title: Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion.
abstract: OBJECTIVE
  The Andersen's syndrome is a hereditary disease, which is characterized by cardiac arrhythmias, periodic paralysis and dysmorphic features. Recently, mutations of the KCNJ2 gene, which encodes the inward rectifying potassium channel subunit Kir2.1, have been identified in affected individuals. However, the functional effects of these mutations have not yet been fully elucidated.
  
  
  RESULTS
  To clarify this situation we generated known Andersen disease mutants of KCNJ2 which did not yield any measurable K(+) currents in CHO cells indicating that the Andersen mutants failed to form functional homomultimeric complexes. EGFP-tagged KCNJ2 wild-type and mutant channels distributed in a similar homogeneous pattern in the cell membrane suggesting that protein trafficking was not altered by the Andersen mutations but rather implicating that the mutations rendered the KCNJ2 channel non-functional. In heterologous coexpression experiments the Andersen mutants exerted a dominant-negative effect on wild-type KCNJ2. However, the extent of suppression varied between the different KCNJ2 mutants. Given our results in CHO cells, we expressed the disease mutant KCNJ2-S136F in neonate rat cardiomyocytes using adenoviral gene transfer to test the effect of Andersen mutants on native I(K1). I(K1) density was indeed significantly reduced in KCNJ2-S136F-infected cells (n=9) compared to control cells (n=9) over a voltage range from -70 to -150 mV (P<0.05).
  
  
  CONCLUSIONS
  These results support that Kir2.x channels are a critical component of native I(K1) in neonate rat cardiomyocytes and that a dominant-negative suppression of I(K1) in native cells is the pathophysiological correlate of the Andersen's syndrome.
authors.affiliation: Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany.
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Lange
authors.forename: Fikret
authors.initials: F
authors.lastname: Er
authors.forename: Natig
authors.initials: N
authors.lastname: Gassanov
authors.forename: Uta C
authors.initials: UC
authors.lastname: Hoppe
mesh_terms: D000818:Animals; D006224:Cricetinae; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006011:Glycogen Storage Disease Type IV / Q000235:genetics*; D006801:Humans; D018613:Microscopy, Confocal; D023421:Models, Animal; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism*; D051381:Rats
chemical_list: D024661:Potassium Channels, Inwardly Rectifying