Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome
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Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. / Delpón, Eva; Cordeiro, Jonathan M; Núñez, Lucía; Thomsen, Poul Erik Bloch; Guerchicoff, Alejandra; Pollevick, Guido D; Wu, Yuesheng; Kanters, Jørgen K.; Larsen, Carsten Toftager; Hofman-Bang, H. Jacob Peider; Burashnikov, Elena; Christiansen, Michael; Antzelevitch, Charles.
In: Circulation. Arrhythmia and Electrophysiology, Vol. 1, No. 3, 2008, p. 209-218.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome
AU - Delpón, Eva
AU - Cordeiro, Jonathan M
AU - Núñez, Lucía
AU - Thomsen, Poul Erik Bloch
AU - Guerchicoff, Alejandra
AU - Pollevick, Guido D
AU - Wu, Yuesheng
AU - Kanters, Jørgen K.
AU - Larsen, Carsten Toftager
AU - Hofman-Bang, H. Jacob Peider
AU - Burashnikov, Elena
AU - Christiansen, Michael
AU - Antzelevitch, Charles
PY - 2008
Y1 - 2008
N2 - 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
AB - 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
KW - Action Potentials
KW - Adolescent
KW - Adult
KW - Aged
KW - Brugada Syndrome
KW - Cells, Cultured
KW - Child
KW - DNA
KW - DNA Mutational Analysis
KW - Female
KW - Follow-Up Studies
KW - Genetic Predisposition to Disease
KW - Humans
KW - Immunoprecipitation
KW - Male
KW - Middle Aged
KW - Mutation, Missense
KW - Myocardium
KW - Patch-Clamp Techniques
KW - Pedigree
KW - Potassium Channels, Voltage-Gated
KW - Young Adult
U2 - 10.1161/CIRCEP.107.748103
DO - 10.1161/CIRCEP.107.748103
M3 - Journal article
C2 - 19122847
VL - 1
SP - 209
EP - 218
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
SN - 1941-3149
IS - 3
ER -
ID: 10913052