Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3

Yanfei Ruan, Marco Denegri, Nian Liu, Tiziana Bachetti, Morena Seregni, Stefano Morotti, Stefano Severi, Carlo Napolitano, Silvia G. Priori

Research output: Contribution to journalArticle

Abstract

Rationale: Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations. Objective: We sought to investigate the unexpected deleterious effect of mexiletine in a mutation combining gain-offunction and trafficking abnormalities. Methods and Results: A long-QT syndrome type 3 child experienced paradoxical QT prolongation and worsening of arrhythmias after mexiletine treatment. The SCN5A mutation F1473S expressed in HEK293 cells presented a right-ward shift of steady-state inactivation, enlarged window current, and huge sustained sodium current. Unexpectedly, it also reduced the peak sodium current by 80%. Immunostaining showed that mutant Nav1.5 is retained in the cytoplasm. Incubation with 10 μmol/L mexiletine rescued the trafficking defect of F1473S, causing a significant increase in peak current, whereas sustained current was unchanged. Using a Markovian model of the Na channel and a model of human ventricular action potential, we showed that simulated exposure of F1473S to mexiletine paradoxically increased action potential duration, mimicking QT prolongation seen in the index patient on mexiletine treatment. Conclusions: Sodium channel blockers are largely used to shorten QT intervals in carriers of SCN5A mutations. We provided evidence that these agents may facilitate trafficking of mutant proteins, thus exacerbating QT prolongation. These data suggest that caution should be used when recommending this class of drugs to carriers of mutations with undefined electrophysiological properties.

Original languageEnglish
Pages (from-to)1374-1383
Number of pages10
JournalCirculation Research
Volume106
Issue number8
DOIs
Publication statusPublished - Apr 30 2010

Fingerprint

Mexiletine
Genetic Therapy
Mutation
Sodium Channel Blockers
Action Potentials
Sodium
Drug Carriers
Sodium Channels
HEK293 Cells
Mutant Proteins
Therapeutics
Genes
Long QT syndrome type 3
Cardiac Arrhythmias
Cytoplasm

Keywords

  • Electrophysiology
  • Genetics
  • Ion channels
  • Long-QT syndrome
  • Pharmacology

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3. / Ruan, Yanfei; Denegri, Marco; Liu, Nian; Bachetti, Tiziana; Seregni, Morena; Morotti, Stefano; Severi, Stefano; Napolitano, Carlo; Priori, Silvia G.

In: Circulation Research, Vol. 106, No. 8, 30.04.2010, p. 1374-1383.

Research output: Contribution to journalArticle

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abstract = "Rationale: Sodium channel blockers are used as gene-specific treatments in long-QT syndrome type 3, which is caused by mutations in the sodium channel gene (SCN5A). Response to treatment is influenced by biophysical properties of mutations. Objective: We sought to investigate the unexpected deleterious effect of mexiletine in a mutation combining gain-offunction and trafficking abnormalities. Methods and Results: A long-QT syndrome type 3 child experienced paradoxical QT prolongation and worsening of arrhythmias after mexiletine treatment. The SCN5A mutation F1473S expressed in HEK293 cells presented a right-ward shift of steady-state inactivation, enlarged window current, and huge sustained sodium current. Unexpectedly, it also reduced the peak sodium current by 80{\%}. Immunostaining showed that mutant Nav1.5 is retained in the cytoplasm. Incubation with 10 μmol/L mexiletine rescued the trafficking defect of F1473S, causing a significant increase in peak current, whereas sustained current was unchanged. Using a Markovian model of the Na channel and a model of human ventricular action potential, we showed that simulated exposure of F1473S to mexiletine paradoxically increased action potential duration, mimicking QT prolongation seen in the index patient on mexiletine treatment. Conclusions: Sodium channel blockers are largely used to shorten QT intervals in carriers of SCN5A mutations. We provided evidence that these agents may facilitate trafficking of mutant proteins, thus exacerbating QT prolongation. These data suggest that caution should be used when recommending this class of drugs to carriers of mutations with undefined electrophysiological properties.",
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AU - Seregni, Morena

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AU - Severi, Stefano

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