Aim: The Na+ channel mutation (p.S216L), previously associated to an LQT3 phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada Syndrome (BS) ECG pattern. The study aimed to assess 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 ac ion penti l waveforms. Expression of S216L channels was associated with a 60% red ction i ximu Na+ urrent (INa) density, attributable to protein misfolding (rescued by mexiletine pretreatment), and moderate slowing of inactivation. INa density partially recovered in S216L-H558R channels, but INa inactivation and its recovery were further delayed. The persistent component of INa (INaL) was unchanged. Under dynamic clamp conditions, INa decreased in S216L channels and displayed a "resurgent" component during late repolarization. In S216L-H558R channels INa density partially recovered and did not display a resurgent component. INa changes during dynamic clamp were interpreted by numerical modeling. Conclusions: the BS pattern of p.S216L might result fro a deease in INa density, which masked gating abnormalities that might otherwise esult i LQT enot pe. 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.

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

SUMMA, AURORA;SEVERI, STEFANO;
2011

Abstract

Aim: The Na+ channel mutation (p.S216L), previously associated to an LQT3 phenotype, and a common polymorphism (p.H558R) were detected in a patient with an intermittent Brugada Syndrome (BS) ECG pattern. The study aimed to assess 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 ac ion penti l waveforms. Expression of S216L channels was associated with a 60% red ction i ximu Na+ urrent (INa) density, attributable to protein misfolding (rescued by mexiletine pretreatment), and moderate slowing of inactivation. INa density partially recovered in S216L-H558R channels, but INa inactivation and its recovery were further delayed. The persistent component of INa (INaL) was unchanged. Under dynamic clamp conditions, INa decreased in S216L channels and displayed a "resurgent" component during late repolarization. In S216L-H558R channels INa density partially recovered and did not display a resurgent component. INa changes during dynamic clamp were interpreted by numerical modeling. Conclusions: the BS pattern of p.S216L might result fro a deease in INa density, which masked gating abnormalities that might otherwise esult i LQT enot pe. 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.
2011
S. Marangoni; C; Di Resta; M. Rocchetti; L. Barile; R. Rizzetto; A. Summa; S. Severi; E. Sommariva; C. Pappone; M. Ferrari; S. Benedetti; A. Zaza
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/117078
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