Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome

Rossenbacker, T.; Mubagwa, K.; Jongbloed, R.J.; Vereecke, J.; Devriendt, K.; Gewillig, M.; Carmeliet, E.; Collen, D.; Heidbüchel, H.; Carmeliet, P.

doi:10.1161/01.CIR.0000156327.35255.D8

Title

Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome

Author

Rossenbacker, T.

Mubagwa, K.

Jongbloed, R.J.

Vereecke, J.

Devriendt, K.

Gewillig, M.

Carmeliet, E.

Collen, D.

Heidbüchel, H.

Carmeliet, P.

Abstract

Background - It has been proposed that the highest risk for cardiac events in patients with long-QT syndrome subtype 2 (LQT2) is related to mutations in the pore region of the KCNH2 channel. It has also been suggested that a subpopulation of LQT2 patients may benefit from pharmacological therapy with modified KCNH2 channel - blocking drugs. Methods and Results - In a large LQT2 family (n = 33), we have identified a novel nonpore missense mutation (K28E) in the Per-Arnt-Sim (PAS) domain of the KCNH2 channel associated with a malignant phenotype: One third of the suspected gene carriers experienced a major cardiac event. Wild-type and K28E-KCNH2 channels were transiently transfected in HEK293 cells. For the mutant channel, whole-cell patch-clamp analysis showed a reduced current density, a negative shift of voltage-dependent channel availability, and an increased rate of deactivation. Western blot analysis and confocal imaging revealed a trafficking deficiency for the mutant channel that could be rescued by the K+ channel blocker E-4031. In cells containing both wild-type and mutant channels, deactivation kinetics were normal. In these cells, reduced current density was restored with E-4031. Conclusions - Our data suggest that besides pore mutations, mutations in the PAS domain may also exhibit a malignant outcome. Pharmacological restoration of current density is promising as a mutation-specific therapy for patients carrying this trafficking-defective mutant.

Language

English

Source (journal)

Circulation / American Heart Association. - New York, N.Y.

Publication

New York, N.Y. : 2005

ISSN

0009-7322

DOI

10.1161/01.CIR.0000156327.35255.D8

Volume/pages

111 :8 (2005) , p. 961-968