Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
plasma membrane
A Mutation in the G-Protein Gene <i>GNB2</i> Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction.
<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 node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB.<h4>Methods and results</h4>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 <i>GNB2</i> gene that strictly cosegregated with the SND+AVB phenotype. <i>GNB2</i> encodes the β<sub>2</sub> subunit (Gβ<sub>2</sub>) 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 <i>Xenopus laevis</i> oocytes), an enhanced activation of the G-protein-activated K<sup>+</sup> channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gβ<sub>2</sub> was coexpressed with Gγ<sub>2</sub>; this was in contrast to coexpression of mutant Gβ<sub>2</sub>-Gγ<sub>2</sub> with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ<sub>2</sub> to cardiac GIRK channels when compared with native Gβ<sub>2</sub>.<h4>Conclusions</h4>A <i>GNB2</i> 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.