SCN4A Mutation Contributing to Sodium Channel Myotonia

SCN4A Mutation Contributing to Sodium Channel Myotonia: Comparison

Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Huang Chiung-Wei.

Abstract: Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the

Myotonia congenita (MC) is a rare disorder characterized by stiffness and weakness of the limb and trunk muscles. Mutations in the

SCN4A

gene encoding the alpha-subunit of the voltage-gated sodium channel Na

1.4 have been reported to be responsible for sodium channel myotonia (SCM). The Na

1.4 channel is expressed in skeletal muscles, and its related channelopathies affect skeletal muscle excitability, which can manifest as SCM, paramyotonia, and periodic paralysis. In this study, the missense mutation p.V445M was identified in two individual families with MC. To determine the functional consequences of having a mutated Na

1.4 channel, whole-cell patch-clamp recording of transfected Chinese hamster ovary cells was performed. Evaluation of the transient Na

⁺

current found that a hyperpolarizing shift occurs at both the activation and inactivation curves with an increase of the window currents in the mutant channels. The Na

1.4 channel’s co-expression with the Na

β4 peptide can generate resurgent Na

⁺

currents at repolarization following a depolarization. The magnitude of the resurgent currents is higher in the mutant than in the wild-type (WT) channel. Although the decay kinetics are comparable between the mutant and WT channels, the time to the peak of resurgent Na

⁺

currents in the mutant channel is significantly protracted compared with that in the WT channel. These findings suggest that the p.V445M mutation in the Na

1.4 channel results in an increase of both sustained and resurgent Na

⁺

currents, which may contribute to hyperexcitability with repetitive firing and is likely to facilitate recurrent myotonia in SCM patients.

Myotonia congenita, SCN4A mutation, sodium channel

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