Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome

J Biol Chem. 2003 Dec 19;278(51):51779-85. doi: 10.1074/jbc.M310278200. Epub 2003 Oct 1.


Andersen-Tawil syndrome is a skeletal and cardiac muscle disease with developmental features caused by mutations in the inward rectifier K+ channel gene KCNJ2. Patients harboring these mutations exhibit extremely variable expressivities. To explore whether these mutations can be correlated with a specific patient phenotype, we expressed both wild-type (WT) and mutant genes cloned into a bi-cistronic vector. Functional expression in human embryonic kidney 293 cells showed that none of the mutant channels express current when present alone. When co-expressed with WT channels, only construct V302M-WT yields inward current. Confocal microscopy fluorescence revealed three patterns of channel expression in the cell: 1) mutations D71V, N216H, R218Q, and pore mutations co-assemble and co-localize to the membrane with the WT and exert a dominant-negative effect on the WT channels; 2) mutation V302M leads to channels that lose their ability to co-assemble with WT and traffic to the cell surface; 3) deletions Delta 95-98 and Delta 314-315 lead to channels that do not traffic to the membrane but retain their ability to co-assemble with WT channels. These data show that the Andersen-Tawil syndrome phenotype may occur through a dominant-negative effect as well as through haplo-insufficiency and reveal amino acids critical in trafficking and conductance of the inward rectifier K+ channels.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Cell Line
  • Electrophysiology
  • Humans
  • Long QT Syndrome / genetics*
  • Microscopy, Fluorescence
  • Models, Molecular
  • Mutation / physiology
  • Potassium Channels, Inwardly Rectifying / deficiency
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Protein Transport / genetics
  • Transfection


  • Potassium Channels, Inwardly Rectifying