Wehner M, Rueffert H, Koenig F, Neuhaus J, Olthoff D
Department of Anaesthesiology and Intensive Care Medicine, Department of Urology, University Hospital of Leipzig, Leipzig, Germany.
Clin Genet. 2002 Aug;62(2):135-46. doi: 10.1034/j.1399-0004.2002.620206.x.
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.
恶性高热（MH）是一种常染色体显性骨骼肌疾病，由挥发性麻醉剂和去极化肌松药引发。致病缺陷在于骨骼肌肌浆网中Ca(2+)释放的控制。在兰尼碱受体1（RyR1）基因中已检测到众多突变，但到目前为止，仅16种人类RyR1突变的MH致病作用得到了证实。在本报告中，我们表明，源自携带RyR1 Thr2206Met（C6617T）突变个体的肌管对4-氯间甲酚和咖啡因的细胞内钙浓度有异常反应。卫星细胞取自因诊断MH而接受检查的患者的肌肉活检样本。通过荧光钙成像研究了对4-氯间甲酚和咖啡因反应时的细胞内钙浓度。在肌管中，4-氯间甲酚的半数最大激活浓度（EC(50)）从203微摩尔（野生型）降至98微摩尔（Thr2206Met），咖啡因的则从3.8毫摩尔降至1.8毫摩尔。从EC(50)的降低，我们得出结论，RyR1 Thr2206Met突变对MH具有致病性。
