The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na + Channel
Abstract
Abstract —The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorders linked to autosomal dominant mutations in SCN5A , the gene encoding the human cardiac Na + channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutations induce a gain of function, whereas Brugada syndrome mutations reduce Na + channel function. Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of both syndromes: QT-interval prolongation (LQT3) at slow heart rates and distinctive ST-segment elevations (Brugada syndrome) with exercise. In the present study, we show that the insertion of the amino acid 1795insD has opposite effects on two distinct kinetic components of Na + channel gating (fast and slow inactivation) that render unique, simultaneous effects on cardiac excitability. The mutation disrupts fast inactivation, causing sustained Na + current throughout the action potential plateau and prolonging cardiac repolarization at slow heart rates. At the same time, 1795insD augments slow inactivation, delaying recovery of Na + channel availability between stimuli and reducing the Na + current at rapid heart rates. Our findings reveal a novel molecular mechanism for the Brugada syndrome and identify a new dual mechanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na + channel gating function. The full text of this article is available at http://www.circresaha.org.
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Cites
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Genetic basis and molecular mechanism for idiopathic ventricular fibrillation
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SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome
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Molecular mechanism for an inherited cardiac arrhythmia
Bennett, P. B., Yazawa, K., Makita, N., & George, A. L. (1995) · Nature · doi:10.1038/376683a0 · Cited by 957
A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.
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A Single Na + Channel Mutation Causing Both Long-QT and Brugada Syndromes
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Cited by
Calcium Cycling and Signaling in Cardiac Myocytes
Bers, D. M. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100455 · Cited by 1,302
Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels
Wagner, S., Dybkova, N., Rasenack, E. C. L., Jacobshagen, C., Fabritz, L., Kirchhof, P., Maier, S. K. G., Zhang, T., Hasenfuss, G., Brown, J. H., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci26620 · Cited by 553
CaMKII in myocardial hypertrophy and heart failure
Anderson, M. E., Brown, J. H., & Bers, D. M. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.01.012 · Cited by 465
Kyndt, F., Probst, V., Potet, F., Demolombe, S., Chevallier, J.-C., Baro, I., Moisan, J.-P., Boisseau, P., Schott, J.-J., Escande, D., et al. (2001) · Circulation · doi:10.1161/hc5001.100834 · Cited by 363
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Metadata
- Authors
- Veldkamp, M. W., Viswanathan, P. C., Bezzina, C., Baartscheer, A., Wilde, A. A. M., & Balser, J. R.
- Venue
- Circulation Research
- Published
- 2000-05-12
- Volume
- 86
- Issue
- 9
- Pages
- E91-7
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2107958165
- Cited by
- 323
- References
- 23
- FWCI
- 17.86
- Type
- journal article
- Language
- en
- Open access
- closed
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- Veldkamp, M. W., Viswanathan, P. C., Bezzina, C., Baartscheer, A., Wilde, A. A. M., & Balser, J. R. (2000). Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na + Channel. Circulation Research. https://doi.org/10.1161/01.res.86.9.e91
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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