KCNJ2 (Kir2.1)
Details
KCNJ2 encodes the Kir2.1 inward rectifier potassium channel, which carries the IK1 current responsible for terminal repolarization and maintenance of the resting membrane potential in cardiac cells. Loss-of-function variants in KCNJ2 impair terminal repolarization, causing prominent U waves and susceptibility to delayed afterdepolarization-triggered ventricular arrhythmias. KCNJ2 is the causative gene for Andersen-Tawil Syndrome (LQT7), while gain-of-function variants are also described in Short QT Syndrome type 3.
Key Facts
- Loss-of-function: Reduces IK1 → impaired terminal repolarization → prolonged QU interval, prominent U waves → risk of DAD-triggered arrhythmias including bidirectional VT. Causes Andersen-Tawil Syndrome (LQT7). (sources/VA-SCD-ESC-2022)
- Gain-of-function: Increases IK1 → accelerated terminal repolarization → shortened QT interval → SQTS type 3. (sources/channelopathies-jaha-2025)
- Clinical expression: Pathogenic KCNJ2 variants also produce extra-cardiac features in ATS: dysmorphic features (low-set ears, hypertelorism, small mandible, clinodactyly) and periodic paralysis (hypo-, normo-, or hyperkalaemic). (sources/VA-SCD-ESC-2022)
- CPVT differential: KCNJ2 is listed among minor/rare CPVT genes — gain-of-function RYR2 dominates CPVT pathogenesis, but KCNJ2 variants appear in a small subset of CPVT-like phenotypes. (sources/channelopathies-jaha-2025)
- Gene therapy: Dominant-negative Kir2.1AAA (suppression of IK1) has been explored as a gene therapy strategy for biological pacemaker development — suppressing IK1 allows spontaneous depolarization in ventricular cardiomyocytes, mimicking sinoatrial automaticity. (sources/gene-therapy-arrhythmia-2025)
- Genetic testing (Class I, ESC 2022): Recommended in all patients with suspected Andersen-Tawil Syndrome. (sources/VA-SCD-ESC-2022)
Contradictions / Open Questions
- Gain-of-function vs. loss-of-function clinical distinction: KCNJ2 variants can cause either SQTS3 (gain-of-function, shortened QT) or ATS/LQT7 (loss-of-function, prolonged QU) — two phenotypically opposite diseases. Comprehensive genetic testing report interpretation must specify variant effect direction; VUS interpretation is complicated by this bidirectional pathogenicity. (sources/channelopathies-jaha-2025, sources/VA-SCD-ESC-2022)
- ATS SCD risk vs. arrhythmia burden: In ATS, arrhythmia burden (bidirectional VT, frequent PVCs) is often high, yet SCD is less common than in other LQTS subtypes. Whether this reflects a genuinely lower malignant potential or a surveillance/misdiagnosis artifact is unresolved. The appropriate ICD threshold in ATS therefore remains empirical. (sources/VA-SCD-ESC-2022)
Connections
- Related to entities/Andersen-Tawil-Syndrome
- Related to entities/Short-QT-Syndrome
- Related to entities/CPVT
- Related to concepts/Cardiac-Action-Potential
- Related to concepts/Bidirectional-Ventricular-Tachycardia
- Related to concepts/Biological-Pacemaker