The Mutation P.T613a in the Pore Helix of the Kv 11.1 Potassium Channel is Associated with Long QT Syndrome.

Background: Loss-of-function mutations in the voltage gated potassium channel Kv 11.1 have been associated with the Long QT Syndrome (LQTS) type 2. We identified the p.T613A mutation in Kv 11.1 in a family with LQTS. T613A is located in the outer part of the pore helix, a structure that is involved in C-type inactivation. Here we characterize the effect of p.T613A on the functional properties of KV 11.1.

Methods: The p.T613A mutation was introduced into KV 11.1 (T613A). Wild-type KV 11.1 (WT) and T613A were expressed in Xenopus laevis oocytes and characterized by two-electrode-voltage-clamp.

Results: T613A currents were reduced to <20% of WT currents and T613A induced a minor negative shift in half maximal rectification, indicating that the voltage-dependent onset on inactivation occurred at more negative voltages compared to WT. Co-expression of T613A with WT revealed intermediate phenotype and there was no dominant negative effect of T613A.

Conclusion: These findings suggest that p.T613A causes a loss-of-function of Kv 11.1. This results in a reduced repolarizing reserve which may result in LQTS2 and sudden cardiac death.