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Circulation. 2002 Mar 12;105(10):1208-13.

Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.

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1
Cardiac Bioelectricity Research and Training Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106-7207, USA.

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.

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PMID:
11889015
PMCID:
PMC1997279
[Indexed for MEDLINE]
Free PMC Article
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