Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.
Channels (Austin)
; 12(1): 176-186, 2018.
Article
em En
| MEDLINE
| ID: mdl-29983085
ABSTRACT
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome do QT Longo
/
Canal de Sódio Disparado por Voltagem NAV1.5
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Doença do Sistema de Condução Cardíaco
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Mexiletina
/
Antiarrítmicos
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
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Infant
Idioma:
En
Revista:
Channels (Austin)
Ano de publicação:
2018
Tipo de documento:
Article