November 12, 1996Proceedings of the National Academy of Sciences267 citations
Characterization of human cardiac Na + channel mutations in the congenital long QT syndrome
Key Points
- This research aims to characterize mutations in the sodium channel gene associated with congenital long QT syndrome (LQTS).
- Identified three distinct mutations in the SCN5A gene linked to LQT3.
- Performed biophysical and functional characterization of mutant channels via heterologous expression in mammalian cell lines.
- Measured sodium current and examined gating properties during prolonged depolarizations.
- Each mutation caused a sustained, non-inactivating sodium current of a few percent of the peak inward current.
- Altered voltage dependence and inactivation rates compared to wild-type channels.
- Common defect in channel gating observed across mutations, leading to prolonged action potential and increased risk of arrhythmias.
Abstract
The congenital long QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential. This delay in cellular repolarization can lead to potentially fatal arrhythmias. One form of LQTS (LQT3) has been linked to the human cardiac voltage-gated sodium channel gene (SCN5A). Three distinct mutations have been identified in the sodium channel gene. The biophysical and functional characteristics of each of these mutant channels were determined by heterologous expression of a recombinant human heart sodium channel in a mammalian cell line. Each mutation caused a sustained, non-inactivating sodium current amounting to a few percent of the peak inward sodium current, observable during long (> 50 msec) depolarizations. The voltage dependence and rate of inactivation were altered, and the rate of recovery from inactivation was changed compared with wild-type channels. These mutations in diverse regions of the ion channel protein, all produced a common defect in channel gating that can cause the long QT phenotype. The sustained inward current caused by these mutations will prolong the action potential. Furthermore, they may create conditions that promote arrhythmias due to prolonged depolarization and the altered recovery from inactivation. These results provide insights for successful intervention in the disease.