Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome

Research output: Contribution to journalJournal articleResearchpeer-review

Eva Delpón, Jonathan M Cordeiro, Lucía Núñez, Poul Erik Bloch Thomsen, Alejandra Guerchicoff, Guido D Pollevick, Yuesheng Wu, Jørgen K. Kanters, Carsten Toftager Larsen, H. Jacob Peider Hofman-Bang, Elena Burashnikov, Michael Christiansen, Charles Antzelevitch

INTRODUCTION: 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. METHODS AND 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
Udgivelsesdato: 2008
Original languageEnglish
JournalCirculation. Arrhythmia and Electrophysiology
Volume1
Issue number3
Pages (from-to)209-218
Number of pages10
ISSN1941-3149
DOIs
Publication statusPublished - 2008

    Research areas

  • Action Potentials, Adolescent, Adult, Aged, Brugada Syndrome, Cells, Cultured, Child, DNA, DNA Mutational Analysis, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Immunoprecipitation, Male, Middle Aged, Mutation, Missense, Myocardium, Patch-Clamp Techniques, Pedigree, Potassium Channels, Voltage-Gated, Young Adult

ID: 10913052