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Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold‐induced myotonia in French Canadians
Author(s) -
Zhao Juan,
Duprè Nicolas,
Puymirat Jack,
Chahine Mohamed
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2011.223461
Subject(s) - myotonia , mexiletine , missense mutation , mutant , sodium channel , mutation , skeletal muscle , population , potassium channel , chemistry , medicine , genetics , endocrinology , biology , microbiology and biotechnology , sodium , gene , myotonic dystrophy , organic chemistry , environmental health
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.