Retention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome

J Mol Cell Cardiol. 2000 Dec;32(12):2327-37. doi: 10.1006/jmcc.2000.1263.


Mutations in the cardiac potassium channel HERG (KCNH2) cause chromosome 7-linked long QT syndrome (LQT2) characterized by a prolonged QT interval, recurrent syncope and sudden cardiac death. Most mutations in HERG exhibit "loss of function" phenotypes with defective channels either inserted into the plasma membrane or retained in the endoplasmic reticulum. "Loss of function" mutations reduce I(Kr), the cardiac delayed rectifier current encoded by HERG, due to haploinsufficiency or suppression of wild-type function by a dominant-negative mechanism. One explanation for dominant-negative current suppression is that mutant subunits render tetrameric channel complexes non-conducting on co-assembly. In the present paper we describe an alternative mechanism for this phenomenon. We show (1) that the dominant-negative HERG mutation A561V is retained in the endoplasmic reticulum and (2) that wild-type channels are tagged for retention in the ER by co-assembly with trafficking deficient A561V subunits. Thus, in HERG A561V dominant-negative suppression of wild-type function is the result of an acquired trafficking defect.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • COS Cells
  • Cation Transport Proteins*
  • Cell Membrane / metabolism
  • Cloning, Molecular
  • Codon
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins*
  • ERG1 Potassium Channel
  • Endoplasmic Reticulum / metabolism*
  • Ether-A-Go-Go Potassium Channels
  • Genes, Dominant
  • Humans
  • Immunoblotting
  • Long QT Syndrome / genetics*
  • Microscopy, Fluorescence
  • Mutation*
  • Patch-Clamp Techniques
  • Phenotype
  • Potassium Channels / genetics
  • Potassium Channels, Voltage-Gated*
  • Suppression, Genetic
  • Trans-Activators*
  • Transcriptional Regulator ERG


  • Cation Transport Proteins
  • Codon
  • DNA, Complementary
  • DNA-Binding Proteins
  • ERG protein, human
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • KCNH6 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Trans-Activators
  • Transcriptional Regulator ERG