Clinical comparison and functional study of the L703P: a recurrent mutation in human SCN4A that causes sodium channel myotonia

Published:August 16, 2022DOI:


      • We identified a SCN4A mutation (p.L703P) in a Chinese family with non-dystrophic myotonias (NDM).
      • Characterization of mutant channel revealed both gain-of-function and loss-of-function changes in gating properties.
      • Literature search results in two independent case reports of NDM patients carrying L703P mutation in Nav1.4 channels.
      • The L703P is a recurrent mutation associated with NDM.


      The non-dystrophic myotonias are inherited skeletal muscle disorders characterized by skeletal muscle stiffness after voluntary contraction, without muscle atrophy. Based on their clinical features, non-dystrophic myotonias are classified into myotonia congenita, paramyotonia congenita, and sodium channel myotonia. Using whole-exome next-generation sequencing, we identified a L703P mutation (c.2108T>C, p.L703P) in SCN4A in a Chinese family diagnosed with non-dystrophic myotonias. The clinical findings of patients in this family included muscle stiffness and hypertrophy. The biophysical properties of wildtype and mutant channels were investigated using whole-cell patch clamp. L703P causes both gain-of-function and loss-of-function changes in Nav1.4 properties, including decreased current density, impaired recovery, enhanced activation and slow inactivation. Our study demonstrates that L703P is a pathogenic variant for myotonia, and provides additional electrophysiological information for understanding the pathogenic mechanism of SCN4A-associated channelopathies.


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