PMID- 15699249
OWN - NLM
STAT- MEDLINE
DCOM- 20050930
LR  - 20161124
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 111
IP  - 8
DP  - 2005 Mar 1
TI  - Novel mutation in the Per-Arnt-Sim domain of KCNH2 causes a malignant form of 
      long-QT syndrome.
PG  - 961-8
AB  - 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.
FAU - Rossenbacker, Tom
AU  - Rossenbacker T
AD  - Centre for Transgene Technology and Gene Therapy, Flanders Interuniversitary 
      Institute for Biotechnology, KU Leuven, Leuven, Belgium.
FAU - Mubagwa, Kanigula
AU  - Mubagwa K
FAU - Jongbloed, Roselie J
AU  - Jongbloed RJ
FAU - Vereecke, Johan
AU  - Vereecke J
FAU - Devriendt, Koen
AU  - Devriendt K
FAU - Gewillig, Marc
AU  - Gewillig M
FAU - Carmeliet, Edward
AU  - Carmeliet E
FAU - Collen, Desire
AU  - Collen D
FAU - Heidbuchel, Hein
AU  - Heidbuchel H
FAU - Carmeliet, Peter
AU  - Carmeliet P
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050207
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (Peptides)
RN  - 0 (Piperidines)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Proteins)
RN  - 0 (Pyridines)
RN  - 113558-89-7 (E 4031)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Adult
MH  - Blotting, Western/methods
MH  - Cell Line
MH  - Death, Sudden, Cardiac/etiology
MH  - ERG1 Potassium Channel
MH  - Electrophysiology
MH  - Ether-A-Go-Go Potassium Channels
MH  - Female
MH  - Glutamic Acid/genetics
MH  - Humans
MH  - Kidney/cytology/embryology
MH  - Long QT Syndrome/drug therapy/genetics/*mortality/*pathology
MH  - Lysine/genetics
MH  - Male
MH  - Microscopy, Confocal/methods
MH  - Middle Aged
MH  - Mutation, Missense/*genetics
MH  - Patch-Clamp Techniques
MH  - Pedigree
MH  - Peptides/*genetics
MH  - Phenotype
MH  - Piperidines/therapeutic use
MH  - Potassium Channels, Voltage-Gated/*genetics
MH  - Protein Structure, Tertiary/genetics
MH  - Proteins/metabolism
MH  - Pyridines/therapeutic use
EDAT- 2005/02/09 09:00
MHDA- 2005/10/01 09:00
CRDT- 2005/02/09 09:00
PHST- 2005/02/09 09:00 [pubmed]
PHST- 2005/10/01 09:00 [medline]
PHST- 2005/02/09 09:00 [entrez]
AID - 01.CIR.0000156327.35255.D8 [pii]
AID - 10.1161/01.CIR.0000156327.35255.D8 [doi]
PST - ppublish
SO  - Circulation. 2005 Mar 1;111(8):961-8. doi: 10.1161/01.CIR.0000156327.35255.D8. 
      Epub 2005 Feb 7.