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Complex interactions in a novel SCN5A compound mutation associated with long QT and Brugada syndrome: Implications

Jie Liu1, Jason D Bayer2,3, Roozbeh Aschar-Sobbi1

  • 1Department of Biology, York University, Toronto, Ontario, Canada.

Plos One
|May 24, 2018
PubMed
Abstract

Insights

The SCN5A P1332L mutation causes long QT syndrome, but the A647D mutation alters its presentation and reduces mexiletine effectiveness. This dual mutation creates a new phenotype where mexiletine is not a suitable treatment.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Ion Channel Physiology

Background:

  • The SCN5A P1332L mutation is associated with congenital long QT syndrome type 3 (LQT3), typically responsive to mexiletine.
  • The SCN5A A647D mutation causes Brugada syndrome.
  • A patient with both mutations presented with atypical symptoms and lacked response to mexiletine.

Observation:

  • Investigated the biophysical properties of SCN5A P1332L and A647D mutations, individually and combined, using heterologous expression and myocyte modeling.
  • Assessed the impact of these mutations on sodium channel (Na+) function and mexiletine binding kinetics.

Findings:

  • P1332L channels exhibited altered inactivation and increased late Na+ currents (INa).
  • A647D reduced Na+ current density and mexiletine sensitivity when co-expressed with P1332L.
  • Modeling indicated that the combined mutations result in shortened action potential durations and reduced peak INa compared to individual mutations.

Implications:

  • The A647D mutation can mitigate the LQT3 phenotype but also reduces mexiletine efficacy.
  • The co-expression of P1332L and A647D creates a novel cardiac phenotype with conduction defects.
  • Mexiletine is not a suitable pharmacotherapy for patients with this combined SCN5A mutation profile.

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