Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5a mutation, N406K, found in LQT3 patients

Rou Mu Hu, David J. Tester, Ryan Li, Tianyu Sun, Blaise Z. Peterson, Michael John Ackerman, Jonathan C. Makielski, Bi Hua Tan

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)176-186
Number of pages11
JournalChannels
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Mexiletine
Sodium Channels
Phenotype
Mutation
Torsades de Pointes
Mutagenesis
HEK293 Cells
Clamping devices
Patch-Clamp Techniques
Site-Directed Mutagenesis
Cardiac Arrhythmias
Sleep
Seizures
Sodium
Electric potential

Keywords

  • Mexiletine
  • Mixed phenotype
  • Mutation
  • SCN5A
  • Sodium channel

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5a mutation, N406K, found in LQT3 patients. / Hu, Rou Mu; Tester, David J.; Li, Ryan; Sun, Tianyu; Peterson, Blaise Z.; Ackerman, Michael John; Makielski, Jonathan C.; Tan, Bi Hua.

In: Channels, Vol. 12, No. 1, 01.01.2018, p. 176-186.

Research output: Contribution to journalArticle

Hu, Rou Mu ; Tester, David J. ; Li, Ryan ; Sun, Tianyu ; Peterson, Blaise Z. ; Ackerman, Michael John ; Makielski, Jonathan C. ; Tan, Bi Hua. / Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5a mutation, N406K, found in LQT3 patients. In: Channels. 2018 ; Vol. 12, No. 1. pp. 176-186.
@article{04036edf979249ad8edbcf11f1306b04,
title = "Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5a mutation, N406K, found in LQT3 patients",
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 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.",
keywords = "Mexiletine, Mixed phenotype, Mutation, SCN5A, Sodium channel",
author = "Hu, {Rou Mu} and Tester, {David J.} and Ryan Li and Tianyu Sun and Peterson, {Blaise Z.} and Ackerman, {Michael John} and Makielski, {Jonathan C.} and Tan, {Bi Hua}",
year = "2018",
month = "1",
day = "1",
doi = "10.1080/19336950.2018.1475794",
language = "English (US)",
volume = "12",
pages = "176--186",
journal = "Channels",
issn = "1933-6950",
publisher = "Landes Bioscience",
number = "1",

}

TY - JOUR

T1 - Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5a mutation, N406K, found in LQT3 patients

AU - Hu, Rou Mu

AU - Tester, David J.

AU - Li, Ryan

AU - Sun, Tianyu

AU - Peterson, Blaise Z.

AU - Ackerman, Michael John

AU - Makielski, Jonathan C.

AU - Tan, Bi Hua

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Mexiletine

KW - Mixed phenotype

KW - Mutation

KW - SCN5A

KW - Sodium channel

UR - http://www.scopus.com/inward/record.url?scp=85056089165&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056089165&partnerID=8YFLogxK

U2 - 10.1080/19336950.2018.1475794

DO - 10.1080/19336950.2018.1475794

M3 - Article

VL - 12

SP - 176

EP - 186

JO - Channels

JF - Channels

SN - 1933-6950

IS - 1

ER -