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Whole exome sequencing in RVOT patients

ABSTRACT: In a patient with right ventricular outflow tract (RVOT) tachycardia we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2P potassium channel TREK-1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1 In addition, mutant channels exhibit a hypersensitivity to stretch-activation, suggesting that the selectivity filter is directly involved in stretch-induced activation and desensitization. Increased sodium permeability and stretch-sensitivity of mutant TREK-1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK-1 pore. Our findings provide important insights for future studies of K2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.

PROVIDER: EGAS00001002319 | EGA |

REPOSITORIES: EGA

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A Mutation in the G-Protein Gene <i>GNB2</i> Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction.

Stallmeyer Birgit B Kuß Johanna J Kotthoff Stefan S Zumhagen Sven S Vowinkel Kirsty K Rinné Susanne S Matschke Lina A LA Friedrich Corinna C Schulze-Bahr Ellen E Rust Stephan S Seebohm Guiscard G Decher Niels N Schulze-Bahr Eric E

Circulation research 20170220 10

<h4>Rationale</h4>Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved.<h4>Objective</h4>We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus n ...[more]

PMID: 28219978

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