title: The novel C-terminal KCNQ1 mutation M520R alters protein trafficking.
abstract: The long QT-syndrome is characterized by a prolongation of the QT-interval and tachyarrhythmias causing syncopes and sudden death. We identified the missense mutation M520R in the calmodulin binding domain of the Kv7.1 channel from a German family with long QT-syndrome. Heterologous expression of the mutant did not reveal any whole-cell currents independent of the auxiliary subunit KCNE1. Co-expression of the wild-type Kv7.1 channels and the mutant showed that the mutant did not have a dominant negative effect. In immunocytochemical assays of transfected COS-1 cells wild-type Kv7.1 showed an immunopositive labeling of the plasma membrane. For M520R no plasma membrane staining was visible, instead a strong signal in the ER was observed. These results indicate that the LQT1 mutation M520R leads to ER-retention and dysfunctional trafficking of the mutant channel resulting in haploinsufficiency.
authors.affiliation: Department of Biomedical Sciences, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. nschmitt@mfi.ku.dk
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: Nathalie Hélix
authors.initials: NH
authors.lastname: Nielsen
authors.forename: Maria
authors.initials: M
authors.lastname: Buschmann
authors.forename: Erwin-Josef
authors.initials: EJ
authors.lastname: Speckmann
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Martin
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008133:Long QT Syndrome / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human