A Mutation in the G-Protein Gene GNB2 Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction
Rationale: Familial sinus node and atrioventricular (AV) conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue and syncope due to a temporarily or permanent reduced heart rate. To date, only a few genes for familial sinus and/or AV conduction dysfunction are known and the majority of cases remain etiologically unresolved.
Objective: We aim to identify the disease gene in a large three-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and AV block (AVB) and to characterise 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 LOD score: 4.64; θ=0); in this region targeted exome sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the GNB2 gene that strictly co-segregated 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 (GPCRs) upon vagal stimulation. In two 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 co-expressed with Gγ2; this was in contrast to co-expression of mutant Gβ2-Gγ2 with other cardiac ion channels (HCN4, HCN2, Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ2 to cardiac GIRK channels when compared to 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 non-syndromic pacemaker disease due to GIRK channel activation.
- Congenital sinus node dysfunction
- atrioventricular dysfunction
- sinus bradycardia
- G proteins
- gene mutation
- genetic heart disease
- sick sinus syndrome
- atrioventricular block
- Received October 7, 2016.
- Revision received February 16, 2017.
- Accepted February 20, 2017.