The model is according to the paper Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Original model comes from ModelDB with accession number: 62661. This is the wide type model. All the values and reactions obtained from Data Supplement6: Appendix of the paper. Figure3 has been reproduced by MathSBML. The stimulus v=-30mV during the time from 5ms to 20 ms displayed in the event. The meaning for the keyword, C: Close states; O: Open states; IF: Fast inactivation states; IC: Closed-Inactivation states; IM: Intermediat Inactivation states.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
- Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.
- Clancy CE, Rudy Y
- Circulation , 3/ 2002 , Volume 105 , pages: 1208-1213
- Cardiac Bioelectricity Research and Training Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106-7207, USA.
- 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.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.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.
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- Model originally submitted by : Enuo He
- Submitted: Jul 27, 2007 9:21:28 PM
- Last Modified: Oct 10, 2014 11:23:22 AM
(added: 18 Jul 2007, 00:52:55, updated: 18 Jul 2007, 00:52:55)