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

International audienceBackground-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