Key result
The novel Val302del KCNJ2 mutation identified in an ATS patient showed normal membrane trafficking but abolished potassium conductivity and exerted a dominant-negative effect on wild-type currents.
The novel KCNJ2 Val302del mutation causes Andersen-Tawil syndrome through a dominant-negative loss-of-function effect on Kir2.1 potassium channels.
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Val302del clarifies dominant-negative ATS mechanism; leaves open targeted therapies pending clinical validation.
Loss-of-function mutations of the KCNJ2 gene encoding for the inward rectifier potassium channel subunit Kir2.1 cause Andersen-Tawil Syndrome (ATS), a rare genetic disorder characterised by periodic paralysis, ventricular arrhythmias, and dysmorphic features. Clinical manifestations of the disease appear to vary greatly with the nature of mutation, therefore, functional characterisation of ATS-causing mutations is of clinical importance. In this study, we describe the identification and functional analysis of a novel KCNJ2 mutation, Val302del, identified in a patient with ATS. Heterologously expressed wild type (WT) and Val302del mutant alleles showed similar subcellular distribution of the Kir2.1 protein with high intensity labelling from the membrane region, demonstrating normal membrane trafficking of the Val302del Kir2.1 variant. Cells transfected with the WT allele displayed a robust current with strong inward rectification, while no current above background was detected in cells expressing the Val302del Kir2.1 subunit. Co-transfection of CHO cells with the WT and the Val302del Kir2.1 revealed a dose-dependent inhibitory effect of the Val302del Kir2.1 mutant subunit on WT Kir2.1 currents. These observations indicate that the WT and the Val302del mutant subunits co-assemble in the cell membrane and that the mutation affects potassium conductivity and (or) gating of the WT/Val302del heteromeric Kir2.1 channels.
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Ördög et al. (2015) studied Andersen-Tawil Syndrome (n=1). Val302del KCNJ2 mutation vs. Wild type (WT) KCNJ2 allele was evaluated on Potassium conductivity and gating (inward rectifier potassium channel currents). The novel Val302del KCNJ2 mutation identified in an ATS patient showed normal membrane trafficking but abolished potassium conductivity and exerted a dominant-negative effect on wild-type currents.
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