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Original Articles

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

Eva Delpón, PhD; Jonathan M. Cordeiro, PhD; Lucía Núñez, PhD; Poul Erik Bloch Thomsen, MD; Alejandra Guerchicoff, PhD; Guido D. Pollevick, PhD; Yuesheng Wu, MD; Jørgen K. Kanters, MD; Carsten Toftager Larsen, MD; Elena Burashnikov, BS; Michael Christiansen, MD and Charles Antzelevitch, PhD, FAHA

From the Masonic Medical Research Laboratory (J.M.C., A.G., G.D.P.,Y.W., E.B., C.A.), Utica, N.Y., Department of Pharmacology (E.D., L.N.), School of Medicine, Universidad Complutense, Madrid, Spain, Department of Cardiology P (P.E.B.T., J.K.K., C.T.L.), Gentofte University Hospital, Copenhagen, Denmark, The Danish National Research Foundation Center (J.K.K.), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark, Department of Clinical Biochemistry (M.C.), Statens Serum Institut, Copenhagen, Denmark.

Correspondence to Charles Antzelevitch, PhD, FAHA, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501-1787. E-mail ca{at}mmrl.edu

Received October 24, 2007; accepted May 5, 2008.

Background— The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 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 five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members. Chinese hamster ovary-K1 cells were cotransfected 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 coimmunoprecipitation experiments in human atrial samples. Cotransfection of R99H-KCNE3 with KCNQ1 produced no alteration in tail current magnitude or kinetics. However, cotransfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I_to intensity compared with WT KCNE3+KCND3. Using tissues isolated from the left atrial appendages of human hearts, we also demonstrate that Kv4.3 and KCNE3 can be coimmunoprecipitated.

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 the Brugada syndrome.

Key Words: genetics • sudden cardiac death • potassium channels • channelopathy • electrophysiology

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