Key result
Novel Andersen–Tawil syndrome KCNJ2 variants show three distinct dysfunction mechanisms, with Q310R linked to milder disease.
Why the study?
Several KCNJ2 variants identified in the Japanese Andersen–Tawil syndrome registry lacked detailed electrophysiological characterization and had an unclear relationship with clinical phenotypes.
Observational
Functional characterization of six KCNJ2 variants in Andersen-Tawil syndrome reveals distinct gating, trafficking, and tetramerization defects that directly correlate with the severity of clinical phenotypes.
May refine Andersen-Tawil syndrome prognostication via mechanism-specific classification; leaves open clinical translation pending human validation.
Background Andersen–Tawil syndrome (ATS) is a rare inherited arrhythmia disorder caused by loss-of-function variants in KCNJ2, which encodes the inward rectifier potassium channel Kir2.1. ATS is characterized by the clinical triad of skeletal anomalies, periodic paralysis, and ventricular arrhythmias. In the Japanese ATS registry, several variants have been identified without detailed electrophysiological characterization. This study aimed to investigate the functional properties of six such variants and to clarify their relationship with clinical phenotypes. Methods Six previously uncharacterized variants identified in Japanese ATS patients (p.I72T, p.76insT, p.103_104del, p.F135S, p.N190I, and p.Q310R) were analyzed. KCNJ2 plasmids harboring each variant were expressed in HEK293 cells, and current density was measured using the patch-clamp technique. Dominant-negative (DN) effects were evaluated by co-expression with wild-type (WT) channels. Channel localization and trafficking were assessed by immunocytochemistry and confocal microscopy. Results Based on the underlying mechanisms of dysfunction, the variants were classified into three groups:Gating defects (76insT, N190I, I72T):Membrane localization was preserved, but currents were abolished with strong DN effects. I72T retained partial function.Trafficking defects (103_104del, F135S):Membrane expression was markedly reduced, accompanied by strong DN effects, indicating impaired folding and defective trafficking likely due to disruption of pore-region structures.Tetramerization defect (Q310R):No membrane expression and no DN effect were observed, suggesting failure of mutant subunits to assemble with WT channels, consistent with haploinsufficiency. Clinically, carriers of Q310R showed a milder phenotype lacking the full ATS triad, concordant with the experimental findings. Conclusion These results demonstrate variant-specific mechanisms of KCNJ2 dysfunction and highlight the importance of functional characterization for genotype–phenotype correlation in ATS.
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Kato et al. (2026) conducted an observational in Andersen–Tawil syndrome. KCNJ2 loss-of-function variants (p.I72T, p.76insT, p.103_104del, p.F135S, p.N190I, p.Q310R) vs. Wild-type KCNJ2 channels was evaluated on Electrophysiological current density, dominant-negative effects, channel localization/trafficking, and clinical phenotype correlation. Six KCNJ2 variants in Andersen–Tawil syndrome exhibited three distinct dysfunction mechanisms (gating, trafficking, and tetramerization defects), with Q310R showing a milder clinical phenotype.
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