Dysfunction of the Voltage-Gated K + Channel b2 Subunit in a Familial Case of Brugada Syndrome Vincent Portero, PhD;* Solena Le Scouarnec, PhD;* Zeineb Es-Salah-Lamoureux, PhD;* Sophie Burel, MS; Jean-Baptiste Gourraud, MD, PhD; St ephanie Bonnaud, PhD; Pierre Lindenbaum, PhD; Floriane Simonet, MS; Jade Violleau, BS; Estelle Baron, BS; El eonore Moreau, MS; Carol Scott, MS; St ephanie Chatel, PhD; Gildas Loussouarn, PhD; Thomas O’Hara, PhD; Philippe Mabo, MD; Christian Dina, PhD; Herv e Le Marec, MD, PhD; Jean-Jacques Schott, PhD; Vincent Probst, MD, PhD; Isabelle Bar o, PhD; C eline Marionneau, PhD; Flavien Charpentier, PhD; † Richard Redon, PhD; † Background-—The 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 Results-—We 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 b2-subunit (Kvb2-R12Q). Kvb2 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 Kvb2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvb2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvb2-R12Q were significantly increased in comparison with wild-type Kvb2. Conclusions-—Altogether, our results indicate that Kvb2 dysfunction can contribute to the Brugada electrocardiographic pattern. ( J Am Heart Assoc. 2016;5:e003122 doi: 10.1161/JAHA.115.003122) Key Words: Brugada syndrome • cardiac arrhythmia • clinical electrophysiology • genetics • KCNAB2/Kvb2 • potassium ion channels • whole exome sequencing S udden cardiac death is a major health burden in industrialized countries, with 250 000 events recorded annually in the United States alone. 1 Although coronary artery disease remains the first underlying cause of sudden cardiac death, 5% to 10% of events occur in the absence of detectable cardiac structural abnormalities. 1 A large proportion of these autopsy-negative cases are a likely consequence of inherited cardiac arrhythmia disorders. 1,2 Among such disorders, From the INSERM, UMR 1087, l’Institut du Thorax, Nantes, France (V. Portero, S.L.S., Z.E.-S.-L., S. Burel, J.-B.G., S. Bonnaud, P.L., F.S., J.V., E.B., G.L., C.D., H.L.M., J.-J.S., V. Probst, I.B., C.M., F.C., R.R.); CNRS, UMR 6291, Nantes, France (V. Portero, S.L.S., Z.E.-S.-L., S. Burel, J.-B.G., S. Bonnaud, P.L., F.S., J.V., E.B., G.L., C.D., H.L.M., J.-J.S., V. Probst, I.B., C.M., F.C., R.R.); Universit e de Nantes, Nantes, France (V. Portero, S.L.S., Z.E.-S.-L., S. Burel, J.-B.G., S. Bonnaud, P.L., F.S., J.V., E.B., E.M., G.L., C.D., H.L.M., J.-J.S., V. Probst, I.B., C.M., F.C., R.R.); The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (S.L.S., C.S.); CHU Nantes, l’Institut du Thorax, Service de Cardiologie, Nantes, France (J-B.G., S. Bonnaud, P.L., J.V., S.C., C.D., H.L.M., J.-J.S., V. Probst, F.C., R.R.); Johns Hopkins University, Baltimore, MD (T.O.); University Hospital of Rennes, Rennes, France (P.M.). Accompanying Figures S1 through S4 and Tables S1 through S4 are available at http://jaha.ahajournals.org/content/5/6/e003122/DC1/embed/ inline-supplementary-material-1.pdf *Dr Portero, Dr Le Scouarnec, and Dr Es-Salah-Lamoureux contributed equally to this work. † Dr Charpentier and Dr Redon jointly directed this work. Correspondence to: Richard Redon, PhD, INSERM UMR 1087/CNRS UMR 6291, l’Institut du Thorax, IRS-UN, 8 Quai Moncousu, Nantes, France. E-mail: richard. redon@inserm.fr Received December 17, 2015; accepted April 22, 2016. ª 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. DOI: 10.1161/JAHA.115.003122 Journal of the American Heart Association 1 ORIGINAL RESEARCH by guest on September 23, 2017 http://jaha.ahajournals.org/ Downloaded from