Gain of function in the novel Nav1.4 paramyotonia congenita mutant N440K by Prof. Myeong-Kyu Kim given during the 15th Congress of the European Federation of Neurological Societies powered by - MULTIWEBCAST

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Voltage-gated Na+ channels (Navs) initiate action potentials in brain, heart, and muscle. Dysfunction of these important excitation regulators leads to a wide spectrum of disorders with distinct phenotypes. Mutations in SCN4A, the gene coding for the isoform predominating in skeletal muscle, have been tied to various myotonic disorders such as hyperkalemic periodic paralysis, sodium channel myotonia, as well as paramyotonia congenita. The biophysical abnormalities brought about by the associated amino acid changes have been described in detail for some, which has led to a better mechanistic understanding of the associated disorders, although reliable genotype-phenotype predictions remain impossible. We here report a new SCN4A mutation identified in a paramyotonia congenita patient. Genetic analysis via candidate approach revealed a substitution c.1320T>A, which is predicted to re-code the wildtype asparagine at position 440 into a lysine (i.e., p.Asn440Lys or N440K). We introduced this variation into the cDNA of human Nav1.4 and transiently co-expressed it along with the Nav b1 subunit in HEK293 cells. Whole-cell voltage-clamping showed that N440K rendered Nav1.4 with behavior that is overall consistent with a gain of function, based on fast- and slow-inactivation abnormalities. In fast inactivation, we observed a depolarizing shift in the voltage dependence as well as accelerated recovery. In slow inactivation, we found N440K requiring longer and stronger depolarization compared to the wildtype. Implications for pharmacological intervention are discussed.

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