Abstract 2339: Characterization of a Novel KCNQ1 Mutation (R259H) That Abbreviates Repolarization and Causes Short QT Syndrome 2
The short QT syndrome 2 (SQT2) is a rare disorder due to KCNQ1 mutations that causes sudden cardiac death (SCD) in young individuals. Only two SQTS2 mutations have been identified so far. We report the electrophysiological characterization of a novel SQTS2 mutant (R259H) identified in 1 out of 25 SQT probands screened. Wild Type (WT) KCNQ1-KCNE1 and R259H KCNQ1-KCNE1 were heterologously expressed in HEK293 cells; membrane currents were measured 72h after transfection. Current density of R259H was significantly increased vs WT: 173.2±28.5 vs. 86.9±16.9 pA/pF (n=13, p<0.001). The density of R259H current was about 3-fold larger than WT after 1s depolarizing pulse (Figure A⇓) while the difference with WT was less marked at 4s thus suggesting that the kinetic of activation of mutant was faster than that of the WT. At variance with what previously described for the other two mutations involved in SQT2 (V307L and V141M) the tail current recorded upon repolarization from +80 mV to −40 mV was increased in R259H vs WT: 65.3±8.6 vs. 29.7±8.5 pA/pF (p <0.01) (Figure A⇓) and the I-V relation curve for WT and R259H showed a similar threshold potential (around −40 mV, Figure B⇓). Moreover, R259H produced a prolongation of time-constant of deactivation (>−80 mV) suggesting a slow deactivation procedure.
Conclusion: We demonstrate that the R259H mutation in the KCNQ1 gene produces a gain of function mediated by novel electrophysiological properties not present in the two SQT2 mutations previously reported. The evidence that only 1/25 SQTS probands carry a KCNQ1 mutation suggests that this genetic variant is an uncommon cause of SQTS. Current (A) and I-V relation curve (B) of WT and R259H