Dysfunction of the Voltage‐Gated K+ Channel β2 Subunit in a Familial Case of Brugada Syndrome

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Stéphanie Chatel¹  Sophie Burel²  Estelle Baron²  Christian Dina²  Solena Le Scouarnec²  Zeineb Es‐Salah‐Lamoureux²  Flavien Charpentier²  Jean‐Jacques Schott²  Céline Marionneau²  Vincent Probst²  Stéphanie Bonnaud²  Floriane Simonet²  Jean‐Baptiste Gourraud²  Jade Violleau²  Richard Redon²  Pierre Lindenbaum²  Vincent Portero²  Gildas Loussouarn²  Hervé Le Marec²  Isabelle Baró²  Thomas O'Hara³  Carol Scott⁴  Philippe Mabo⁵  Eléonore Moreau⁶ 

[1] CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France;INSERM, UMR 1087, l'Institut du Thorax, Nantes, France;Johns Hopkins University, Baltimore, MD;The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK;University Hospital of Rennes, Rennes, France;Université de Nantes, Nantes, France;

关键词: Brugada syndrome;    cardiac arrhythmia;    clinical electrophysiology;    genetics;    KCNAB2/Kvβ2;    potassium ion channels;   

DOI  :  10.1161/JAHA.115.003122

来源: DOAJ

【 摘 要 】

BackgroundThe Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. Methods and ResultsWe combined whole‐exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage‐gated K+ channel β2‐subunit (Kvβ2‐R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K+ channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch‐clamp experiments performed in COS‐7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2‐R12Q were significantly increased in comparison with wild‐type Kvβ2. ConclusionsAltogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.

【 授权许可】

Unknown