title: p.D1690N Nav1.5 rescues p.G1748D mutation gating defects in a compound heterozygous Brugada syndrome patient.
abstract: BACKGROUND
  We identified 2 compound heterozygous mutations (p.D1690N and p.G1748D) in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) in a proband diagnosed with Brugada syndrome type 1. Furthermore, in the allele encoding the p.D1690N mutation, the p.H558R polymorphism was also detected.
  
  
  OBJECTIVE
  The purpose of this study was to analyze the functional properties of the mutated channels as well as the putative modulator effects produced by the presence of the polymorphism.
  
  
  METHODS
  Wild-type and mutated human Nav1.5 channels were expressed in Chinese hamster ovary cells and recorded using whole-cell patch-clamp technique.
  
  
  RESULTS
  Separately, both p.D1690N and p.G1748D mutations produced a marked reduction in peak Na(+) current density (>80%), mainly due to their limited trafficking toward the membrane. Furthermore, p.G1748D mutation profoundly affected channel gating. Both p.D1690N and p.G1748D produced a marked dominant negative effect when cotransfected with either wild-type or p.H558R channels. Conversely, p.H558R was able to rescue defective trafficking of p.D1690N channels toward the membrane when both polymorphism and mutation were in the same construct. Surprisingly, cotransfection with p.D1690N, either alone or together with the polymorphism (p.H558R-D1690N), completely restored the profound gating defects exhibited by p.G1748D channels but only slightly rescued their trafficking.
  
  
  CONCLUSIONS
  Our results add further support to the hypothesis that Nav1.5 subunits interact among them before trafficking toward the membrane and suggest that a missense mutation can "rescue" the defective gating produced by another missense mutation.
authors.affiliation: Complejo Hospitalario Universitario de A Coruña and Instituto de Ciencias de la Salud-INIBIC, Universidad de A Coruña, Coruña, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Núñez
authors.forename: Adriana
authors.initials: A
authors.lastname: Barana
authors.forename: Irene
authors.initials: I
authors.lastname: Amorós
authors.forename: Marta González
authors.initials: MG
authors.lastname: de la Fuente
authors.forename: Pablo
authors.initials: P
authors.lastname: Dolz-Gaitón
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gómez
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez-García
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mosquera
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Monserrat
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
authors.forename: Alfonso
authors.initials: A
authors.lastname: Castro-Beiras
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
mesh_terms: D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D012680:Sensitivity and Specificity
chemical_list: D018076:DNA, Complementary; D062554:NAV1.5 Voltage-Gated Sodium Channel