Key result
The p.T613A mutation in the Kv11.1 potassium channel reduced currents to <20% of wild-type currents, indicating a loss-of-function that may result in Long QT Syndrome type 2.
Why the study?
Does the p.T613A mutation in the Kv11.1 potassium channel alter its functional properties in a way that explains its association with Long QT Syndrome?
Does the p.T613A mutation in the Kv11.1 potassium channel alter its functional properties in a way that explains its association with Long QT Syndrome?
The p.T613A mutation in the Kv11.1 channel causes a loss-of-function, reducing repolarizing reserve and providing a mechanistic basis for its association with LQTS2 and sudden cardiac death.
Supports p.T613A pathogenicity in LQTS2; leaves open human validation before clinical use.
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.
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Poulsen et al. (2015) studied Long QT Syndrome (LQTS) type 2. p.T613A mutation in Kv11.1 vs. Wild-type Kv11.1 was evaluated on Functional properties of Kv11.1 (currents and half maximal rectification). The p.T613A mutation in the Kv11.1 potassium channel reduced currents to <20% of wild-type currents, indicating a loss-of-function that may result in Long QT Syndrome type 2.
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