Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

Abstract

Corrochano Sanchez et al. identify a novel mutation (I588V) in SCN4A, which encodes the Nav1.4 voltage-gated sodium channel, in a patient with myotonia and periodic paralysis. By generating and characterizing a mouse model (‘draggen’) carrying the equivalent point mutation (I582V), they uncover novel pathological and metabolic features of SCN4A channelopathies.

Abstract

Mutations in the skeletal muscle channel ( SCN4A), encoding the Na _v1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Na _v1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Na _v1.4 channel. Using N-ethyl- N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target.