KCNJ8 – Brugada syndrome

Brugada syndrome (BrS) is an autosomal dominant inherited arrhythmia characterized by coved ST-segment elevation in the right precordial leads and increased risk of ventricular fibrillation and sudden death. KCNJ8 encodes the Kir6.1 subunit of the cardiac ATP-sensitive potassium (KATP) channel, and has emerged as a susceptibility gene for J-wave syndromes including BrS (and early repolarization syndrome).

Genetic screening of 204 unrelated BrS and ERS probands identified the same missense variant c.1265C>T (p.Ser422Leu) in 3 BrS and 1 ERS probands, absent in 430 ethnically matched controls (PMID:22056721). An earlier study also reported p.Ser422Leu in one BrS case and one ERS case but not in 600 controls (PMID:20558321). In a kindred with early repolarization and atrial fibrillation, p.Ser422Leu co-segregated with disease in an affected relative (PMID:22562657).

Segregation analysis reveals at least one affected relative with the variant, consistent with autosomal dominant inheritance. Overall, four unrelated BrS probands and one segregation event support a moderate level of genetic evidence.

Functional assays in TSA201 cells co-expressing mutant Kir6.1-S422L with SUR2A-WT demonstrated a two-fold increase in glibenclamide-sensitive KATP current and a marked shift in ATP‐inhibition (IC₅₀ 785.5 ± 2 µM vs 38.4 ± 3 µM for WT), indicating gain of channel function under normoxic conditions (PMID:22056721). Conversely, transgenic mice overexpressing Kir6.1-S422L exhibited ECG changes but no clear J-wave phenotype, suggesting species- or context-specific effects (PMID:28928055).

Integration of genetic and experimental data supports a pathogenic gain-of-function mechanism for KCNJ8-p.Ser422Leu in Brugada syndrome. While animal models yield mixed findings, robust human cellular electrophysiology aligns with the clinical phenotype.

Key Take-home: The KCNJ8 p.Ser422Leu variant demonstrates a gain-of-function mechanism and meets criteria for inclusion in Brugada syndrome genetic testing.

References

• Heart rhythm • 2012 • Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. PMID:22056721
• Heart rhythm • 2010 • Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. PMID:20558321
• Europace • 2012 • A KCNJ8 mutation associated with early repolarization and atrial fibrillation. PMID:22562657
• Journal of pharmacological sciences • 2017 • Electrophysiological analyses of transgenic mice overexpressing KCNJ8 with S422L mutation in cardiomyocytes. PMID:28928055

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