title: Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.
abstract: BACKGROUND
  The Brugada Syndrome (BrS), an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in four different genes leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (I(to)) is thought to play a prominent role in the expression of the syndrome, mutations in I(to)-related genes have not been identified as yet.
  
  
  RESULTS
  One hundred and five probands with BrS were screened for ion channel gene mutations using single strand conformation polymorphism (SSCP) electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in one proband. The R99H mutation was found 4/4 phenotype positive and 0/3 phenotype-negative family members. Chinese hamster ovary (CHO)-K1 cells were co-transfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in co-immunoprecipitation experiments in human atrial samples. Co-transfection of R99H-KCNE3 with KCNQ1 produced no alteration in current magnitude or kinetics. However, co-transfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I(to) intensity compared to WT KCNE3+KCND3. Using tissues isolated from left atrial appendages of human hearts, we also demonstrate that K(v)4.3 and KCNE3 can be co-immunoprecipitated.
  
  
  CONCLUSIONS
  These results provide definitive evidence for a functional role of KCNE3 in the modulation of I(to) in the human heart and suggest that mutations in KCNE3 can underlie the development of BrS.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Lucía
authors.initials: L
authors.lastname: Núñez
authors.forename: Poul Erik Bloch
authors.initials: PE
authors.lastname: Thomsen
authors.forename: Alejandra
authors.initials: A
authors.lastname: Guerchicoff
authors.forename: Guido D
authors.initials: GD
authors.lastname: Pollevick
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Wu
authors.forename: Jørgen K
authors.initials: JK
authors.lastname: Kanters
authors.forename: Carsten Toftager
authors.initials: CT
authors.lastname: Larsen
authors.forename: Jacob
authors.initials: J
authors.lastname: Hofman-Bang
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D002648:Child; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C418492:KCNE3 protein, human; D024642:Potassium Channels, Voltage-Gated; D004247:DNA