Na ⁺ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes

• Colleen E. Clancy

  From the Cardiac Bioelectricity Research and Training Center, Department of Biomedical Engineering and Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.

• Yoram Rudy

  From the Cardiac Bioelectricity Research and Training Center, Department of Biomedical Engineering and Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio.

書誌事項

タイトル別名

• A Simulation Study of Mechanism

抄録

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.

収録刊行物

• Circulation

  Circulation 105 (10), 1208-1213, 2002-03-12

  Ovid Technologies (Wolters Kluwer Health)

キーワード

• Physiology (medical)
• Cardiology and Cardiovascular Medicine

詳細情報

• CRID: 1360011146612135936
• NII論文ID: 30022667043
• DOI: 10.1161/hc1002.105183
• ISSN: 15244539
• ISSN: 00097322
• ISSN: http://id.crossref.org/issn/00097322
• Web Site: https://www.ahajournals.org/doi/full/10.1161/hc1002.105183
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