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; H. Jacob Peider Hofman-Bang; Elena Burashnikov; Michael Christiansen; Charles Antzelevitch

doi:10.1161/CIRCEP.107.748103

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, H. Jacob Peider Hofman-Bang, Elena Burashnikov, Michael Christiansen, Charles Antzelevitch

Physiology of circulation, kidney and lung

264 Citations (Scopus)

Abstract

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 language	English
Journal	Circulation. Arrhythmia and Electrophysiology
Volume	1
Issue number	3
Pages (from-to)	209-218
Number of pages	10
ISSN	1941-3149
DOIs	https://doi.org/10.1161/CIRCEP.107.748103
Publication status	Published - 2008

Keywords

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

Access to Document

10.1161/CIRCEP.107.748103

Cite this

Delpón, E., Cordeiro, J. M., Núñez, L., Thomsen, P. E. B., Guerchicoff, A., Pollevick, G. D., Wu, Y., Kanters, J. K., Larsen, C. T., Hofman-Bang, H. J. P., Burashnikov, E., Christiansen, M., & Antzelevitch, C. (2008). Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circulation. Arrhythmia and Electrophysiology, 1(3), 209-218. https://doi.org/10.1161/CIRCEP.107.748103

Delpón, E, Cordeiro, JM, Núñez, L, Thomsen, PEB, Guerchicoff, A, Pollevick, GD, Wu, Y, Kanters, JK, Larsen, CT, Hofman-Bang, HJP, Burashnikov, E, Christiansen, M & Antzelevitch, C 2008, 'Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome', Circulation. Arrhythmia and Electrophysiology, vol. 1, no. 3, pp. 209-218. https://doi.org/10.1161/CIRCEP.107.748103

@article{123c897005aa11deb05e000ea68e967b,

title = "Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome",

abstract = "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",

keywords = "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",

author = "Eva Delp{\'o}n and Cordeiro, {Jonathan M} and Luc{\'i}a N{\'u}{\~n}ez and Thomsen, {Poul Erik Bloch} and Alejandra Guerchicoff and Pollevick, {Guido D} and Yuesheng Wu and Kanters, {J{\o}rgen K.} and Larsen, {Carsten Toftager} and Hofman-Bang, {H. Jacob Peider} and Elena Burashnikov and Michael Christiansen and Charles Antzelevitch",

year = "2008",

doi = "10.1161/CIRCEP.107.748103",

language = "English",

volume = "1",

pages = "209--218",

journal = "Circulation: Arrhythmia and Electrophysiology",

issn = "1941-3149",

publisher = "Lippincott Williams & Wilkins",

number = "3",

}

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

SN - 1941-3149

VL - 1

SP - 209

EP - 218

JO - Circulation: Arrhythmia and Electrophysiology

JF - Circulation: Arrhythmia and Electrophysiology

IS - 3

ER -