• Gene Information: PRKAG2 locates on human chromosome 7q36.1 and encodes the γ2 regulatory subunit of heterotrimeric AMPK, containing conserved CBS domains for AMP/ATP binding
•  Protein Expression: PRKAG2 protein exhibits predominant enrichment in cardiomyocytes and moderate expression in skeletal muscle, brain and liver.
• Signaling Pathway: PRKAG2 governs AMPK signal transduction. Disease-causing mutations cause constitutive basal AMPK activation, disrupt metabolic feedback, enhance glycogen synthase activity and dysregulate downstream mTOR and lipid metabolism pathways, leading to cardiomyocyte structural remodeling.
• Therapeutic Inhibition: Novel investigational strategies include mutant allele-specific siRNA silencing and gene editing to restore normal AMPK activity and relieve pathological glycogen deposition in the myocardium.

•  Human PRKAG2 coding sequence as well as 3’ UTR regions, including a R302Q mutation, driven by α MHC promoter, were randomly inserted into mouse genome in B-Tg(hPRKAG2*R302Q) mice.

Histopathological characterization of B-Tg(hPRKAG2*R302Q) mice heart tissues via hematoxylin-eosin (HE) staining. Heart tissues were collected from wild-type control C57BL/6JNifdc mice and B-Tg(hPRKAG2*R302Q) mice (1TGA0090-0013, 1TGA0090-0098, 1TGA0090-0124) (8-11 weeks old, male). Wild-type control hearts exhibit orderly arranged cardiomyocytes with uniform cytoplasm, intact cellular structure, and no obvious vacuolation or degenerative changes in the myocardium. B-Tg(hPRKAG2*R302Q) mice display progressive, severe myocardial lesions characterized by prominent cardiomyocyte vacuolization and diffuse myocardial degeneration; with widespread cytoplasmic vacuole formation, disrupted myofibril organization, and marked disarray of myocardial tissue architecture, recapitulating the core histopathological hallmarks of human hypertrophic cardiomyopathy.

PAS staining of paraffin-embedded heart sections demonstrates glycogen accumulation in B-Tg(hPRKAG2*R302Q) mice. Heart tissues were collected from wild-type control C57BL/6JNifdc mice and B-Tg(hPRKAG2*R302Q) mice (1TGA0090-0013, 1TGA0090-0098, 1TGA0090-0124) (8-11 weeks old, male). The wild-type C57BL/6JNifdc showed no visible lesion (NVL) with minimal cytoplasmic PAS-positive glycogen. B-Tg(hPRKAG2*R302Q) mice display abundant magenta PAS-positive cytoplasmic glycogen deposits, recapitulating the core histopathological hallmarks of human hypertrophic cardiomyopathy.

PAS staining and diastase-pretreated PAS (DPAS) staining of frozen heart sections demonstrates glycogen accumulation in B-Tg(hPRKAG2*R302Q) mice. Heart tissues were collected from wild-type control C57BL/6JNifdc mice and B-Tg(hPRKAG2*R302Q) mice (1TGA0090-0014, 1TGA0090-0093, 1TGA0090-0096) (13 weeks old, male). The wild-type C57BL/6JNifdc showed no visible lesion (NVL) with minimal cytoplasmic PAS-positive glycogen and DPAS positive signal. B-Tg(hPRKAG2*R302Q) mice display abundant magenta PAS-positive cytoplasmic glycogen deposits (upper), while DPAS staining showed marked clearing of the excessive glycogen deposition (bottom).