Referenced in: none

Automatically associated channels: Kir2.1

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

Authors: Saïd Bendahhou, Matthew R Donaldson, Nikki M Plaster, Martin Tristani-Firouzi, Ying-Hui Fu, Louis J Ptácek

Journal, date & volume: J. Biol. Chem., 2003 Dec 19 , 278, 51779-85

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/14522976

Abstract
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.