Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Export

@article{Clancy2002, 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. 10.1161/hc1002.105183}, author = {Clancy, Colleen E. and Rudy, Yoram}, citeulike-article-id = {5087646}, citeulike-linkout-0 = {http://dx.doi.org/10.1161/hc1002.105183}, citeulike-linkout-1 = {http://circ.ahajournals.org/cgi/content/abstract/105/10/1208}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/11889015}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=11889015}, day = {12}, doi = {10.1161/hc1002.105183}, journal = {Circulation}, keywords = {a, as, drug, except, in, later, markov, model, paper, pseudo, same, the, used, without, yse}, month = {March}, number = {10}, pages = {1208--1213}, posted-at = {2009-07-07 16:40:47}, priority = {2}, title = {Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism}, url = {http://dx.doi.org/10.1161/hc1002.105183}, volume = {105}, year = {2002} }

TY - JOUR ID - Clancy2002 L3 - citeulike-article-id:5087646 N2 - 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. 10.1161/hc1002.105183 IS - 10 JF - Circulation EP - 1213 TI - Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism VL - 105 SP - 1208 KW - a KW - as KW - drug KW - except KW - in KW - later KW - markov KW - model KW - paper KW - pseudo KW - same KW - the KW - used KW - without KW - yse AU - Clancy, Colleen AU - Rudy, Yoram PY - 2002/03/12/ UR - http://dx.doi.org/10.1161/hc1002.105183 ER -