**3.4 CMS due to defects in skeletal muscle sodium channel, NaV1.4**

Another class of postsynaptic CMS is due to mutations in skeletal muscle sodium channel, NaV1.4, encoded by *SCN4A* (Tsujino *et al.*, 2003). Dominant gain-of-function mutations in this gene cause hyperkalemic periodic paralysis (Ptacek *et al.*, 1991), paramyotonia congenita (McClatchey *et al.*, 1992; Ptacek *et al.*, 1992), potassium-aggravated myotonia (Lerche *et al.*, 1993), and hypokalemic periodic paralysis type 2 (Bulman *et al.*, 1999). On the other hand, loss-of-function mutations cause a CMS.

Failure of normal-amplitude endplate potential depolarizing the resting potential to -40 mV in intercostal muscle of a CMS patient with episodes of apnea and myasthenic symptoms since birth prompted us to search for mutations in *SCN4A*. We identified two heteroallelic missense mutations, S246L and V1442E (Tsujino *et al.*, 2003). Activation kinetics of the mutant NaV1.4 was normal for both S246L and V1442E, but the fast inactivation curves were shifted to hyperpolarization by 7.3 mV for S246L and 33.2 mV for V1442E, indicating that both mutations enhance fast inactivation of the NaV1.4 immediately after it is activated. Moreover, a high proportion of the V1442 channel was in the inactivated state even at a normal resting membrane potential. Recovery from the fast-inactivated state was slowed for both mutations. This was in contrast to gain-of-function mutations in other diseases, which shift the fast inactivation curves to depolarization. Neither S246L nor V1442E affected slow inactivation. Analysis of use-dependent inactivation in HEK293 cells by stimulating at 50 Hz for 3 ms revealed that wild-type and S246L channels decreased the peak current only by 5% and V1442E channel decreased it by 30% during the first few pulses and suggested that the S246L mutation is relatively benign.
