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Impaired Golgi export underlies one type of Andersen‐Tawil syndrome channelopathies

Andersen‐Tawil syndrome is caused by mutations in the inward rectifier potassium channel gene KCNJ2, encoding Kir2.1. Here, we explore the molecular mechanism by which one ATS1 mutation (Del314‐15) abrogates cell surface expression, revealing a novel Golgi‐export signal. The mutant channels accumulate in Golgi. Dynamic live cell imaging of Kir2.1 revealed that the Del314‐315 mutation does, in fact, slow the egress of channels from the Golgi to the surface. Biochemical analysis reveals that the block likely occurs between medial and trans Golgi compartment. Mistrafficking of Del314‐315 Kir 2.1 is much different than mis‐folded proteins. In fact, as assessed by immunoprecipitation analysis and supported by the dominant negative colocalization of WT and Del 314‐315 Kir 2.1 subunits at the Golgi, the Del314‐315 mutant is capable of appropriately assembling with the wild type subunit. Collectively, the observations are most consistent with a mutation that perturbs a local trafficking signal rather than induces a global‐folding defect. Mutagenesis, rationalized by the atomic structure of the Kir2.1 cytoplasmic domain, revealed that a track of nearby residues forms a novel Golgi‐export determinant. The study underscores the utility of elucidating the mechanisms by which disease‐causing mutations alter channel function to illuminate aspects of channel biology, which have previously escaped detection.