Na$^+$ channel mutation that causes both Brugada and long-QT
syndrome phenotypes: a simulation study of mechanism.
C. Clancy, and Y. Rudy. Circulation, 105 (10):
1208--1213(March 2002)
Abstract
BACKGROUND: Complex physiological interactions determine the functional
consequences of gene abnormalities and make mechanistic interpretation
of phenotypes extremely difficult. A recent example is a single mutation
in the C terminus of the cardiac Na$^+$ channel, 1795insD. The
mutation causes two distinct clinical syndromes, long QT (LQT) and
Brugada, leading to life-threatening cardiac arrhythmias. Coexistence
of these syndromes is seemingly paradoxical; LQT is associated with
enhanced Na$^+$ channel function, and Brugada with reduced function.
METHODS AND RESULTS: Using a computational approach, we demonstrate
that the 1795insD mutation exerts variable effects depending on the
myocardial substrate. We develop Markov models of the wild-type and
1795insD cardiac Na$^+$ channels. By incorporating the models
into a virtual transgenic cell, we elucidate the mechanism by which
1795insD differentially disrupts cellular electrical behavior in
epicardial and midmyocardial cell types. We provide a cellular mechanistic
basis for the ECG abnormalities observed in patients carrying the
1795insD gene mutation. CONCLUSIONS: We demonstrate that the 1795insD
mutation can cause both LQT and Brugada syndromes through interaction
with the heterogeneous myocardium in a rate-dependent manner. The
results highlight the complexity and multiplicity of genotype-phenotype
relationships, and the usefulness of computational approaches in
establishing a mechanistic link between genetic defects and functional
abnormalities.
%0 Journal Article
%1 Clan_2002_1208
%A Clancy, Colleen E
%A Rudy, Yoram
%D 2002
%J Circulation
%K 11889029 Action Arrhythmia, Cardiovascular, Chains, Channel Channels, Computer Electrocardiography, Gating, Gov't, Heart Humans, Internet, Ion Long Markov Models, Mutation, Myocardium, Non-U.S. P.H.S., Phenotype, Potentials, QT Relationship, Reproducibility Research Results, Simulation, Sodium Sodium, Structure-Activity Support, Syndrome, U.S. Ventricles, of
%N 10
%P 1208--1213
%T Na$^+$ channel mutation that causes both Brugada and long-QT
syndrome phenotypes: a simulation study of mechanism.
%U http://circ.ahajournals.org/cgi/content/full/105/10/1208
%V 105
%X BACKGROUND: Complex physiological interactions determine the functional
consequences of gene abnormalities and make mechanistic interpretation
of phenotypes extremely difficult. A recent example is a single mutation
in the C terminus of the cardiac Na$^+$ channel, 1795insD. The
mutation causes two distinct clinical syndromes, long QT (LQT) and
Brugada, leading to life-threatening cardiac arrhythmias. Coexistence
of these syndromes is seemingly paradoxical; LQT is associated with
enhanced Na$^+$ channel function, and Brugada with reduced function.
METHODS AND RESULTS: Using a computational approach, we demonstrate
that the 1795insD mutation exerts variable effects depending on the
myocardial substrate. We develop Markov models of the wild-type and
1795insD cardiac Na$^+$ channels. By incorporating the models
into a virtual transgenic cell, we elucidate the mechanism by which
1795insD differentially disrupts cellular electrical behavior in
epicardial and midmyocardial cell types. We provide a cellular mechanistic
basis for the ECG abnormalities observed in patients carrying the
1795insD gene mutation. CONCLUSIONS: We demonstrate that the 1795insD
mutation can cause both LQT and Brugada syndromes through interaction
with the heterogeneous myocardium in a rate-dependent manner. The
results highlight the complexity and multiplicity of genotype-phenotype
relationships, and the usefulness of computational approaches in
establishing a mechanistic link between genetic defects and functional
abnormalities.
@article{Clan_2002_1208,
abstract = {BACKGROUND: Complex physiological interactions determine the functional
consequences of gene abnormalities and make mechanistic interpretation
of phenotypes extremely difficult. A recent example is a single mutation
in the C terminus of the cardiac {N}a$^{+}$ channel, 1795insD. The
mutation causes two distinct clinical syndromes, long QT (LQT) and
Brugada, leading to life-threatening cardiac arrhythmias. Coexistence
of these syndromes is seemingly paradoxical; LQT is associated with
enhanced {N}a$^{+}$ channel function, and Brugada with reduced function.
METHODS AND RESULTS: Using a computational approach, we demonstrate
that the 1795insD mutation exerts variable effects depending on the
myocardial substrate. We develop Markov models of the wild-type and
1795insD cardiac {N}a$^{+}$ channels. By incorporating the models
into a virtual transgenic cell, we elucidate the mechanism by which
1795insD differentially disrupts cellular electrical behavior in
epicardial and midmyocardial cell types. We provide a cellular mechanistic
basis for the ECG abnormalities observed in patients carrying the
1795insD gene mutation. CONCLUSIONS: We demonstrate that the 1795insD
mutation can cause both LQT and Brugada syndromes through interaction
with the heterogeneous myocardium in a rate-dependent manner. The
results highlight the complexity and multiplicity of genotype-phenotype
relationships, and the usefulness of computational approaches in
establishing a mechanistic link between genetic defects and functional
abnormalities.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Clancy, Colleen E and Rudy, Yoram},
biburl = {https://www.bibsonomy.org/bibtex/28ec927d7761920e557c6a9393f3da634/hake},
description = {The whole bibliography file I use.},
file = {Clan_2002_1208.pdf:Clan_2002_1208.pdf:PDF;Clan_2002_1208_appendix.doc:Clan_2002_1208_appendix.doc:Word},
interhash = {ebb10b5dfb3c0a10468d7a444f678e56},
intrahash = {8ec927d7761920e557c6a9393f3da634},
journal = {Circulation},
key = 89,
keywords = {11889029 Action Arrhythmia, Cardiovascular, Chains, Channel Channels, Computer Electrocardiography, Gating, Gov't, Heart Humans, Internet, Ion Long Markov Models, Mutation, Myocardium, Non-U.S. P.H.S., Phenotype, Potentials, QT Relationship, Reproducibility Research Results, Simulation, Sodium Sodium, Structure-Activity Support, Syndrome, U.S. Ventricles, of},
month = Mar,
number = 10,
pages = {1208--1213},
pmid = {11889029},
timestamp = {2009-06-03T11:21:08.000+0200},
title = {{N}a$^{+}$ channel mutation that causes both Brugada and long-QT
syndrome phenotypes: a simulation study of mechanism.},
url = {http://circ.ahajournals.org/cgi/content/full/105/10/1208},
volume = 105,
year = 2002
}