Key result
Novel GNB2 mutation linked to familial SND and AV block via sustained GIRK channel activation.
Observational (n=25)
A novel heterozygous mutation (p.Arg52Leu) in the GNB2 gene causes familial sinus node dysfunction and atrioventricular block by inducing sustained activation of cardiac GIRK channels.
No immediate clinical implications for conduction disease; leaves open whether GNB2-GIRK targeting merits human investigation.
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 β 2 subunit (Gβ 2 ) 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 Gβ 2 was coexpressed with Gγ 2 ; this was in contrast to coexpression of mutant Gβ 2 -Gγ 2 with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gβ 2 to cardiac GIRK channels when compared with native Gβ 2 . 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.
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Stallmeyer et al. (2017) conducted an observational in Familial sinus node dysfunction and atrioventricular block (n=25). GNB2 gene mutation (p.Arg52Leu) vs. Native GNB2 was evaluated on Disease locus mapping and gene identification. A novel heterozygous mutation (p.Arg52Leu) in the GNB2 gene was identified as the cause of familial sinus node dysfunction and atrioventricular block via sustained activation of cardiac GIRK channels.
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