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



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 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.



Altogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Vincent
V
Portero
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Solena
S
Le Scouarnec
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Zeineb
Z
Es-Salah-Lamoureux
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Sophie
S
Burel
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Jean-Baptiste
JB
Gourraud
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Stéphanie
S
Bonnaud
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Pierre
P
Lindenbaum
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Floriane
F
Simonet
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Jade
J
Violleau
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Estelle
E
Baron
Université de Nantes, Nantes, France.
Eléonore
E
Moreau
The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Carol
C
Scott
CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Stéphanie
S
Chatel
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Gildas
G
Loussouarn
Johns Hopkins University, Baltimore, MD.
Thomas
T
O'Hara
University Hospital of Rennes, Rennes, France.
Philippe
P
Mabo
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Christian
C
Dina
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Hervé
H
Le Marec
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Jean-Jacques
JJ
Schott
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Vincent
V
Probst
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Isabelle
I
Baró
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France.
Céline
C
Marionneau
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France.
Flavien
F
Charpentier
INSERM, UMR 1087, l'Institut du Thorax, Nantes, France CNRS, UMR 6291, Nantes, France Université de Nantes, Nantes, France CHU Nantes, l'Institut du Thorax, Service de Cardiologie, Nantes, France richard.redon@inserm.fr.
Richard
R
Redon
D053840:Brugada Syndrome / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D000073659:Gain of Function Mutation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D051637:Shaker Superfamily of Potassium Channels; D051672:Shal Potassium Channels / Q000235:genetics; D000073359:Exome Sequencing
C498948:KCNAB2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D051637:Shaker Superfamily of Potassium Channels; D051672:Shal Potassium Channels
Brugada syndrome; KCNAB2/Kvβ2; cardiac arrhythmia; clinical electrophysiology; genetics; potassium ion channels; whole exome sequencing