实了其促进钙释放的作用。这是确认RyR1突变对MH致病作用的先决条件。通过钙成像测定了人肌管中由4-氯间甲酚（4CmC）、咖啡因和氟烷诱导的肌浆网钙释放。在MH易感个体中已鉴定出RyR1 Ile2182Phe突变和RyR1 Gly2375Ala突变。在携带RyR1 Ile2182Phe或RyR1 Gly2375Ala突变的个体的肌管中，咖啡因和氟烷的半数有效浓度（EC50）降低；在Ile2182Phe肌管中，4CmC的EC50也降低，所有这些均与肌浆网钙释放促进一致。从这些数据我们得出结论，这两种突变对MH均具有致病性。
