Prkag2 encodes the γ2 regulatory subunit of 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK), an enzyme that modulates glucose uptake and glycolysis [3]. AMPK is crucial in regulating the glucose metabolic pathway in muscle, and thus Prkag2 plays a significant role in cardiac metabolism [5].

Mutations in Prkag2 lead to Glycogen storage disease of the heart, a fetal congenital disorder known as PRKAG2 syndrome, which is an autosomal dominant disorder with full penetrance [1]. The syndrome is characterized by the accumulation of glycogen in heart tissue, clinically presenting as hypertrophic cardiomyopathy, along with ventricular pre-excitation and progressive conduction system disease [1,2,3]. There is intrafamilial phenotypical variability, and the condition can mimic Pompe disease in infancy [3,6]. Also, a novel heterozygous variant in Prkag2 has been reported in a family with liver cirrhosis, expanding the mutational spectrum [1]. Additionally, a specific transcription variant of Prkag2, PRKAG2.2, is essential for FoxA1+ regulatory T cell differentiation and metabolic rewiring distinct from FoxP3+ regulatory T cells [4].

In conclusion, Prkag2 is vital for cardiac metabolism and glucose regulation. Its mutations are associated with various cardiac and other disorders such as PRKAG2 syndrome, which presents with a range of phenotypes including cardiac hypertrophy, pre-excitation, and conduction system diseases. The discovery of its role in T cell differentiation also adds to our understanding of its broader biological functions. The study of Prkag2 through genetic models can further enhance our knowledge of related disease mechanisms [1,2,3,4,5,6].