Dataset Information

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

ABSTRACT: 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 ?2-subunit (Kv?2-R12Q). Kv?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?2 revealed a significant increase in the current density in presence of the R12Q and L13F Kv?2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kv?2-R12Q were significantly increased in comparison with wild-type Kv?2.Altogether, our results indicate that Kv?2 dysfunction can contribute to the Brugada electrocardiographic pattern.

SUBMITTER: Portero V

PROVIDER: S-EPMC4937261 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Portero Vincent V Le Scouarnec Solena S Es-Salah-Lamoureux Zeineb Z Burel Sophie S Gourraud Jean-Baptiste JB Bonnaud Stéphanie S Lindenbaum Pierre P Simonet Floriane F Violleau Jade J Baron Estelle E Moreau Eléonore E Scott Carol C Chatel Stéphanie S Loussouarn Gildas G O'Hara Thomas T Mabo Philippe P Dina Christian C Le Marec Hervé H Schott Jean-Jacques JJ Probst Vincent V Baró Isabelle I Marionneau Céline C Charpentier Flavien F Redon Richard R

Journal of the American Heart Association 20160610 6

<h4>Background</h4>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.<h4>Methods and results</h4>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 ...[more]

PMID: 27287695

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Project description:BackgroundSudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS.MethodsWe did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system.FindingsFour (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057).InterpretationRare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths.FundingUK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

Dataset Information

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

Publications

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

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