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 resultsThe mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216LH558R 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 (INa) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. INa density partially recovered in S216LH558R 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 S216LH558R channels, INa density partially recovered and did not display a resurgent component. INa changes during dynamic clamp were interpreted by numerical modelling. ConclusionThe BS pattern of p.S216L might result from a decrease in INa 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.

Marangoni, S., Di Resta, C., Rocchetti, M., Barile, L., Rizzetto, R., Summa, A., et al. (2011). A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization. CARDIOVASCULAR RESEARCH, 91(4), 606-616 [10.1093/cvr/cvr142].

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

MARANGONI, STEFANO FEDERICO;ROCCHETTI, MARCELLA;BARILE, LUCIO;RIZZETTO, RICCARDO;ZAZA, ANTONIO
2011

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 resultsThe mutation was expressed alone (S216L channels), or in combination with the polymorphism (S216LH558R 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 (INa) density, attributable to protein misfolding (rescued by mexiletine pretreatment) and moderate slowing of inactivation. INa density partially recovered in S216LH558R 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 S216LH558R channels, INa density partially recovered and did not display a resurgent component. INa changes during dynamic clamp were interpreted by numerical modelling. ConclusionThe BS pattern of p.S216L might result from a decrease in INa 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.
Articolo in rivista - Articolo scientifico
Polymorphism, Genetic; Humans; Child; Sodium Channels; Phenotype; Patch-Clamp Techniques; Electrocardiography; Adult; Brugada Syndrome; Long QT Syndrome; Mutation; Female; Male; NAV1.5 Voltage-Gated Sodium Channel
English
2011
91
4
606
616
none
Marangoni, S., Di Resta, C., Rocchetti, M., Barile, L., Rizzetto, R., Summa, A., et al. (2011). A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization. CARDIOVASCULAR RESEARCH, 91(4), 606-616 [10.1093/cvr/cvr142].
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/43647
Citazioni
  • Scopus 50
  • ???jsp.display-item.citation.isi??? 48
Social impact