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

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Ion Channel Physiology

Background:

• Familial sinus node and atrioventricular conduction dysfunction is a rare inherited disorder affecting heart rate.
• Existing genetic causes are limited, leaving many cases unresolved.

Purpose of the Study:

• Identify the causative gene in a large family with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB).
• Elucidate the molecular mechanisms underlying familial SND+AVB.

Main Methods:

• Genome-wide linkage analysis and exome sequencing were performed on a 3-generation family.
• Functional studies in heterologous expression systems (HEK-293T cells, Xenopus oocytes) and molecular dynamics simulations were utilized.

Main Results:

• A novel heterozygous GNB2 mutation (p.Arg52Leu) was identified and strictly cosegregated with the SND+AVB phenotype.
• Mutant GNB2 (Gβ2) enhanced G-protein-activated inwardly rectifying potassium (GIRK) channel activation.
• Molecular dynamics suggested reduced binding of mutant Gβ2 to cardiac GIRK channels.

Conclusions:

• GNB2 gene mutations are associated with familial SND+AVB.
• Sustained GIRK channel activation by the mutant GNB2 protein likely causes myocellular hyperpolarization and reduced pacemaker activity.
• This study reveals a role for mutant G-protein- GIRK channel interactions in nonsyndromic pacemaker disease.