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

---

Denis Abramochkin^1,2,a, Bowen Li^1,b, Han Zhang^1,c, Ekaterina Kravchuk^2,d, Tatiana Nesterova^3,4,e, Grigory Glukhov^1,2,f, Anna Shestak^5,g, Elena Zaklyazminskaya^5,h, and Olga S. Sokolova^1,2,i*

¹Shenzhen MSU-BIT University, Shenzhen, China

²Lomonosov Moscow State University, 119234, Moscow, Russia

³Institute of Immunology and Physiology, Ural Branch of Russian Academy of Sciences, 620049 Ekaterinburg, Russia

⁴Institute of Natural Sciences and Mathematics, Ural Federal University, 620075 Ekaterinburg, Russia

⁵Petrovsky National Research Center of Surgery, 119991 Moscow, Russia

Received December 6, 2023; Revised February 20, 2024; Accepted February 27, 2024

---

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.

---

KEY WORDS: Brugada syndrome, BrS, KCNH2, Kv11.1, I_Kr, patch-clamp, inherited channelopathy, Short QT syndrome, gain-of-function

DOI: 10.1134/S000629792403012X

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

---