2. Academic Validation
  3. A Mutation in the G-Protein Gene GNB2 Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction

A Mutation in the G-Protein Gene GNB2 Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction

  • Circ Res. 2017 May 12;120(10):e33-e44. doi: 10.1161/CIRCRESAHA.116.310112.
Birgit Stallmeyer 1,  Johanna Kuß 1,  Stefan Kotthoff 1,  Sven Zumhagen 1,  Kirsty Vowinkel 1,  Susanne Rinné 1,  Lina A Matschke 1,  Corinna Friedrich 1,  Ellen Schulze-Bahr 1,  Stephan Rust 1,  Guiscard Seebohm 1,  Niels Decher 1,  Eric Schulze-Bahr 2
Affiliations

Affiliations

  • 1 From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.).
  • 2 From the Institute for Genetics of Heart Diseases, Department of Cardiology and Angiology, University Hospital Muenster, Germany (B.S., J.K., S.Z., C.F., E.S.-B., G.S., E.S.-B.); Department of Pediatric Cardiology (S.K.) and Department of General Pediatrics (S.R.), University Children's Hospital Muenster, Germany; and Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps University of Marburg, Germany (K.V., S.R., L.A.M., N.D.). eric.schulze-bahr@ukmuenster.de.
PMID: 28219978 DOI: 10.1161/CIRCRESAHA.116.310112
Abstract

Rationale: 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.

Objective: We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB.

Methods and results: Genome-wide linkage analysis mapped the SND+AVB disease locus to chromosome 7q21.1-q31.1 (2-point logarithm of the odds score: 4.64; θ=0); in this region, targeted exome Sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the GNB2 gene that strictly cosegregated with the SND+AVB phenotype. GNB2 encodes the β2 subunit (Gβ2) of the heterotrimeric G-protein complex that is being released from G-protein-coupled receptors on vagal stimulation. In 2 heterologous expression systems (HEK-293T cells and Xenopus laevis oocytes), an enhanced activation of the G-protein-activated K+ channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gβ2 was coexpressed with Gγ2; this was in contrast to coexpression of mutant Gβ2-Gγ2 with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ2 to cardiac GIRK channels when compared with native Gβ2.

Conclusions: A GNB2 gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity. Our findings describe for the first time a role of a mutant G-protein in the nonsyndromic pacemaker disease because of GIRK channel activation.

Keywords

atrial fibrillation; atrioventricular block; bradycardia; dizziness; sick sinus syndrome.

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