title: A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Marangoni
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Resta
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.forename: Lucio
authors.initials: L
authors.lastname: Barile
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rizzetto
authors.forename: Aurora
authors.initials: A
authors.lastname: Summa
authors.forename: Stefano
authors.initials: S
authors.lastname: Severi
authors.forename: Elena
authors.initials: E
authors.lastname: Sommariva
authors.forename: Carlo
authors.initials: C
authors.lastname: Pappone
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ferrari
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
mesh_terms: D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics*; D000075224:Cardiac Conduction System Disease; D002648:Child; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011110:Polymorphism, Genetic; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels