PMID- 10517660
OWN - NLM
STAT- MEDLINE
DCOM- 19991109
LR  - 20190910
IS  - 1045-3873 (Print)
IS  - 1045-3873 (Linking)
VI  - 10
IP  - 9
DP  - 1999 Sep
TI  - Characterization of a novel missense mutation in the pore of HERG in a patient
      with long QT syndrome.
PG  - 1262-70
AB  - INTRODUCTION: A new strategy to elucidate the molecular mechanisms underlying the
      long QT syndrome (LQTS) is now available with genetic mutational analyses and
      characterization of ion channel mutations. METHODS AND RESULTS: In a 26-year-old 
      woman with LQTS, we identified a novel missense mutation in the pore of HERG by
      using polymerase chain reaction/single-strand conformation polymorphism
      (PCR/SSCP) and sequencing of her genomic DNA. The mutation resulted in an amino
      acid substitution of a positively charged lysine for a highly conserved uncharged
      asparagine at codon 629 (N629K). Whole cell, patch clamp studies were conducted
      in COS7 cells by transfecting with wild-type (WT) and/or the mutant N629K HERG.
      The WT HERG produced an I(Kr)-like, E-4031-sensitive conductance with an inward
      rectification. In contrast, the cells transfected with the N629K HERG did not
      display any time-dependent current. Cotransfection of WT and N629K HERG (at a
      ratio of 1:1) produced a significantly smaller conductance when compared with WT 
      HERG (WT 59.9 +/- 7.3 pA/pF [n = 22] vs WT+N629K 5.5 +/- 2.3 pA/pF [n = 11]; P < 
      0.01), but did not alter K+ ion selectivity and tail current-voltage dependence. 
      Because aprindine hydrochloride was effective in preventing ventricular
      tachycardias, we also tested the effect of the drug on WT HERG (I(Kr)) and
      KvLQT1/KCNE1 (I(Ks)) currents expressed in COS7. CONCLUSION: Functional analyses 
      of a novel missense mutation in the pore of HERG suggest that the mutation causes
      marked reduction of I(Kr) via a dominant negative effect.
FAU - Yoshida, H
AU  - Yoshida H
AD  - Department of Cardiovascular Medicine, Kyoto University Graduate School of
      Medicine, Japan.
FAU - Horie, M
AU  - Horie M
FAU - Otani, H
AU  - Otani H
FAU - Takano, M
AU  - Takano M
FAU - Tsuji, K
AU  - Tsuji K
FAU - Kubota, T
AU  - Kubota T
FAU - Fukunami, M
AU  - Fukunami M
FAU - Sasayama, S
AU  - Sasayama S
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cardiovasc Electrophysiol
JT  - Journal of cardiovascular electrophysiology
JID - 9010756
RN  - 0 (Cation Transport Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (ERG protein, human)
RN  - 0 (ERG1 Potassium Channel)
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (KCNH2 protein, human)
RN  - 0 (KCNH6 protein, human)
RN  - 0 (Potassium Channels)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcriptional Regulator ERG)
SB  - IM
MH  - Adult
MH  - Animals
MH  - COS Cells
MH  - *Cation Transport Proteins
MH  - *DNA-Binding Proteins
MH  - ERG1 Potassium Channel
MH  - Ether-A-Go-Go Potassium Channels
MH  - Female
MH  - Heart Conduction System/physiopathology
MH  - Humans
MH  - Long QT Syndrome/*genetics/physiopathology
MH  - *Mutation, Missense
MH  - Patch-Clamp Techniques
MH  - Potassium Channels/*genetics
MH  - *Potassium Channels, Voltage-Gated
MH  - *Trans-Activators
MH  - Transcriptional Regulator ERG
MH  - Transfection
EDAT- 1999/10/12 00:00
MHDA- 1999/10/12 00:01
CRDT- 1999/10/12 00:00
PHST- 1999/10/12 00:00 [pubmed]
PHST- 1999/10/12 00:01 [medline]
PHST- 1999/10/12 00:00 [entrez]
AID - 10.1111/j.1540-8167.1999.tb00304.x [doi]
PST - ppublish
SO  - J Cardiovasc Electrophysiol. 1999 Sep;10(9):1262-70. doi:
      10.1111/j.1540-8167.1999.tb00304.x.