Malignant hyperthermia (MH) is an autosomal-dominant disorder of skeletal muscle, triggered by volatile anaesthetics and depolarizing muscle relaxants. The causative defect lies in the control of Ca(2+) release from the sarcoplasmic reticulum in skeletal muscle. Numerous mutations have been detected in the ryanodine receptor 1 (RyR1) gene, but so far an MH-causative role has only been confirmed for 16 human RyR1 mutations. In this report we show that myotubes derived from individuals carrying the RyR1 Thr2206Met (C6617T) mutation have an abnormal response of the intracellular calcium concentration to 4-chloro-m-cresol and to caffeine. Satellite cells were obtained from muscle biopsies of patients referred for diagnosing MH. The intracellular calcium concentration in response to 4-chloro-m-cresol and to caffeine was investigated by fluorescence calcium imaging. In myotubes the half-maximal activation concentration (EC(50)) for 4-chloro-m-cresol was reduced from 203 micro m (wild type) to 98 micro m (Thr2206Met), and for caffeine from 3.8 mm to 1.8 mm. From the reduction of EC(50) we conclude that the RyR1 Thr2206Met mutation is pathogenic for MH.

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