title: Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1).
abstract: OBJECTIVE
  In the hereditary long QT syndromes the commonest defect is in the K+ channel pore forming subunit, KCNQ1. In this study we investigated the role that abnormal KCNQ1 trafficking has in the pathogenesis of the hereditary long QT syndrome (LQT1).
  
  
  METHODS
  We introduced nine missense and nonsense mutations occurring in LQT1 into the cDNA encoding KCNQ1 fused in frame to the green fluorescent protein. These mutations occur in syndromes that are inherited in both autosomal dominant and recessive fashions. We used biochemistry, electrophysiology and cell imaging to examine the behaviour of wildtype and mutant channel subunits expressed together with the auxiliary subunit KCNE1 expressed in CHO-K1 and C2C12 cells.
  
  
  RESULTS
  We found that a number of mutations in KCNQ1 are retained in the endoplasmic reticulum and unable to translocate to the plasma membrane. Furthermore, some mutations act in a dominant negative fashion and have the ability to suppress the trafficking of wildtype channel. We use fluorescence resonance energy transfer microscopy to show that this occurs because of direct interaction between the mutant subunit and wildtype channel in the endoplasmic reticulum. Finally, a number of specific and nonspecific pharmacological tools are unable to promote the delivery of these mutants to the plasma membrane.
  
  
  CONCLUSIONS
  Our data revealed that channel trafficking may contribute to the pathogenesis of LQT1.
authors.affiliation: BHF Laboratories and Department of Medicine, University College London, 5 University Street, London, WC1E 6JJ, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Quinn
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Graves
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D016466:CHO Cells; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D021381:Protein Transport; D029597:Romano-Ward Syndrome / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human