Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening

• Published in: Biochemistry (Moscow) 2024-03, Vol.89 (3), p.543-552
• Main Authors: Abramochkin, Denis, Li, Bowen, Zhang, Han, Kravchuk, Ekaterina, Nesterova, Tatiana, Glukhov, Grigory, Shestak, Anna, Zaklyazminskaya, Elena, Sokolova, Olga S.
• Format: Article
• Language: English
• Subjects: Action potential; Adult; Animals; Arrhythmia; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Brugada Syndrome - genetics; Brugada Syndrome - metabolism; Cardiac arrhythmia; CHO Cells; Cricetulus; EKG; Electrocardiography; Electrophysiology; ERG1 Potassium Channel - genetics; ERG1 Potassium Channel - metabolism; Gain of Function Mutation; Genetic diversity; Genetic variance; Hereditary diseases; Humans; Inactivation; Life Sciences; Long QT Syndrome - genetics; Long QT Syndrome - metabolism; Male; Microbiology; Middle Aged; Missense mutation; Mutation; Mutation, Missense; Pathogenicity; Pathogens; Phenotypes; Potassium channels (voltage-gated)
• ISSN: 0006-2979; 1608-3040
• DOI: 10.1134/S000629792403012X

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2  gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter I Kr -current and may be causative for the rare non- SCN5A -related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on I Kr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the I Kr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.