Key result
In vitro treatment with mexiletine rescued the mixed biophysical phenotype of the SCN5A-N406K mutation by increasing peak INa 2.8-fold and decreasing late INa by approximately 60%.
Why the study?
Does mexiletine improve the biophysical properties of the SCN5A-N406K mutant sodium channel in an in vitro model?
Does mexiletine improve the biophysical properties of the SCN5A-N406K mutant sodium channel in an in vitro model?
In an in vitro model, mexiletine successfully rescued both the loss-of-function (decreased peak INa) and gain-of-function (increased late INa) biophysical defects caused by the SCN5A-N406K mutation found in LQT3.
Answers are grounded in this paper and cite their sources.
Mexiletine rescues SCN5A-N406K channel defects in vitro; hypothesis-generating for LQT3 therapy and requires clinical validation.
Introduction: Individual mutations in the SCN5A-encoding cardiac sodium channel α-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. Methods and Results: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. Conclusion: SCN5A-N406K channel displays both “gain-of-function” in late INa and “loss-of-function” in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both “gain-of-function” and “loss-of-function” of the mutant sodium channel.
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Hu et al. (2018) studied Long QT syndrome type 3 (LQT3) with SCN5A-N406K mutation (n=1). Mexiletine vs. No mexiletine (control non-incubated mutant channels) was evaluated on Peak INa density in SCN5A-N406K mutant channels (2.8-fold increase, p=<0.01). In vitro treatment with mexiletine rescued the mixed biophysical phenotype of the SCN5A-N406K mutation by increasing peak INa 2.8-fold and decreasing late INa by approximately 60%.
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