• Vincent Portero, Solena Le Scouarnec, Zeineb Es-Salah-Lamoureux, Sophie Burel, Jean-Baptiste Gourraud, Stéphanie Bonnaud, Pierre Lindenbaum, Floriane Simonet, Jade Violleau, Estelle Baron, Eléonore Moreau, Carol Scott, Stéphanie Chatel, Gildas Loussouarn, Thomas O'Hara, Philippe Mabo, Christian Dina, Hervé Le Marec, Jean-Jacques Schott, Vincent Probst, Isabelle Baró, Céline Marionneau, Flavien Charpentier, and Richard Redon.
• INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
• J Am Heart Assoc. 2016 Jun 10; 5 (6).

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.© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

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