Abstract 14835: Ultra-Fast Recovery from Inactivation Distinguishes SCN5A Dysfunction in Fetal vs Later Onset Long-QT Syndrome
Background: SCN5A mutations are associated with severe perinatal forms of long-QT syndrome (LQTS) but the biological basis for LQTS presenting in early life is poorly understood. Here we compared the biophysical mechanisms of two SCN5A mutations associated with either fetal LQTS (L409P/R558) or more typical onset LQTS (delKPQ).
Methods: Electrophysiological studies were conducted on heterologously expressed wild-type (WT) and mutant human cardiac sodium channels (NaV1.5) in either the canonical or fetal-expressed splice isoform.
Results: Both mutants exhibited elevated levels of persistent sodium current that were potentiated in the fetal NaV1.5 splice isoform. For NaV1.5-delKPQ, persistent current measured as a percentage of peak current was 1.2% (n = 6) vs. 0.1% (n = 5) for WT in canonical NaV1.5 and 2.1% (n = 10) in fetal NaV1.5. A much greater potentiation of persistent current was previously observed for fetal NaV1.5-L409P/R558 (11.1%, n = 10 vs 1.4%, n = 7 canonical NaV1.5-L409P/R558). We also observed that fetal NaV1.5-L409P/R558 exhibited an ultra-fast recovery from inactivation (-120mV) with nearly 60% of current restored after only 1 ms, as compared with 9% for fetal NaV1.5-delKPQ and 5% for WT fetal NaV1.5 channels. Time constants for recovery from inactivation were significantly smaller for fetal NaV1.5-L409P/R558 at voltages between -140 and -90mV compared to WT fetal channels (n > 5). Fetal NaV1.5-delKPQ also exhibited faster recovery kinetics between -110 to -90mV but the acceleration was much less dramatic than L409P/R558. During 1 Hz pulse trains from a holding potential of -90mV, fetal NaV1.5-L409P/R558 exhibited markedly attenuated use-dependent loss of channel availability compared to fetal NaV1.5-delKPQ, which was more similar to WT channels (n > 5).
Conclusions: Ultra-fast recovery from inactivation and attenuated use-dependent loss of channel availability may contribute to the early onset and severity of fetal LQTS associated with for NaV1.5-L409P/R558. These features were not observed for NaV1.5-delKPQ expressed in fetal NaV1.5 indicating that differences in recovery kinetics further distinguish SCN5A mutations associated with early vs later onset LQTS.
- © 2012 by American Heart Association, Inc.