Dysfunction of the Voltage-Gated K+ Channel beta 2 Subunit in a Familial Case of Brugada Syndrome

Vincent Portero 1 Solena Le Scouarnec 1 Zeineb Es-Salah-Lamoureux 1 Sophie Burel 1 Jean-Baptiste Gourraud 1 Stephanie Bonnaud 1 Pierre Lindenbaum 1 Floriane Simonet 1 Jade Violleau 1 Estelle Baron 1 Eleonore Moreau 1 Carol Scott 2 Stephanie Chatel 1 Gildas Loussouarn 1 Thomas O'Hara Philippe Mabo 3, 4, 5 Christian Dina 1 Herve Le Marec 1 Jean-Jacques Schott 1 Vincent Probst 1 Isabelle Baró 1 Céline Marionneau 1 Flavien Charpentier 1 Richard Redon 1
1 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291
2 The Wellcome Trust Sanger Institute [Cambridge]
3 CIC-IT Rennes
4 LTSI - Laboratoire Traitement du Signal et de l'Image
5 Service de cardiologie et maladies vasculaires
Abstract : 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 beta 2-subunit (Kv beta 2-R12Q). Kv beta 2 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 Kv beta 2 revealed a significant increase in the current density in presence of the R12Q and L13F Kv beta 2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kv beta 2-R12Q were significantly increased in comparison with wild-type Kv beta 2. Conclusions-Altogether, our results indicate that Kv beta 2 dysfunction can contribute to the Brugada electrocardiographic pattern.
Keywords : sudden cardiac death j-wave syndromes gene prioritization potassium channels mutations abnormalities modulation disease risk maps
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Vincent Portero, Solena Le Scouarnec, Zeineb Es-Salah-Lamoureux, Sophie Burel, Jean-Baptiste Gourraud, et al.. Dysfunction of the Voltage-Gated K+ Channel beta 2 Subunit in a Familial Case of Brugada Syndrome. Journal of the American Heart Association, Wiley-Blackwell, 2016, 5 (6), pp.e003122. ⟨10.1161/JAHA.115.003122⟩. ⟨hal-01414464⟩

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