PMID- 19959132
OWN - NLM
STAT- MEDLINE
DCOM- 20110128
LR  - 20161222
IS  - 1556-3871 (Electronic)
IS  - 1547-5271 (Linking)
VI  - 6
IP  - 12
DP  - 2009 Dec
TI  - Trafficking-deficient long QT syndrome mutation KCNQ1-T587M confers severe 
      clinical phenotype by impairment of KCNH2 membrane localization: evidence for 
      clinically significant IKr-IKs alpha-subunit interaction.
PG  - 1792-801
LID - 10.1016/j.hrthm.2009.08.009 [doi]
AB  - BACKGROUND: KCNQ1-T587M is a trafficking-deficient long QT syndrome (LQTS) 
      missense mutation. Affected patients exhibit severe clinical phenotypes that are 
      not explained by the mutant's effects on I(Ks). Previous work showed a KCNH2 and 
      KCNQ1 alpha-subunit interaction that increases KCNH2 membrane localization and 
      function. OBJECTIVE: We hypothesized that failure of trafficking-deficient 
      KCNQ1-T587M to enhance KCNH2 membrane expression could reduce KCNH2 current 
      versus wild-type KCNQ1 (KCNQ1-WT), contributing to the LQTS phenotype of 
      KCNQ1-T587M carriers. METHODS: Patch-clamp, protein biochemical studies, confocal 
      imaging, and in vivo transfection of guinea pig cardiomyocytes were performed. 
      RESULTS: KCNQ1-T587M failed to generate functional current when coexpressed with 
      KCNE1 and caused haploinsufficiency when coexpressed with KCNQ1-WT/KCNE1. 
      Coexpression of KCNQ1-WT with KCNH2 increased I(KCNH2) versus KCNH2 alone (P 
      <.05). Immunoblots and confocal microscopy indicated increased plasma membrane 
      localization of KCNH2 alpha-subunits in cells cotransfected with KCNQ1-WT 
      plasmid, while total KCNH2 protein synthesis and KCNH2 glycosylation remained 
      unaffected, which suggests a chaperone effect of KCNQ1-WT to enhance the membrane 
      localization of KCNH2. KCNH2 also coimmunoprecipitated with KCNQ1-WT. Although 
      KCNQ1-T587M coprecipitated with KCNH2, the mutant was retained intracellularly 
      and failed to increase KCNH2 membrane localization, abolishing the KCNQ1-WT 
      chaperone function and reducing I(KCNH2) upon coexpression substantially compared 
      with coexpression with KCNQ1-WT (P <.05). In vivo transfection of KCNQ1-T587M in 
      guinea pigs suppressed I(Kr) in isolated cardiomyocytes. CONCLUSION: The 
      trafficking-deficient LQTS mutation KCNQ1-T587M fails to show the chaperoning 
      function that enhances KCNH2 membrane localization with KCNQ1-WT. This novel 
      mechanism results in reduced I(KCNH2), which would be expected to decrease 
      repolarization reserve and synergize with reduced I(KCNQ1) caused directly by the 
      mutation, potentially explaining the malignant clinical phenotype in affected 
      patients.
FAU - Biliczki, Peter
AU  - Biliczki P
AD  - Div. of Cardiology, Section of Electrophysiology, Goethe-Universitat, Frankfurt, 
      Germany.
FAU - Girmatsion, Zenawit
AU  - Girmatsion Z
FAU - Brandes, Ralf P
AU  - Brandes RP
FAU - Harenkamp, Sabine
AU  - Harenkamp S
FAU - Pitard, Bruno
AU  - Pitard B
FAU - Charpentier, Flavien
AU  - Charpentier F
FAU - Hebert, Terence E
AU  - Hebert TE
FAU - Hohnloser, Stefan H
AU  - Hohnloser SH
FAU - Baro, Isabelle
AU  - Baro I
FAU - Nattel, Stanley
AU  - Nattel S
FAU - Ehrlich, Joachim R
AU  - Ehrlich JR
LA  - eng
GR  - MOP 68929/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090813
PL  - United States
TA  - Heart Rhythm
JT  - Heart rhythm
JID - 101200317
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (KCNQ1 Potassium Channel)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - CHO Cells
MH  - Canada
MH  - Cell Line
MH  - Cricetinae
MH  - Cricetulus
MH  - Death, Sudden, Cardiac/pathology
MH  - Ether-A-Go-Go Potassium Channels/*genetics
MH  - Guinea Pigs
MH  - Humans
MH  - KCNQ1 Potassium Channel/*genetics
MH  - Long QT Syndrome/*genetics
MH  - Microscopy, Confocal
MH  - Mutation, Missense
MH  - Myocytes, Cardiac/physiology
MH  - Phenotype
MH  - Torsades de Pointes/genetics
MH  - Transfection
EDAT- 2009/12/05 06:00
MHDA- 2011/02/01 06:00
CRDT- 2009/12/05 06:00
PHST- 2009/02/26 00:00 [received]
PHST- 2009/08/06 00:00 [accepted]
PHST- 2009/12/05 06:00 [entrez]
PHST- 2009/12/05 06:00 [pubmed]
PHST- 2011/02/01 06:00 [medline]
AID - S1547-5271(09)00877-7 [pii]
AID - 10.1016/j.hrthm.2009.08.009 [doi]
PST - ppublish
SO  - Heart Rhythm. 2009 Dec;6(12):1792-801. doi: 10.1016/j.hrthm.2009.08.009. Epub 
      2009 Aug 13.