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


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.
Rossenbacker
Tom
T
Centre for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology, KU Leuven, Leuven, Belgium.
Mubagwa
Kanigula
K
Jongbloed
Roselie J
RJ
Vereecke
Johan
J
Devriendt
Koen
K
Gewillig
Marc
M
Carmeliet
Edward
E
Collen
Désiré
D
Heidbüchel
Hein
H
Carmeliet
Peter
P
D000328:Adult; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics / Q000401:mortality* / Q000473:pathology*; D008239:Lysine / Q000235:genetics; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D010880:Piperidines / Q000627:therapeutic use; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010455:Peptides; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D011725:Pyridines; C063968:E 4031; D018698:Glutamic Acid; D008239:Lysine