%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 }