title: A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents.
abstract: BACKGROUND
  Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes.
  
  
  OBJECTIVE
  To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS).
  
  
  METHODS
  All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques.
  
  
  RESULTS
  Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3.
  
  
  CONCLUSIONS
  Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martínez
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Christian
authors.initials: C
authors.lastname: Veltmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.forename: Janire
authors.initials: J
authors.lastname: Urrutia
authors.forename: Aintzane
authors.initials: A
authors.lastname: Alday
authors.forename: Oscar
authors.initials: O
authors.lastname: Casis
authors.forename: Ryan
authors.initials: R
authors.lastname: Pfeiffer
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Gabriel
authors.initials: G
authors.lastname: Caceres
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Christian
authors.initials: C
authors.lastname: Wolpert
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Peter
authors.initials: P
authors.lastname: Schwartz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008967:Molecular Biology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D013398:Sudden Infant Death / Q000235:genetics*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit / Q000235:genetics* / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; C470379:SCN1B protein, human; C568320:SCN5A protein, human; D062547:Voltage-Gated Sodium Channel beta-1 Subunit