A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization

Cardiovasc Res. 2011 Sep 1;91(4):606-16. doi: 10.1093/cvr/cvr142. Epub 2011 Jun 24.

Abstract

Aims: The Na(+) channel mutation (p.S216L), previously associated with type 3 long-QT syndrome (LQT3) phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada syndrome (BS) ECG pattern. The study was aimed to assess the p.S216L electrical phenotype, its modulation by p.H558R, and to identify abnormalities compatible with a mixed BS-LQT3 phenotype.

Methods and results: The mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216L-H558R channels), in a mammalian cell line (TSA201). Functional analysis included standard voltage clamp and dynamic clamp with endo- and epicardial action potential waveforms. Expression of S216L channels was associated with a 60% reduction in maximum Na(+) current (I(Na)) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. I(Na) density partially recovered in S216L-H558R channels, but I(Na) inactivation and its recovery were further delayed. The persistent component of I(Na) (I(NaL)) was unchanged. Under dynamic clamp conditions, I(Na) decreased in S216L channels and displayed a 'resurgent' component during late repolarization. In S216L-H558R channels, I(Na) density partially recovered and did not display a resurgent component. I(Na) changes during dynamic clamp were interpreted by numerical modelling.

Conclusion: The BS pattern of p.S216L might result from a decrease in I(Na) density, which masked gating abnormalities that might otherwise result in a LQT phenotype. The p.H558R polymorphism decreased p.S216L expressivity, partly by lessening p.S216L effects and partly through the induction of further gating abnormalities suitable to blunt p.S216L effects during repolarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brugada Syndrome / genetics*
  • Cardiac Conduction System Disease
  • Child
  • Electrocardiography
  • Female
  • Humans
  • Long QT Syndrome / genetics
  • Male
  • Mutation*
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Phenotype
  • Polymorphism, Genetic*
  • Sodium Channels / genetics*
  • Sodium Channels / physiology

Substances

  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Sodium Channels

Supplementary concepts

  • Long QT syndrome type 3