Autosomal recessive Andersen-Tawil syndrome with a novel mutation L94P in Kir2.1

Aim Dominant negative mutations of the inwardly rectifying K+ channel, Kir2.1, cause Andersen–Tawil syndrome (ATS), an autosomal dominant disorder. Here, we identified a novel Kir2.1 mutation causing autosomal recessive ATS, and explored the underlying mechanism. Methods We sequenced the coding region of KCJN2. We assessed protein subcellular localization by transfecting cells with Kir2.1-enhanced green fluorescent protein fusions and observing them by confocal microscopy. We measured K+ currents using patch clamping. Results We identified the novel Kir2.1 missense mutation L94P in a patient with ATS. L94P-enhanced green fluorescent protein (EGFP) was barely detected at the plasma membrane, in contrast to wild-type (WT)-EGFP and L94P-EGFP + WT. The excitability of L94P-expressing cells was significantly lower than that of WT-expressing cells and L94P + WT-expressing cells (P < 0.001). Conclusions Most L94P mutant Kir2.1 fails to reach the plasma membrane, but heterotetrameric channels comprising L94P + WT can traffic normally to the plasma membrane and generate currents. The L94P mutation is transmitted as an autosomal recessive trait.