KCNJ2 – Short QT Syndrome Type 3

Short QT syndrome type 3 (SQTS3) is an autosomal dominant arrhythmia characterized by markedly abbreviated QT intervals and a predisposition to atrial fibrillation due to gain-of-function mutations in KCNJ2, encoding the inward rectifier potassium channel Kir2.1. A single de novo missense variant, c.896A>T (p.Glu299Val), was identified in a patient with extreme QT shortening and paroxysmal atrial fibrillation, confirming a causal role for this substitution ([PMID:23440193]). No additional affected relatives were reported, and family segregation data are lacking.

In vivo functional assessment using cardiac-specific AAV-mediated expression of Kir2.1^E299V in mice faithfully recapitulated the human phenotype, including shortened QT and PR intervals and atrial-specific arrhythmias, while preserving ventricular electrical stability ([PMID:38261726]). Electrophysiological studies revealed that the E299V mutation abolishes inward rectification, leading to increased I_K1 at voltages positive to –80 mV in atrial and ventricular myocytes and augmented sodium current in Purkinje fibers. Three-dimensional in silico simulations predicted atrial-specific impairment of polyamine block and reduced pore diameter in heterotetrameric Kir2.1–Kir2.2 channels.

Mechanistically, Kir2.1^E299V confers a gain-of-function by eliminating rectification, enhancing repolarizing currents, and shifting sodium channel activation/inactivation to hyperpolarized potentials, which underlies atrial vulnerability and ventricular protection against arrhythmias. These concordant genetic and experimental data support a Limited clinical validity per ClinGen due to a single unrelated proband, but Moderate functional evidence from robust in vivo and in vitro models.

Key Take-home: KCNJ2 gain-of-function mutations such as p.Glu299Val should be considered in patients with SQTS and atrial fibrillation, enabling targeted genetic testing and risk stratification.

References

• Cardiovascular research • 2024 • The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3. PMID:38261726
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • KCNJ2 mutation in short QT syndrome 3 results in atrial fibrillation and ventricular proarrhythmia. PMID:23440193

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