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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1208-1213 |
| Number of pages | 6 |
| Journal | Circulation |
| Volume | 105 |
| Issue number | 10 |
| DOIs | |
| State | Published - Mar 12 2002 |
| Externally published | Yes |
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Keywords
- Arrhythmia
- Brugada syndrome
- Genes
- Long-QT syndrome
- Sodium
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Na+ channel mutation that causes both Brugada and long-QT syndrome phenotypes : A simulation study of mechanism. / Clancy, Colleen E; Rudy, Yoram.
In: Circulation, Vol. 105, No. 10, 12.03.2002, p. 1208-1213.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Na+ channel mutation that causes both Brugada and long-QT syndrome phenotypes
T2 - A simulation study of mechanism
AU - Clancy, Colleen E
AU - Rudy, Yoram
PY - 2002/3/12
Y1 - 2002/3/12
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.
AB - 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.
KW - Arrhythmia
KW - Brugada syndrome
KW - Genes
KW - Long-QT syndrome
KW - Sodium
UR - http://www.scopus.com/inward/record.url?scp=0037066036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037066036&partnerID=8YFLogxK
U2 - 10.1161/hc1002.105183
DO - 10.1161/hc1002.105183
M3 - Article
C2 - 11889015
AN - SCOPUS:0037066036
VL - 105
SP - 1208
EP - 1213
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 10
ER -