title: Cardiac sodium channel dysfunction in sudden infant death syndrome.
abstract: BACKGROUND
  Mutations in genes responsible for the congenital long-QT syndrome, especially SCN5A, have been identified in some cases of sudden infant death syndrome. In a large-scale collaborative genetic screen, several SCN5A variants were identified in a Norwegian sudden infant death syndrome cohort (n=201). We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts.
  
  
  RESULTS
  Whole-cell sodium currents were measured in tsA201 cells transiently transfected with recombinant wild-type or mutant SCN5A cDNA (hH1) coexpressed with the human beta1 subunit. All variants exhibited defects in the kinetics and voltage dependence of inactivation. Five variants (S216L, T1304M, F1486L, F2004L, and P2006A) exhibited significantly increased persistent sodium currents (range, 0.5% to 1.7% of peak current) typical of SCN5A mutations associated with long-QT syndrome. These same 5 variants also displayed significant depolarizing shifts in voltage dependence of inactivation (range, 5 to 14 mV) and faster recovery from inactivation, but F1486L uniquely exhibits a depolarizing shift in the conductance-voltage relationship. Three alleles (delAL586-587, R680H, and V1951L) exhibited increased persistent current only under conditions of internal acidosis (R680H) or when expressed in the context of a common splice variant (delQ1077), indicating that they have a latent dysfunctional phenotype.
  
  
  CONCLUSIONS
  Our present results greatly expand the spectrum of functionally characterized SCN5A variants associated with sudden infant death syndrome and provide further biophysical correlates of arrhythmia susceptibility in this syndrome.
authors.affiliation: Departments of Pharmacology, Vanderbilt University, Nashville, Tenn, USA.
authors.forename: Dao W
authors.initials: DW
authors.lastname: Wang
authors.forename: Reshma R
authors.initials: RR
authors.lastname: Desai
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Marianne
authors.initials: M
authors.lastname: Arnestad
authors.forename: Roberto
authors.initials: R
authors.lastname: Insolia
authors.forename: Matteo
authors.initials: M
authors.lastname: Pedrazzini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.forename: Ashild
authors.initials: A
authors.lastname: Vege
authors.forename: Torleiv
authors.initials: T
authors.lastname: Rognum
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000483:Alleles; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D015331:Cohort Studies; D018076:DNA, Complementary / Q000235:genetics; D004562:Electrocardiography; D004594:Electrophysiology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D008433:Mathematics; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009664:Norway; D010641:Phenotype; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*; D013398:Sudden Infant Death / Q000209:etiology* / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels