Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism
Catherine
Lloyd
Auckland Bioengineering Institute, University of Auckland
Model Status
This CellML model represents the wildtype endocardial cell. For more details on the curation status of this model please see this separate notes document.
Model Structure
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.
The original paper reference is cited below:
Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism, Colleen E. Clancy and Yoram Rudy, 2002,
Circulation
, 105, 1208-1213. PubMed ID: 11889015
cell diagram
A Markovian model for the wild-type cardiac Na+ channel, embedded within an updated version of the Luo-Rudy dynamic model. C, indicates a closed channel state; IC, a closed-inactivation state; IF, a fast inactivation state; IM, an intermediate inactivation state, and O, an open state.
cell diagram2
A Markovian model for the mutant 1795insD cardiac Na+ channel, embedded within an updated version of the Luo-Rudy dynamic model. U (upper) indicates background mode of gating; L (lower), represents a small population of bursting channels which fail to inactivate.
cardiac
Brugada Syndrome
Long QT Syndrome
electrophysiology
na channel
Na Channel Mutation That Causes Both Brugada Syndrome and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism (Wild Type Endocardial Cell)
The University of Auckland, The Bioengineering Institute
The University of Auckland
The Bioengineering Institute
updated curation status,
removed publication link in documentation
James Lawson
2007-08-16T12:26:07+12:00
This is the CellML description of Clancy and Rudy's 2002 mathematical model of a Na channel mutation that causes both Brugada and long-QT syndrome phenotypes.
This model is currently unable to be supported due to its dependence on the Luo Rudy 1994 model, which contains delay elements in its model of the CIRC, which can not yet be represented in CellML (as of CellML 1.1). Therefore this model is unconstrained and does not load or run in any simulator.
Colleen
Clancy
E
Catherine Lloyd
Added value of 1.5e-2 to variable I_NaK (note, not i_NaK) in component "sodium_potassium_pump". This value was obtained from the LR94 dynamic model
Catherine
Lloyd
May
Circulation
11889015
2002-03-12
James
Lawson
Richard
Yoram
Rudy
The Clancy and Rudy's 2002 mathematical model of a Na channel mutation that causes both Brugada and long-QT syndrome phenotypes.
Ventricular Myocyte
Mammalia
Na Channel Mutation That Causes Both Brugada Syndrome and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism
105
1208
1213
keyword
c.lloyd@auckland.ac.nz
2009-06-05T15:14:35+12:00
James
Lawson
Richard
2003-08-20T00:00:00+00:00