Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold‐induced myotonia in French Canadians

Key points•  Na + channels are pores present at the surface of every muscle cell; the initiation of muscle contraction requires the opening of a large number of Na + channels. •  Na v 1.4 channels are encoded by the SCN4A gene and represent over 90% of Na + channels in adult skeletal muscle cells; the M1476I mutation of Na v 1.4 causes potassium‐aggravated myotonia in a French Canadian population of the Saguenay‐Lac‐Saint‐Jean region of Quebec. •  Individuals carrying this mutation exhibit typical features ranging from asymptomatic myotonic discharges on electromyography to severe diffuse myotonia, as well as unusual cold‐induced, painful myotonia. •  Our study provides a detailed characterization of the underlying biophysical defect of the M1476I mutation, including an increased persistent Na + current, a disruption of fast inactivation and an accelerated recovery from inactivation; cooling further enhances the abnormalities of fast inactivation of the mutant channels. •  Our data suggest that mexiletine could be used as a therapeutic for patients carrying this mutation.