抄録
We reported a dominantly inherited Japanese family with myotonia and cold-induced hypokalemic periodic paralysis. The proband showed hypokalemia and flaccid paralysis in cold atmospheric temperatures. This phenotype is associated with a novel mutation in the voltage dependent skeletal muscle sodium channel (Nav1.4) alpha subunit gene (SCN4A). This P1158S mutation is localized between the fourth and fifth transmembrane segments of domain III in Nav1.4. Using the amphotericin B-perforated-patch clamp method, sodium currents were recorded at 22°C and 32°C from the wild type (WT) and P1158S mutant Nav1.4 expressed in tsA201 cells. Computer simulation was performed incorporating the gating-parameters of the P1158S mutant Nav1.4. P1158S mutant Nav1.4 exhibited hyperpolarizing shifts in voltage-dependence of both activation and inactivation curves at a cold temperature and a slower rate of inactivation than the WT. Computer simulation reproduced the abnormal skeletal muscle electrical activities of both paralysis at a low potassium concentration in the cold, and myotonia at a normal potassium concentration. For the first time we found that a single amino acid mutant sodium channel shifted the voltage dependency in the hyperpolarizing direction in a temperature dependent manner. Recently, it was reported that generalized epilepsy with febrile seizures plus (GEFS+) were caused by sodium channel mutations, and the heat-induced paralysis of the smellblind drosophila mutant was also found to be due to a sodium channel mutation. Thus, sodium channel abnormalities may be responsible for the temperature sensitive pathological states of various diseases. [Jpn J Physiol 55 Suppl:S7 (2005)]
