KCNJ2 mutations in Andersen-Tawil syndrome cause loss of inward K+ current through dominant-negative effects on wild-type channel co-assembly and trafficking, as well as haplo-insufficiency.
Andersen-Tawil syndrome mutations in Kir2.1 cause disease through distinct mechanisms including dominant-negative effects on channel trafficking and haplo-insufficiency.
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.
Bendahhou et al. (Mon,) conducted a other in Andersen-Tawil syndrome. KCNJ2 mutations vs. Wild-type KCNJ2 was evaluated on Channel expression, trafficking, and inward current. KCNJ2 mutations in Andersen-Tawil syndrome cause loss of inward K+ current through dominant-negative effects on wild-type channel co-assembly and trafficking, as well as haplo-insufficiency.