V1763M - (CCD)

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FUNCTIONAL EFFECTS AND COMMENTS
This mutation occurred as de novo in a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia. At the age of 3 days,bradycardia due to an extremely prolonged QT interval anda 2:1 AV block was noted. At the age of 6 and 8 days, the newborn experienced torsade de pointes ventricular tachycardia that could be converted by intravenous lidocaine or DC shock. The electrocardiogram showed a prolonged QT interval (QTc 611 ms) and 2:1 AV conduction. Intravenous lidocaine infusion shortened the corrected QT to 588 ms, and 1:1 AV conduction resumed.

Expression of this mutant channel in tsA201 mammalian cells revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with:

• Steeper activation curve: slope factor: WT 6.5±0.3mV vs VM 4.7±0.5 mV
• Faster recovery from inactivation: V1/2 WT: 107±0.9mV vs VM 95.5±1.0mV - Tau: WT 6.1±0.7ms vs VM 4.1±04ms.
• Late sustained current: 1% of peak @-30mV. Lidocaine 200uM did not block late current.

Overall, these data are compatible with a LQTS phenotype. The lack of effect of lidocaine in vitro is apparently in contrast with the clinical effect. The authors suggested that the in vitro concentration to effectively suppress the mutant Na channel in over expressed tsA201 cells may be much higher than in vivo. However, no experimental data have provided to support this hypothesis.