Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic 
paralyses and abnormal ventricular repolarization. After genotyping a large set 
of patients with congenital long-QT syndrome, we identified two novel, 
heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the 
Kir2.1 subunit. These mutations have a different localization than classical ATS 
mutations which are mostly located at a potential interaction face with the 
slide helix or at the interface between the C-termini. Mutation carriers were 
without the key features of ATS, causing an isolated cardiac phenotype. While 
the N318S mutants regularly reached the plasma membrane, W322C mutants primarily 
resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 
reduced current amplitudes only by 20-25 %. This mild loss-of-function for the 
heteromeric channels resulted from defective channel trafficking (W322C) or 
gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, 
neither mutant caused a dominant-negative suppression of wild-type Kir2.1, 
Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by 
non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.