Published Online
on May 30, 2008

A more recent version of this article appeared on August 1, 2008

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Original Article

Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome

Eva Delpón¹, Jonathan M. Cordeiro², Lucía Núñez¹, Poul Erik Bloch Thomsen³, Alejandra Guerchicoff², Guido D. Pollevick², Yuesheng Wu², Jørgen K. Kanters⁴, Carsten Toftager Larsen⁵, Elena Burashnikov², Michael Christiansen⁶ and Charles Antzelevitch^2,7

¹ Universidad Complutense;
² Masonic Medical Research Laboratory;
³ University Hospital Bispebjer;
⁴ University of Copenhagen;
⁵ Gentofte University Hospital;
⁶ Statens Serum Institut

Correspondence: ⁷ E-mail: ca{at}mmrl.edu

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 Ito-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_v4.3 and KCNE3 can be co-immunoprecipitated.

Conclusions—These results provide definitive evidence for a functional role of KCNE3 in the modulation of Ito in the human heart and suggest that mutations in KCNE3 can underlie the development of BrS.

Key Words: electrophysiology • genetics • Channelopathy • Potassium Channels • Sudden Cardiac Death

Related Article

Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome

Eva Delpón, Jonathan M. Cordeiro, Lucía Núñez, Poul Erik Bloch Thomsen, Alejandra Guerchicoff, Guido D. Pollevick, Yuesheng Wu, Jørgen K. Kanters, Carsten Toftager Larsen, Elena Burashnikov, Michael Christiansen, and Charles Antzelevitch
Circ Arrhythmia Electrophysiol 2008 1: 209-218. [Abstract] [Full Text] [PDF]