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Title: Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of long-QT syndrome
Authors: Rossenbacker, Tom ×
Mubagwa, Kanigula
Jongbloed, Roselie J
Vereecke, Johan
Devriendt, Koenraad
Gewillig, Marc
Carmeliet, Edward
Collen, Desire
Heidbuchel, Hein
Carmeliet, Peter #
Issue Date: Mar-2005
Publisher: American Heart Association
Series Title: Circulation vol:111 issue:8 pages:961-968
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.
URI: 
ISSN: 0009-7322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Experimental Cardiac Surgery
Cardiovascular Developmental Biology
Cardiology
Molecular and Vascular Biology
Physiology Section (-)
Clinical Genetics Section (-)
Laboratory of Molecular and Cellular Signaling
Department of Cellular and Molecular Medicine - miscellaneous
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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