CHARACTERIZATION OF HUMAN CARDIAC NA+ CHANNEL MUTATIONS IN THE CONGENITAL LONG QT SYNDROME

The congenital long QT syndrome (LOTS) is an inherited disorder charac terized by a prolonged cardiac action potential, This delay in cellula r repolarization can lead to potentially fatal arrhythmias. One form o f LOTS (LQT3) has been linked to the human cardiac voltage-gated sodiu m channel gene (SCN5A). Three distinct mutations have been identified in the sodium channel gene, The biophysical and functional characteris tics 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 c urrent amounting to a few percent of the peak inward sodium current, o bservable during long (> 50 msec) depolarizations. The voltage depende nce and rate of inactivation were altered, and the rate of recovery fr om inactivation was changed compared with wild-type channels, These mu tations 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 th e action potential, Furthermore, they may create conditions that promo te arrhythmias due to prolonged depolarization and the altered recover y from inactivation. These results provide insights for successful int ervention in the disease.