{"gene":"PRKAG2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"PRKAG2 mutations (N488I) cause inappropriate activation of AMPK, leading to massive cardiac glycogen accumulation (30-fold above normal), left ventricular hypertrophy, and ventricular preexcitation. Histopathology showed glycogen-engorged myocytes physically disrupting the annulus fibrosis, creating anomalous atrioventricular connections that provide the anatomic substrate for WPW preexcitation — not morphologically distinct bypass tracts.","method":"Transgenic mouse overexpression of mutant PRKAG2 N488I; histopathology; electrophysiological testing; cardiac glycogen quantification","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model with direct histopathological and electrophysiological validation, mechanistic link between glycogen accumulation and annulus fibrosis disruption established; replicated concept across multiple labs","pmids":["12782567"],"is_preprint":false},{"year":2005,"finding":"The R531Q PRKAG2 mutation causes >100-fold reduction in binding affinities for AMP and ATP but enhanced basal AMPK activity and increased phosphorylation of the alpha-subunit, explaining the dominant nature of PRKAG2 disease mutations and the massive glycogen storage phenotype.","method":"Biochemical characterization of recombinant R531Q mutant protein; nucleotide binding affinity assays; AMPK activity assays; alpha-subunit phosphorylation measurement","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant protein, direct measurement of nucleotide binding affinities and kinase activity, clear mechanistic explanation","pmids":["15877279"],"is_preprint":false},{"year":2005,"finding":"PRKAG2 N488I mutation-driven cardiomyopathy is primarily mediated through AMPK complexes containing the alpha2 (not alpha1) catalytic subunit. Genetic inhibition of alpha2-associated AMPK activity using a dominant-negative alpha2 transgene partially or completely rescued the ECG abnormalities, cardiac function, morphology, and exercise capacity in compound-heterozygous mice.","method":"Genetic epistasis using compound-heterozygous transgenic mice (TGgamma2N488I × TGalpha2DN); AMPK activity assays; ECG; cardiac morphology; exercise testing","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis experiment with defined phenotypic rescue, multiple orthogonal readouts, establishes alpha2 subunit as primary mediator","pmids":["16275868"],"is_preprint":false},{"year":2009,"finding":"AMPK activation induced by the PRKAG2 R302Q mutation upregulates glycogen synthase and AS160, increasing glycogen content acutely; however in chronic transgenic hearts, AMPK activity, glycogen synthase activity, and AS160 expression are reduced as a compensatory response to the 37-fold glycogen accumulation. Acute expression in neonatal cardiomyocytes distinguished direct effects from compensatory changes.","method":"Acute adenoviral expression of gamma2R302Q in neonatal rat cardiomyocytes vs. adult transgenic mice; AMPK activity assays; glycogen synthase activity; Western blot for AS160; glycogen quantification","journal":"Circulation. Cardiovascular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal models (acute viral expression + chronic transgenic), multiple biochemical readouts, temporal dissection of direct vs. compensatory effects","pmids":["20031621"],"is_preprint":false},{"year":2010,"finding":"Increased cardiac glucose uptake in PRKAG2 T400N cardiomyopathy is mediated by upregulation of SGLT1 (sodium-dependent glucose cotransporter 1) at the sarcolemma, not GLUT1 or GLUT4. AMPK activity (via the alpha2 subunit) drives SGLT1 mRNA upregulation through increased binding of transcription factors HNF-1 and Sp1 to the SGLT1 promoter. Phlorizin (SGLT1 inhibitor) reduced cardiac glucose uptake ~40% and glycogen content ~25% in mutant mice.","method":"Transgenic mouse model (TGT400N); pharmacological inhibition with phlorizin; AICAR stimulation; double-transgenic cross with TGalpha2DN; mRNA/protein expression; EMSA for transcription factor binding; glucose uptake assays","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pharmacological inhibition, genetic epistasis, transcription factor binding assay), single lab but rigorous mechanistic follow-up","pmids":["20600102"],"is_preprint":false},{"year":2007,"finding":"The PRKAG2 T400N mutation causes biphasic changes in myocardial AMPK activity: initial elevation followed by depression then recovery to wild-type levels. AMPK activity correlated inversely with glycogen content. Despite elevated glycogen stores, T400N hearts are NOT protected against ischemia-reperfusion injury and show greater infarct sizes and apoptosis.","method":"Transgenic mouse model (TGT400N); AMPK activity assays; ischemia-reperfusion protocol; infarct size measurement; apoptosis assays; genetic cross with TGalpha2DN","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined phenotypic readout with AMPK activity measurements and genetic epistasis, single lab with two orthogonal methods","pmids":["17597581"],"is_preprint":false},{"year":2009,"finding":"PRKAG2 T400N mutation activates NF-κB (nuclear translocation of p50 subunit, ~2-3 fold) and Akt/p70S6K signaling (~2-fold elevation) as early as age 2 weeks, mediating cardiac hypertrophy. Genetic reversal of AMPK overactivity (via dominant-negative alpha2 cross) reduced hypertrophy, NF-κB nuclear translocation, and Akt/p70S6K phosphorylation, confirming that inappropriate AMPK activation drives these hypertrophic signaling pathways.","method":"Transgenic mouse model (TGT400N); NF-κB activity assay; nuclear fractionation; phospho-Akt and phospho-p70S6K Western blot; genetic epistasis with TGalpha2DN","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus multiple signaling pathway measurements, single lab with orthogonal methods","pmids":["20005292"],"is_preprint":false},{"year":2014,"finding":"Cardiac-specific knockdown of SGLT1 in TGT400N mice attenuates the PRKAG2 cardiomyopathy phenotype (reduced heart/body weight ratio, hypertrophy markers, glycogen content, LV dilation), confirming SGLT1 as a pathogenic mediator downstream of AMPK activation. Conversely, conditional cardiac overexpression of SGLT1 alone causes pathologic hypertrophy, glycogen accumulation, and progressive LV failure that is reversible upon SGLT1 suppression.","method":"Double-transgenic mice (TGT400N × TGSGLT1-DOWN); conditional Tet-off SGLT1 overexpression transgenic mice; echocardiography; cardiac morphometry; glycogen content; hypertrophy marker expression","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (knockdown + overexpression), reversibility experiment, multiple orthogonal phenotypic readouts establish causal role of SGLT1","pmids":["25092788"],"is_preprint":false},{"year":2016,"finding":"Activating PRKAG2 mutations remodel global cardiac metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism over glycolysis. AMPK activation in PRKAG2-mutant cardiomyocytes increases microtissue twitch force by enhancing myocyte survival. PRKAG2/AMPK activation suppresses cardiac fibrosis through post-transcriptional regulation of TGFβ isoform signaling.","method":"Human iPSC-derived cardiomyocytes combined with 3D cardiac microtissues; RNA sequencing; metabolomics; TGFβ signaling analysis; mouse models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal omics (RNA-seq + metabolomics) with iPSC and mouse models, single lab, novel mechanistic links","pmids":["28009297"],"is_preprint":false},{"year":2013,"finding":"A novel K485E PRKAG2 mutation (in non-CBS domain) forms a salt bridge with residue D248 of the AMPK beta-subunit that is critical for proper enzyme regulation; the K485E substitution disrupts this connection as predicted by electrostatic calculations. The mutation causes a de novo glycogen storage cardiomyopathy.","method":"Direct sequencing; computational electrostatic modeling; conservation analysis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction of salt bridge disruption without in vitro or in vivo functional validation of the specific interaction","pmids":["23741347"],"is_preprint":false},{"year":2013,"finding":"The novel PRKAG2 G100S mutation in a non-CBS domain reduces PRKAG2 protein expression levels and attenuates AMPK activity, resulting in glycogen metabolism dysregulation, without altering intracellular PRKAG2 localization or cell growth. This demonstrates that non-CBS domains are essential for AMPK activity regulation.","method":"Lentiviral transfection of CCL13 cells; Western blot; immunofluorescence localization; ELISA for AMPK activity; PAS staining for glycogen; MTT proliferation assay","journal":"Journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional characterization with multiple orthogonal methods (protein expression, localization, activity, glycogen), single lab","pmids":["23778007"],"is_preprint":false},{"year":2013,"finding":"Overexpression of PRKAG2 G100S mutant in zebrafish causes cardiac wall thickening, decreased AMPK enzymatic activity, and increased cardiac glycogen storage compared to wild-type PRKAG2 or mock controls, confirming G100S as a loss-of-function mutation for AMPK that causes glycogen-related cardiomyopathy.","method":"Zebrafish overexpression model; AMPK kinase activity colorimetric assay; PAS staining for glycogen; cardiac wall thickness measurement","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish model with direct enzyme activity measurement and glycogen quantification, single lab","pmids":["23992123"],"is_preprint":false},{"year":2017,"finding":"The PRKAG2 R302Q mutation in patient-derived iPSC-CMs causes abnormal firing patterns, delayed afterdepolarizations, triggered arrhythmias, augmented beat rate variability, increased glycogen storage, and cardiomyocyte hypertrophy. CRISPR correction of the R302Q mutation in iPSCs eliminated all electrophysiological abnormalities, glycogen accumulation, and hypertrophy, establishing the mutation as the direct cause of these cellular phenotypes.","method":"Patient-derived iPSC-CMs; CRISPR correction generating isogenic lines; patch clamp electrophysiology; microelectrode array; transmission electron microscopy; glycogen quantification","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic CRISPR correction as gold-standard control, multiple orthogonal functional readouts (electrophysiology, ultrastructure, glycogen), rigorous causal attribution","pmids":["28917552"],"is_preprint":false},{"year":2018,"finding":"The PRKAG2 R302Q mutation in patient-derived hiPSC-CMs causes increased AMPK activity, extensive glycogen deposition, and cardiomyocyte hypertrophy. AMPK activity inhibition by small molecules alleviates disease phenotypes, and CRISPR-Cas9 correction of the R302Q mutation rescues all phenotypes, confirming AMPK overactivation as the primary driver.","method":"Patient-derived hiPSC-CMs; CRISPR-Cas9 genome correction; small molecule AMPK inhibition; AMPK activity assays; glycogen quantification; cell size measurement","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic CRISPR correction plus pharmacological rescue with AMPK inhibitors, multiple orthogonal methods, independently replicates findings from Ben Jehuda 2017","pmids":["29452156"],"is_preprint":false},{"year":2017,"finding":"A novel de novo PRKAG2 K475E mutation (in CBS3 domain, critical for AMP binding) markedly increases basal AMPK phosphorylation at T172 and AMPK activity in HEK293 cells, reduces sensitivity to AMP for allosteric activation, and activates mTOR signaling (increased p70S6K and 4E-BP1 phosphorylation) in H9c2 cardiomyocytes. The K475E mutation induces cellular hypertrophy reversible by rapamycin, implicating mTOR pathway in PRKAG2-associated hypertrophy.","method":"HEK293 and H9c2 cells stably expressing K475E mutant; AMPK T172 phosphorylation assay; AMP titration for allosteric activation; p70S6K and 4E-BP1 phosphorylation Western blot; cell size measurement; rapamycin treatment","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cell-based functional assays with pharmacological rescue, multiple orthogonal biochemical readouts, single lab","pmids":["28550180"],"is_preprint":false},{"year":2022,"finding":"Three PRKAG2 missense variants (E506K, E506Q, R531G) in the CBS4 domain all reduce AMPK activity and cause cytoplasmic glycogen deposits in HEK293 cells. E506K variant additionally shows persistent PRKAG2 overexpression in stably transformed cells unlike E506Q and R531G.","method":"In vitro mutagenesis in HEK293 cells; quantitative RT-PCR; immunofluorescence staining; ELISA for AMPK activity; PAS staining for glycogen","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional characterization with multiple methods, three variants studied comparatively, single lab","pmids":["35787834"],"is_preprint":false},{"year":2022,"finding":"PRKAG2 R302Q mutation directly impairs atrial cardiomyocytes causing glycogen deposition and AMPK activity downregulation (not upregulation as seen early in transgenic ventricular models) in human atrial tissue and in HL-1 murine atrial cardiomyocytes. AMPK signaling disruption was confirmed in adenovirally transduced HL-1 cells and hiPSC-derived atrial cardiomyocytes overexpressing R302Q.","method":"Human atrial biopsy from PRKAG2 R302Q proband; H&E, Masson, PAS staining; Western blot for AMPK pathway; adenoviral overexpression in HL-1 cells and hiPSC-ACMs; ELISA for AMPK activity","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human tissue plus two cell models with multiple readouts, single lab; establishes atrial-specific AMPK impairment","pmids":["35360035"],"is_preprint":false},{"year":2009,"finding":"PRKAG2 R302Q mutation is associated with nodoventricular accessory pathways (Mahaim fibers passing through the central fibrous body connecting AV node to interventricular septal working myocardium), distinct from simple annulus fibrosus disruption. Histopathology showed 3 small nodoventricular tracts with concentric LV hypertrophy and myocardial disarray but no lysosomal-bound glycogen.","method":"Histopathological examination of cardiac tissue from suddenly deceased R302Q mutation carrier; electrophysiological studies in living carriers showing AV node-like bypass properties","journal":"Circulation. Arrhythmia and electrophysiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct histopathological identification of nodoventricular tracts in human tissue with corroborating electrophysiology in living carriers, establishes anatomic substrate","pmids":["19808419"],"is_preprint":false},{"year":2013,"finding":"Chronic AMPK dysregulation in PRKAG2 R302Q transgenic hearts produces myocardial insulin resistance: baseline myocardial glucose uptake is reduced 56% and fails to increase following acute insulin stimulation, unlike wild-type hearts. This correlates with reduced phospho-AMPK alpha levels despite fourfold glycogen accumulation. Insulin receptor expression was not different between genotypes.","method":"18F-FDG PET imaging in transgenic R302Q mice; euglycemic hyperinsulinemic clamp; phospho-AMPK alpha Western blot; glycogen quantification; insulin receptor expression","journal":"EJNMMI research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo metabolic imaging with biochemical correlates, negative insulin response as mechanistic finding, single lab","pmids":["23829931"],"is_preprint":false},{"year":2022,"finding":"Overexpression of PRKAG2 R302Q in neonatal rat cardiomyocytes increases AMPK activity, cellular hypertrophy and glycogen storage, and activates the AKT-mTOR signaling pathway (increased phosphorylation of AKT-mTOR). Treatment with β1-adrenergic receptor blocker metoprolol or PKA inhibitor H89 suppresses both AKT-mTOR phosphorylation and AMPK activity, rescuing the HCM-like phenotype.","method":"Adenoviral overexpression of R302Q in NRCMs and H9C2 cells; AMPK activity assay; cell size and glycogen measurements; AKT-mTOR phosphorylation Western blot; pharmacological treatment with metoprolol and H89","journal":"Cardiovascular diagnosis and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays with pharmacological rescue, two orthogonal inhibitors targeting different pathway steps, single lab","pmids":["35800350"],"is_preprint":false},{"year":2023,"finding":"A specific transcript variant of AMPK γ2 subunit, PRKAG2.2, is selectively induced in FoxA1+ regulatory T cells (but not FoxP3+ Tregs) by IFNβ via FoxA1 transcription factor activation. PRKAG2.2 activates AMPK signaling, thereby enhancing mitochondrial respiration and mitophagy via the ULK1-BNIP3 axis, which is required for the suppressive function of FoxA1+ Tregs.","method":"IFNβ stimulation of T cells; FoxA1 induction experiments; PRKAG2.2-specific transcript analysis; AMPK signaling measurement; mitochondrial respiration assay; mitophagy assessment via ULK1-BNIP3; functional suppression assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of specific PRKAG2 isoform in defined immune cell context with multiple mechanistic readouts, single lab","pmids":["38117896"],"is_preprint":false},{"year":2000,"finding":"PRKAG2 encodes a gamma subunit of AMPK with four consecutive cystathionine-beta-synthase (CBS) domains, characteristic of AMPK gamma subunits across species. The gene maps to human chromosome 7q36, spans ~80 kb, consists of 12 exons (for the PRKAG2-b transcript), and produces at least two splice variants (PRKAG2-a and PRKAG2-b) with the highest expression in heart.","method":"cDNA cloning; Northern blot tissue expression analysis; radiation hybrid mapping; genomic organization determination by cDNA-genomic sequence comparison","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental gene characterization (cloning, mapping, expression), foundational molecular identity paper","pmids":["11112354"],"is_preprint":false},{"year":2026,"finding":"PRKAG2 R302Q mutation in iPSC-derived cardiomyocytes reduces glycolytic function and increases maximal mitochondrial respiration with elevated mitochondrial content, alongside increased glycogen accumulation, lipid storage, and alterations in redox regulation pathways. Mutated murine hearts show altered glucose and lipid metabolism with elevated triacylglycerol and enhanced fatty acid oxidation. Metformin treatment reduces mitochondrial content and respiration in mutant iPSC-CMs and attenuates arrhythmias.","method":"iPSC-CMs from WPW/PRKAG2 patient; Seahorse metabolic flux assay; lipidomics; metabolomics; RNA-seq; murine PRKAG2 mutant hearts; metformin pharmacological treatment","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics approach with functional metabolic measurements in two models, pharmacological rescue with metformin, single lab","pmids":["42039356"],"is_preprint":false}],"current_model":"PRKAG2 encodes the γ2 regulatory subunit of the heterotrimeric AMPK complex; disease-causing mutations in its CBS domains impair nucleotide (AMP/ATP) binding and enhance basal AMPK activity (primarily through alpha2-containing complexes), driving inappropriate cardiac glycogen accumulation via SGLT1 upregulation and glycogen synthase activation, which physically disrupts the annulus fibrosis to create anomalous AV connections underlying WPW, while also activating NF-κB and Akt/mTOR hypertrophic signaling pathways; a specific PRKAG2 isoform (PRKAG2.2) is additionally required for metabolic reprogramming and mitophagy in FoxA1+ regulatory T cells via the ULK1-BNIP3 axis."},"narrative":{"mechanistic_narrative":"PRKAG2 encodes the γ2 regulatory subunit of the heterotrimeric AMP-activated protein kinase (AMPK), a heart-enriched protein characterized by four tandem cystathionine-β-synthase (CBS) domains that bind adenine nucleotides and tune kinase activity [PMID:11112354]. Dominant disease mutations dysregulate this nucleotide-sensing function: the R531Q substitution reduces AMP/ATP binding affinity >100-fold yet paradoxically enhances basal AMPK activity and α-subunit phosphorylation, while CBS-domain variants such as K475E blunt allosteric AMP sensitivity and raise basal T172 phosphorylation [PMID:15877279, PMID:28550180]. The pathogenic activity is transmitted primarily through α2-containing AMPK complexes, since a dominant-negative α2 transgene rescues the cardiac phenotype of γ2-mutant mice [PMID:16275868]. Inappropriate AMPK activation drives massive cardiac glycogen accumulation and left ventricular hypertrophy, with glycogen-engorged myocytes physically disrupting the annulus fibrosis to create the anomalous atrioventricular connections underlying ventricular preexcitation/WPW [PMID:12782567]. Mechanistically, glycogen loading is fed by AMPK-driven transcriptional upregulation of the sarcolemmal cotransporter SGLT1 via HNF-1 and Sp1, and SGLT1 is both necessary and sufficient as a downstream pathogenic mediator [PMID:20600102, PMID:25092788], while hypertrophy is propagated through NF-κB and Akt/mTOR(p70S6K) signaling that is reversible by α2 inhibition or rapamycin [PMID:20005292, PMID:28550180, PMID:35800350]. Patient iPSC-derived cardiomyocytes reproduce the arrhythmia, glycogen, and hypertrophy phenotypes, all reversed by CRISPR correction or AMPK inhibition, establishing direct causality [PMID:28917552, PMID:29452156]. Beyond the heart, a specific transcript variant PRKAG2.2 is induced by IFNβ via FoxA1 in FoxA1+ regulatory T cells, where it activates AMPK to drive mitochondrial respiration and ULK1–BNIP3-dependent mitophagy required for suppressive function [PMID:38117896].","teleology":[{"year":2000,"claim":"Established the molecular identity of PRKAG2 as an AMPK γ subunit, defining the CBS-domain architecture and heart-predominant expression that frames all later disease mechanism work.","evidence":"cDNA cloning, radiation hybrid mapping, and Northern blot tissue expression","pmids":["11112354"],"confidence":"Medium","gaps":["Did not address nucleotide-binding function of individual CBS domains","No functional consequence of splice variants tested"]},{"year":2003,"claim":"Answered whether PRKAG2 mutation directly causes the cardiomyopathy/preexcitation triad and revealed the anatomic substrate: glycogen engorgement disrupting the annulus fibrosis rather than discrete bypass tracts.","evidence":"Transgenic mouse overexpression of N488I with histopathology and electrophysiology","pmids":["12782567"],"confidence":"High","gaps":["Overexpression model may not reflect endogenous mutant dosage","Molecular driver of glycogen accumulation not yet defined"]},{"year":2005,"claim":"Resolved the biochemical paradox of dominant gain-of-function: a mutation that abolishes nucleotide binding still enhances basal kinase activity, explaining the dominant inheritance.","evidence":"Recombinant R531Q protein with nucleotide-binding affinity and AMPK activity assays","pmids":["15877279"],"confidence":"High","gaps":["Done in vitro; cardiac cellular context not addressed","Did not test which catalytic α subunit mediates the effect"]},{"year":2005,"claim":"Determined which catalytic subunit transmits the disease, showing α2-containing complexes are the primary effector and a druggable node.","evidence":"Genetic epistasis with compound-heterozygous TGγ2N488I × TGα2DN mice across ECG, morphology and exercise readouts","pmids":["16275868"],"confidence":"High","gaps":["Residual α1 contribution not fully excluded","Downstream metabolic effectors still unidentified"]},{"year":2007,"claim":"Showed AMPK activity is biphasic over disease course and that glycogen stores do not confer ischemic protection, refining the temporal model of pathogenesis.","evidence":"TGT400N mice with serial AMPK assays, ischemia-reperfusion and infarct/apoptosis measurement","pmids":["17597581"],"confidence":"Medium","gaps":["Single lab","Mechanism of the biphasic activity transition unresolved"]},{"year":2009,"claim":"Dissected direct versus compensatory effects, showing acute mutant expression activates glycogen synthase/AS160 while chronic hearts downregulate them in response to glycogen overload.","evidence":"Acute adenoviral γ2R302Q in neonatal cardiomyocytes versus chronic transgenic mice with biochemical readouts","pmids":["20031621"],"confidence":"High","gaps":["Transcriptional basis of compensation not defined","Glucose entry pathway not yet identified"]},{"year":2009,"claim":"Identified a distinct arrhythmic substrate (nodoventricular Mahaim fibers) for R302Q, indicating mutation-specific anatomic pathways beyond simple annulus disruption.","evidence":"Histopathology of a deceased R302Q carrier plus electrophysiology in living carriers","pmids":["19808419"],"confidence":"Medium","gaps":["Single case histopathology","Link between AMPK activity and tract formation mechanistic only by inference"]},{"year":2009,"claim":"Connected AMPK overactivation to hypertrophic transcriptional/growth signaling, identifying NF-κB and Akt/p70S6K as early effectors reversible by α2 inhibition.","evidence":"TGT400N mice with NF-κB nuclear translocation, phospho-Akt/p70S6K blots, and TGα2DN epistasis","pmids":["20005292"],"confidence":"Medium","gaps":["Single lab","Direct AMPK-to-NF-κB link not biochemically mapped"]},{"year":2010,"claim":"Identified SGLT1 as the AMPK-driven glucose entry route fueling glycogen accumulation, via HNF-1/Sp1 promoter activation.","evidence":"TGT400N mice with phlorizin inhibition, TGα2DN cross, EMSA, and glucose uptake assays","pmids":["20600102"],"confidence":"High","gaps":["Single lab","Necessity/sufficiency of SGLT1 not yet genetically proven"]},{"year":2013,"claim":"Extended the mutational spectrum to non-CBS domains, with K485E predicted to disrupt a γ–β salt bridge and G100S reducing protein expression and AMPK activity — showing both gain- and loss-of-activity routes to glycogen cardiomyopathy.","evidence":"Computational electrostatics for K485E; lentiviral/zebrafish G100S expression with activity and glycogen assays","pmids":["23741347","23778007","23992123"],"confidence":"Low","gaps":["K485E salt-bridge disruption awaits in vitro/in vivo functional validation","Reconciling loss-of-activity variants with the dominant gain-of-function model unresolved"]},{"year":2013,"claim":"Demonstrated that chronic AMPK dysregulation produces myocardial insulin resistance, linking the disease to a broader metabolic defect.","evidence":"18F-FDG PET and hyperinsulinemic clamp in R302Q transgenic mice with phospho-AMPK correlates","pmids":["23829931"],"confidence":"Medium","gaps":["Mechanism of insulin unresponsiveness downstream of receptor not defined","Single lab"]},{"year":2014,"claim":"Proved SGLT1 is causally necessary and sufficient downstream of AMPK by bidirectional genetic manipulation and reversibility, validating it as a therapeutic target.","evidence":"TGT400N × SGLT1-knockdown crosses and conditional Tet-off SGLT1 overexpression with echocardiography and glycogen readouts","pmids":["25092788"],"confidence":"High","gaps":["SGLT1-independent residual phenotype not quantified","Transcriptional control in human hearts not directly shown"]},{"year":2016,"claim":"Profiled global metabolic remodeling, showing the mutation shifts transcripts toward glycogen storage/oxidative metabolism and suppresses fibrosis via TGFβ regulation.","evidence":"iPSC-cardiomyocyte 3D microtissues with RNA-seq, metabolomics and mouse models","pmids":["28009297"],"confidence":"Medium","gaps":["Post-transcriptional TGFβ mechanism not detailed","Single lab"]},{"year":2017,"claim":"Established direct causality in human cells, with CRISPR correction of R302Q eliminating arrhythmia, glycogen and hypertrophy phenotypes; a novel CBS3 K475E variant linked AMPK activation to mTOR-driven hypertrophy reversible by rapamycin.","evidence":"Patient iPSC-CMs with isogenic CRISPR correction and patch-clamp; HEK293/H9c2 K475E assays with rapamycin rescue","pmids":["28917552","28550180"],"confidence":"High","gaps":["mTOR contribution relative to SGLT1/glycogen axis not weighted","In vivo confirmation of K475E lacking"]},{"year":2018,"claim":"Independently confirmed AMPK overactivation as the primary driver in human iPSC-CMs by combining CRISPR correction with small-molecule AMPK inhibition rescue.","evidence":"Patient hiPSC-CMs with CRISPR-Cas9 correction, AMPK inhibitors, activity and glycogen assays","pmids":["29452156"],"confidence":"High","gaps":["Specific AMPK inhibitor selectivity in vivo not addressed","Effect on arrhythmic substrate formation not modeled"]},{"year":2022,"claim":"Revealed tissue- and chamber-specific divergence: R302Q downregulates AMPK activity in atrial cardiomyocytes, and additional CBS4 variants reduce activity, complicating the uniform gain-of-function model.","evidence":"Human atrial tissue plus HL-1 and hiPSC-atrial CM models; HEK293 CBS4 variant assays; NRCM AKT-mTOR rescue with metoprolol/H89","pmids":["35360035","35787834","35800350"],"confidence":"Medium","gaps":["Why atrial and ventricular AMPK responses differ is unexplained","Adrenergic/PKA link to AMPK activity mechanistically incomplete"]},{"year":2023,"claim":"Defined a non-cardiac role, showing the PRKAG2.2 isoform is IFNβ/FoxA1-induced in FoxA1+ Tregs to drive AMPK-dependent mitophagy via ULK1-BNIP3 for immunosuppressive function.","evidence":"IFNβ stimulation, isoform-specific transcript analysis, mitochondrial respiration and mitophagy assays in T cells","pmids":["38117896"],"confidence":"Medium","gaps":["Isoform-specific regulation of AMPK not structurally explained","Cardiac versus immune isoform usage not compared"]},{"year":2026,"claim":"Characterized the metabolic rewiring of mutant cardiomyocytes toward mitochondrial respiration and lipid storage and showed metformin attenuates respiration and arrhythmia, pointing to a metabolic therapeutic strategy.","evidence":"Patient iPSC-CMs and mutant mouse hearts with Seahorse flux, lipidomics, metabolomics and metformin treatment","pmids":["42039356"],"confidence":"Medium","gaps":["Mechanism connecting AMPK mutation to mitochondrial biogenesis unresolved","Metformin efficacy not validated clinically"]},{"year":null,"claim":"It remains unresolved how the same mutations produce gain-of-AMPK-activity in ventricular models yet loss-of-activity in atrial tissue and several CBS variants, and how this reconciles with the unified glycogen-storage phenotype.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical model for context-dependent AMPK activity","Structural basis of CBS-domain mutation effects on the holoenzyme incompletely defined","Therapeutic node (AMPK vs SGLT1 vs mTOR vs metabolism) not prioritized in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,13]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,8,22]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,14,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20]}],"complexes":["AMPK heterotrimeric complex"],"partners":["PRKAA2","PRKAB1","ULK1","BNIP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UGJ0","full_name":"5'-AMP-activated protein kinase subunit gamma-2","aliases":["H91620p"],"length_aa":569,"mass_kda":63.1,"function":"AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:14722619, PubMed:24563466). In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation (PubMed:14722619, PubMed:24563466). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:14722619, PubMed:24563466). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:14722619, PubMed:24563466). Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits (PubMed:14722619, PubMed:24563466). ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit (PubMed:14722619, PubMed:24563466). ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive (PubMed:14722619, PubMed:24563466)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UGJ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRKAG2","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRKAA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRKAG2","total_profiled":1310},"omim":[{"mim_id":"619705","title":"IMMUNODEFICIENCY 93 AND HYPERTROPHIC CARDIOMYOPATHY; IMD93","url":"https://www.omim.org/entry/619705"},{"mim_id":"614676","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 21; CMH21","url":"https://www.omim.org/entry/614676"},{"mim_id":"613874","title":"CARDIOMYOPATHY, 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Insights with 68Ga-FAPI PET/CT imaging.","date":"2026","source":"The international journal of cardiovascular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/41989697","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.26.25324696","title":"The expression of insulin signaling and N-methyl-D-aspartate receptor genes in areas of gray matter atrophy is associated with cognitive function in type 2 diabetes","date":"2025-03-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.26.25324696","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.25.619688","title":"Mapping DNA Methylation to Cardiac Pathologies Induced by Beta-Adrenergic Stimulation in a Large Panel of Mice","date":"2024-10-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.25.619688","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44385,"output_tokens":6476,"usd":0.115147,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15598,"output_tokens":5404,"usd":0.106545,"stage2_stop_reason":"end_turn"},"total_usd":0.221692,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PRKAG2 mutations (N488I) cause inappropriate activation of AMPK, leading to massive cardiac glycogen accumulation (30-fold above normal), left ventricular hypertrophy, and ventricular preexcitation. Histopathology showed glycogen-engorged myocytes physically disrupting the annulus fibrosis, creating anomalous atrioventricular connections that provide the anatomic substrate for WPW preexcitation — not morphologically distinct bypass tracts.\",\n      \"method\": \"Transgenic mouse overexpression of mutant PRKAG2 N488I; histopathology; electrophysiological testing; cardiac glycogen quantification\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model with direct histopathological and electrophysiological validation, mechanistic link between glycogen accumulation and annulus fibrosis disruption established; replicated concept across multiple labs\",\n      \"pmids\": [\"12782567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The R531Q PRKAG2 mutation causes >100-fold reduction in binding affinities for AMP and ATP but enhanced basal AMPK activity and increased phosphorylation of the alpha-subunit, explaining the dominant nature of PRKAG2 disease mutations and the massive glycogen storage phenotype.\",\n      \"method\": \"Biochemical characterization of recombinant R531Q mutant protein; nucleotide binding affinity assays; AMPK activity assays; alpha-subunit phosphorylation measurement\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant protein, direct measurement of nucleotide binding affinities and kinase activity, clear mechanistic explanation\",\n      \"pmids\": [\"15877279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PRKAG2 N488I mutation-driven cardiomyopathy is primarily mediated through AMPK complexes containing the alpha2 (not alpha1) catalytic subunit. Genetic inhibition of alpha2-associated AMPK activity using a dominant-negative alpha2 transgene partially or completely rescued the ECG abnormalities, cardiac function, morphology, and exercise capacity in compound-heterozygous mice.\",\n      \"method\": \"Genetic epistasis using compound-heterozygous transgenic mice (TGgamma2N488I × TGalpha2DN); AMPK activity assays; ECG; cardiac morphology; exercise testing\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis experiment with defined phenotypic rescue, multiple orthogonal readouts, establishes alpha2 subunit as primary mediator\",\n      \"pmids\": [\"16275868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AMPK activation induced by the PRKAG2 R302Q mutation upregulates glycogen synthase and AS160, increasing glycogen content acutely; however in chronic transgenic hearts, AMPK activity, glycogen synthase activity, and AS160 expression are reduced as a compensatory response to the 37-fold glycogen accumulation. Acute expression in neonatal cardiomyocytes distinguished direct effects from compensatory changes.\",\n      \"method\": \"Acute adenoviral expression of gamma2R302Q in neonatal rat cardiomyocytes vs. adult transgenic mice; AMPK activity assays; glycogen synthase activity; Western blot for AS160; glycogen quantification\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal models (acute viral expression + chronic transgenic), multiple biochemical readouts, temporal dissection of direct vs. compensatory effects\",\n      \"pmids\": [\"20031621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Increased cardiac glucose uptake in PRKAG2 T400N cardiomyopathy is mediated by upregulation of SGLT1 (sodium-dependent glucose cotransporter 1) at the sarcolemma, not GLUT1 or GLUT4. AMPK activity (via the alpha2 subunit) drives SGLT1 mRNA upregulation through increased binding of transcription factors HNF-1 and Sp1 to the SGLT1 promoter. Phlorizin (SGLT1 inhibitor) reduced cardiac glucose uptake ~40% and glycogen content ~25% in mutant mice.\",\n      \"method\": \"Transgenic mouse model (TGT400N); pharmacological inhibition with phlorizin; AICAR stimulation; double-transgenic cross with TGalpha2DN; mRNA/protein expression; EMSA for transcription factor binding; glucose uptake assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pharmacological inhibition, genetic epistasis, transcription factor binding assay), single lab but rigorous mechanistic follow-up\",\n      \"pmids\": [\"20600102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The PRKAG2 T400N mutation causes biphasic changes in myocardial AMPK activity: initial elevation followed by depression then recovery to wild-type levels. AMPK activity correlated inversely with glycogen content. Despite elevated glycogen stores, T400N hearts are NOT protected against ischemia-reperfusion injury and show greater infarct sizes and apoptosis.\",\n      \"method\": \"Transgenic mouse model (TGT400N); AMPK activity assays; ischemia-reperfusion protocol; infarct size measurement; apoptosis assays; genetic cross with TGalpha2DN\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined phenotypic readout with AMPK activity measurements and genetic epistasis, single lab with two orthogonal methods\",\n      \"pmids\": [\"17597581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PRKAG2 T400N mutation activates NF-κB (nuclear translocation of p50 subunit, ~2-3 fold) and Akt/p70S6K signaling (~2-fold elevation) as early as age 2 weeks, mediating cardiac hypertrophy. Genetic reversal of AMPK overactivity (via dominant-negative alpha2 cross) reduced hypertrophy, NF-κB nuclear translocation, and Akt/p70S6K phosphorylation, confirming that inappropriate AMPK activation drives these hypertrophic signaling pathways.\",\n      \"method\": \"Transgenic mouse model (TGT400N); NF-κB activity assay; nuclear fractionation; phospho-Akt and phospho-p70S6K Western blot; genetic epistasis with TGalpha2DN\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus multiple signaling pathway measurements, single lab with orthogonal methods\",\n      \"pmids\": [\"20005292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cardiac-specific knockdown of SGLT1 in TGT400N mice attenuates the PRKAG2 cardiomyopathy phenotype (reduced heart/body weight ratio, hypertrophy markers, glycogen content, LV dilation), confirming SGLT1 as a pathogenic mediator downstream of AMPK activation. Conversely, conditional cardiac overexpression of SGLT1 alone causes pathologic hypertrophy, glycogen accumulation, and progressive LV failure that is reversible upon SGLT1 suppression.\",\n      \"method\": \"Double-transgenic mice (TGT400N × TGSGLT1-DOWN); conditional Tet-off SGLT1 overexpression transgenic mice; echocardiography; cardiac morphometry; glycogen content; hypertrophy marker expression\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (knockdown + overexpression), reversibility experiment, multiple orthogonal phenotypic readouts establish causal role of SGLT1\",\n      \"pmids\": [\"25092788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Activating PRKAG2 mutations remodel global cardiac metabolism by regulating RNA transcripts to favor glycogen storage and oxidative metabolism over glycolysis. AMPK activation in PRKAG2-mutant cardiomyocytes increases microtissue twitch force by enhancing myocyte survival. PRKAG2/AMPK activation suppresses cardiac fibrosis through post-transcriptional regulation of TGFβ isoform signaling.\",\n      \"method\": \"Human iPSC-derived cardiomyocytes combined with 3D cardiac microtissues; RNA sequencing; metabolomics; TGFβ signaling analysis; mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal omics (RNA-seq + metabolomics) with iPSC and mouse models, single lab, novel mechanistic links\",\n      \"pmids\": [\"28009297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel K485E PRKAG2 mutation (in non-CBS domain) forms a salt bridge with residue D248 of the AMPK beta-subunit that is critical for proper enzyme regulation; the K485E substitution disrupts this connection as predicted by electrostatic calculations. The mutation causes a de novo glycogen storage cardiomyopathy.\",\n      \"method\": \"Direct sequencing; computational electrostatic modeling; conservation analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction of salt bridge disruption without in vitro or in vivo functional validation of the specific interaction\",\n      \"pmids\": [\"23741347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The novel PRKAG2 G100S mutation in a non-CBS domain reduces PRKAG2 protein expression levels and attenuates AMPK activity, resulting in glycogen metabolism dysregulation, without altering intracellular PRKAG2 localization or cell growth. This demonstrates that non-CBS domains are essential for AMPK activity regulation.\",\n      \"method\": \"Lentiviral transfection of CCL13 cells; Western blot; immunofluorescence localization; ELISA for AMPK activity; PAS staining for glycogen; MTT proliferation assay\",\n      \"journal\": \"Journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional characterization with multiple orthogonal methods (protein expression, localization, activity, glycogen), single lab\",\n      \"pmids\": [\"23778007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of PRKAG2 G100S mutant in zebrafish causes cardiac wall thickening, decreased AMPK enzymatic activity, and increased cardiac glycogen storage compared to wild-type PRKAG2 or mock controls, confirming G100S as a loss-of-function mutation for AMPK that causes glycogen-related cardiomyopathy.\",\n      \"method\": \"Zebrafish overexpression model; AMPK kinase activity colorimetric assay; PAS staining for glycogen; cardiac wall thickness measurement\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish model with direct enzyme activity measurement and glycogen quantification, single lab\",\n      \"pmids\": [\"23992123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The PRKAG2 R302Q mutation in patient-derived iPSC-CMs causes abnormal firing patterns, delayed afterdepolarizations, triggered arrhythmias, augmented beat rate variability, increased glycogen storage, and cardiomyocyte hypertrophy. CRISPR correction of the R302Q mutation in iPSCs eliminated all electrophysiological abnormalities, glycogen accumulation, and hypertrophy, establishing the mutation as the direct cause of these cellular phenotypes.\",\n      \"method\": \"Patient-derived iPSC-CMs; CRISPR correction generating isogenic lines; patch clamp electrophysiology; microelectrode array; transmission electron microscopy; glycogen quantification\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic CRISPR correction as gold-standard control, multiple orthogonal functional readouts (electrophysiology, ultrastructure, glycogen), rigorous causal attribution\",\n      \"pmids\": [\"28917552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The PRKAG2 R302Q mutation in patient-derived hiPSC-CMs causes increased AMPK activity, extensive glycogen deposition, and cardiomyocyte hypertrophy. AMPK activity inhibition by small molecules alleviates disease phenotypes, and CRISPR-Cas9 correction of the R302Q mutation rescues all phenotypes, confirming AMPK overactivation as the primary driver.\",\n      \"method\": \"Patient-derived hiPSC-CMs; CRISPR-Cas9 genome correction; small molecule AMPK inhibition; AMPK activity assays; glycogen quantification; cell size measurement\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic CRISPR correction plus pharmacological rescue with AMPK inhibitors, multiple orthogonal methods, independently replicates findings from Ben Jehuda 2017\",\n      \"pmids\": [\"29452156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel de novo PRKAG2 K475E mutation (in CBS3 domain, critical for AMP binding) markedly increases basal AMPK phosphorylation at T172 and AMPK activity in HEK293 cells, reduces sensitivity to AMP for allosteric activation, and activates mTOR signaling (increased p70S6K and 4E-BP1 phosphorylation) in H9c2 cardiomyocytes. The K475E mutation induces cellular hypertrophy reversible by rapamycin, implicating mTOR pathway in PRKAG2-associated hypertrophy.\",\n      \"method\": \"HEK293 and H9c2 cells stably expressing K475E mutant; AMPK T172 phosphorylation assay; AMP titration for allosteric activation; p70S6K and 4E-BP1 phosphorylation Western blot; cell size measurement; rapamycin treatment\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cell-based functional assays with pharmacological rescue, multiple orthogonal biochemical readouts, single lab\",\n      \"pmids\": [\"28550180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Three PRKAG2 missense variants (E506K, E506Q, R531G) in the CBS4 domain all reduce AMPK activity and cause cytoplasmic glycogen deposits in HEK293 cells. E506K variant additionally shows persistent PRKAG2 overexpression in stably transformed cells unlike E506Q and R531G.\",\n      \"method\": \"In vitro mutagenesis in HEK293 cells; quantitative RT-PCR; immunofluorescence staining; ELISA for AMPK activity; PAS staining for glycogen\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional characterization with multiple methods, three variants studied comparatively, single lab\",\n      \"pmids\": [\"35787834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRKAG2 R302Q mutation directly impairs atrial cardiomyocytes causing glycogen deposition and AMPK activity downregulation (not upregulation as seen early in transgenic ventricular models) in human atrial tissue and in HL-1 murine atrial cardiomyocytes. AMPK signaling disruption was confirmed in adenovirally transduced HL-1 cells and hiPSC-derived atrial cardiomyocytes overexpressing R302Q.\",\n      \"method\": \"Human atrial biopsy from PRKAG2 R302Q proband; H&E, Masson, PAS staining; Western blot for AMPK pathway; adenoviral overexpression in HL-1 cells and hiPSC-ACMs; ELISA for AMPK activity\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human tissue plus two cell models with multiple readouts, single lab; establishes atrial-specific AMPK impairment\",\n      \"pmids\": [\"35360035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PRKAG2 R302Q mutation is associated with nodoventricular accessory pathways (Mahaim fibers passing through the central fibrous body connecting AV node to interventricular septal working myocardium), distinct from simple annulus fibrosus disruption. Histopathology showed 3 small nodoventricular tracts with concentric LV hypertrophy and myocardial disarray but no lysosomal-bound glycogen.\",\n      \"method\": \"Histopathological examination of cardiac tissue from suddenly deceased R302Q mutation carrier; electrophysiological studies in living carriers showing AV node-like bypass properties\",\n      \"journal\": \"Circulation. Arrhythmia and electrophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct histopathological identification of nodoventricular tracts in human tissue with corroborating electrophysiology in living carriers, establishes anatomic substrate\",\n      \"pmids\": [\"19808419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Chronic AMPK dysregulation in PRKAG2 R302Q transgenic hearts produces myocardial insulin resistance: baseline myocardial glucose uptake is reduced 56% and fails to increase following acute insulin stimulation, unlike wild-type hearts. This correlates with reduced phospho-AMPK alpha levels despite fourfold glycogen accumulation. Insulin receptor expression was not different between genotypes.\",\n      \"method\": \"18F-FDG PET imaging in transgenic R302Q mice; euglycemic hyperinsulinemic clamp; phospho-AMPK alpha Western blot; glycogen quantification; insulin receptor expression\",\n      \"journal\": \"EJNMMI research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metabolic imaging with biochemical correlates, negative insulin response as mechanistic finding, single lab\",\n      \"pmids\": [\"23829931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of PRKAG2 R302Q in neonatal rat cardiomyocytes increases AMPK activity, cellular hypertrophy and glycogen storage, and activates the AKT-mTOR signaling pathway (increased phosphorylation of AKT-mTOR). Treatment with β1-adrenergic receptor blocker metoprolol or PKA inhibitor H89 suppresses both AKT-mTOR phosphorylation and AMPK activity, rescuing the HCM-like phenotype.\",\n      \"method\": \"Adenoviral overexpression of R302Q in NRCMs and H9C2 cells; AMPK activity assay; cell size and glycogen measurements; AKT-mTOR phosphorylation Western blot; pharmacological treatment with metoprolol and H89\",\n      \"journal\": \"Cardiovascular diagnosis and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays with pharmacological rescue, two orthogonal inhibitors targeting different pathway steps, single lab\",\n      \"pmids\": [\"35800350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A specific transcript variant of AMPK γ2 subunit, PRKAG2.2, is selectively induced in FoxA1+ regulatory T cells (but not FoxP3+ Tregs) by IFNβ via FoxA1 transcription factor activation. PRKAG2.2 activates AMPK signaling, thereby enhancing mitochondrial respiration and mitophagy via the ULK1-BNIP3 axis, which is required for the suppressive function of FoxA1+ Tregs.\",\n      \"method\": \"IFNβ stimulation of T cells; FoxA1 induction experiments; PRKAG2.2-specific transcript analysis; AMPK signaling measurement; mitochondrial respiration assay; mitophagy assessment via ULK1-BNIP3; functional suppression assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of specific PRKAG2 isoform in defined immune cell context with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"38117896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRKAG2 encodes a gamma subunit of AMPK with four consecutive cystathionine-beta-synthase (CBS) domains, characteristic of AMPK gamma subunits across species. The gene maps to human chromosome 7q36, spans ~80 kb, consists of 12 exons (for the PRKAG2-b transcript), and produces at least two splice variants (PRKAG2-a and PRKAG2-b) with the highest expression in heart.\",\n      \"method\": \"cDNA cloning; Northern blot tissue expression analysis; radiation hybrid mapping; genomic organization determination by cDNA-genomic sequence comparison\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental gene characterization (cloning, mapping, expression), foundational molecular identity paper\",\n      \"pmids\": [\"11112354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PRKAG2 R302Q mutation in iPSC-derived cardiomyocytes reduces glycolytic function and increases maximal mitochondrial respiration with elevated mitochondrial content, alongside increased glycogen accumulation, lipid storage, and alterations in redox regulation pathways. Mutated murine hearts show altered glucose and lipid metabolism with elevated triacylglycerol and enhanced fatty acid oxidation. Metformin treatment reduces mitochondrial content and respiration in mutant iPSC-CMs and attenuates arrhythmias.\",\n      \"method\": \"iPSC-CMs from WPW/PRKAG2 patient; Seahorse metabolic flux assay; lipidomics; metabolomics; RNA-seq; murine PRKAG2 mutant hearts; metformin pharmacological treatment\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics approach with functional metabolic measurements in two models, pharmacological rescue with metformin, single lab\",\n      \"pmids\": [\"42039356\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRKAG2 encodes the γ2 regulatory subunit of the heterotrimeric AMPK complex; disease-causing mutations in its CBS domains impair nucleotide (AMP/ATP) binding and enhance basal AMPK activity (primarily through alpha2-containing complexes), driving inappropriate cardiac glycogen accumulation via SGLT1 upregulation and glycogen synthase activation, which physically disrupts the annulus fibrosis to create anomalous AV connections underlying WPW, while also activating NF-κB and Akt/mTOR hypertrophic signaling pathways; a specific PRKAG2 isoform (PRKAG2.2) is additionally required for metabolic reprogramming and mitophagy in FoxA1+ regulatory T cells via the ULK1-BNIP3 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRKAG2 encodes the γ2 regulatory subunit of the heterotrimeric AMP-activated protein kinase (AMPK), a heart-enriched protein characterized by four tandem cystathionine-β-synthase (CBS) domains that bind adenine nucleotides and tune kinase activity [#21]. Dominant disease mutations dysregulate this nucleotide-sensing function: the R531Q substitution reduces AMP/ATP binding affinity >100-fold yet paradoxically enhances basal AMPK activity and α-subunit phosphorylation, while CBS-domain variants such as K475E blunt allosteric AMP sensitivity and raise basal T172 phosphorylation [#1, #14]. The pathogenic activity is transmitted primarily through α2-containing AMPK complexes, since a dominant-negative α2 transgene rescues the cardiac phenotype of γ2-mutant mice [#2]. Inappropriate AMPK activation drives massive cardiac glycogen accumulation and left ventricular hypertrophy, with glycogen-engorged myocytes physically disrupting the annulus fibrosis to create the anomalous atrioventricular connections underlying ventricular preexcitation/WPW [#0]. Mechanistically, glycogen loading is fed by AMPK-driven transcriptional upregulation of the sarcolemmal cotransporter SGLT1 via HNF-1 and Sp1, and SGLT1 is both necessary and sufficient as a downstream pathogenic mediator [#4, #7], while hypertrophy is propagated through NF-κB and Akt/mTOR(p70S6K) signaling that is reversible by α2 inhibition or rapamycin [#6, #14, #19]. Patient iPSC-derived cardiomyocytes reproduce the arrhythmia, glycogen, and hypertrophy phenotypes, all reversed by CRISPR correction or AMPK inhibition, establishing direct causality [#12, #13]. Beyond the heart, a specific transcript variant PRKAG2.2 is induced by IFNβ via FoxA1 in FoxA1+ regulatory T cells, where it activates AMPK to drive mitochondrial respiration and ULK1–BNIP3-dependent mitophagy required for suppressive function [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular identity of PRKAG2 as an AMPK γ subunit, defining the CBS-domain architecture and heart-predominant expression that frames all later disease mechanism work.\",\n      \"evidence\": \"cDNA cloning, radiation hybrid mapping, and Northern blot tissue expression\",\n      \"pmids\": [\"11112354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address nucleotide-binding function of individual CBS domains\", \"No functional consequence of splice variants tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Answered whether PRKAG2 mutation directly causes the cardiomyopathy/preexcitation triad and revealed the anatomic substrate: glycogen engorgement disrupting the annulus fibrosis rather than discrete bypass tracts.\",\n      \"evidence\": \"Transgenic mouse overexpression of N488I with histopathology and electrophysiology\",\n      \"pmids\": [\"12782567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression model may not reflect endogenous mutant dosage\", \"Molecular driver of glycogen accumulation not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the biochemical paradox of dominant gain-of-function: a mutation that abolishes nucleotide binding still enhances basal kinase activity, explaining the dominant inheritance.\",\n      \"evidence\": \"Recombinant R531Q protein with nucleotide-binding affinity and AMPK activity assays\",\n      \"pmids\": [\"15877279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done in vitro; cardiac cellular context not addressed\", \"Did not test which catalytic α subunit mediates the effect\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Determined which catalytic subunit transmits the disease, showing α2-containing complexes are the primary effector and a druggable node.\",\n      \"evidence\": \"Genetic epistasis with compound-heterozygous TGγ2N488I × TGα2DN mice across ECG, morphology and exercise readouts\",\n      \"pmids\": [\"16275868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual α1 contribution not fully excluded\", \"Downstream metabolic effectors still unidentified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed AMPK activity is biphasic over disease course and that glycogen stores do not confer ischemic protection, refining the temporal model of pathogenesis.\",\n      \"evidence\": \"TGT400N mice with serial AMPK assays, ischemia-reperfusion and infarct/apoptosis measurement\",\n      \"pmids\": [\"17597581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of the biphasic activity transition unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Dissected direct versus compensatory effects, showing acute mutant expression activates glycogen synthase/AS160 while chronic hearts downregulate them in response to glycogen overload.\",\n      \"evidence\": \"Acute adenoviral γ2R302Q in neonatal cardiomyocytes versus chronic transgenic mice with biochemical readouts\",\n      \"pmids\": [\"20031621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional basis of compensation not defined\", \"Glucose entry pathway not yet identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a distinct arrhythmic substrate (nodoventricular Mahaim fibers) for R302Q, indicating mutation-specific anatomic pathways beyond simple annulus disruption.\",\n      \"evidence\": \"Histopathology of a deceased R302Q carrier plus electrophysiology in living carriers\",\n      \"pmids\": [\"19808419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case histopathology\", \"Link between AMPK activity and tract formation mechanistic only by inference\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected AMPK overactivation to hypertrophic transcriptional/growth signaling, identifying NF-κB and Akt/p70S6K as early effectors reversible by α2 inhibition.\",\n      \"evidence\": \"TGT400N mice with NF-κB nuclear translocation, phospho-Akt/p70S6K blots, and TGα2DN epistasis\",\n      \"pmids\": [\"20005292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct AMPK-to-NF-κB link not biochemically mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified SGLT1 as the AMPK-driven glucose entry route fueling glycogen accumulation, via HNF-1/Sp1 promoter activation.\",\n      \"evidence\": \"TGT400N mice with phlorizin inhibition, TGα2DN cross, EMSA, and glucose uptake assays\",\n      \"pmids\": [\"20600102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Necessity/sufficiency of SGLT1 not yet genetically proven\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the mutational spectrum to non-CBS domains, with K485E predicted to disrupt a γ–β salt bridge and G100S reducing protein expression and AMPK activity — showing both gain- and loss-of-activity routes to glycogen cardiomyopathy.\",\n      \"evidence\": \"Computational electrostatics for K485E; lentiviral/zebrafish G100S expression with activity and glycogen assays\",\n      \"pmids\": [\"23741347\", \"23778007\", \"23992123\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"K485E salt-bridge disruption awaits in vitro/in vivo functional validation\", \"Reconciling loss-of-activity variants with the dominant gain-of-function model unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that chronic AMPK dysregulation produces myocardial insulin resistance, linking the disease to a broader metabolic defect.\",\n      \"evidence\": \"18F-FDG PET and hyperinsulinemic clamp in R302Q transgenic mice with phospho-AMPK correlates\",\n      \"pmids\": [\"23829931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of insulin unresponsiveness downstream of receptor not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Proved SGLT1 is causally necessary and sufficient downstream of AMPK by bidirectional genetic manipulation and reversibility, validating it as a therapeutic target.\",\n      \"evidence\": \"TGT400N × SGLT1-knockdown crosses and conditional Tet-off SGLT1 overexpression with echocardiography and glycogen readouts\",\n      \"pmids\": [\"25092788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SGLT1-independent residual phenotype not quantified\", \"Transcriptional control in human hearts not directly shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Profiled global metabolic remodeling, showing the mutation shifts transcripts toward glycogen storage/oxidative metabolism and suppresses fibrosis via TGFβ regulation.\",\n      \"evidence\": \"iPSC-cardiomyocyte 3D microtissues with RNA-seq, metabolomics and mouse models\",\n      \"pmids\": [\"28009297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Post-transcriptional TGFβ mechanism not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established direct causality in human cells, with CRISPR correction of R302Q eliminating arrhythmia, glycogen and hypertrophy phenotypes; a novel CBS3 K475E variant linked AMPK activation to mTOR-driven hypertrophy reversible by rapamycin.\",\n      \"evidence\": \"Patient iPSC-CMs with isogenic CRISPR correction and patch-clamp; HEK293/H9c2 K475E assays with rapamycin rescue\",\n      \"pmids\": [\"28917552\", \"28550180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mTOR contribution relative to SGLT1/glycogen axis not weighted\", \"In vivo confirmation of K475E lacking\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Independently confirmed AMPK overactivation as the primary driver in human iPSC-CMs by combining CRISPR correction with small-molecule AMPK inhibition rescue.\",\n      \"evidence\": \"Patient hiPSC-CMs with CRISPR-Cas9 correction, AMPK inhibitors, activity and glycogen assays\",\n      \"pmids\": [\"29452156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific AMPK inhibitor selectivity in vivo not addressed\", \"Effect on arrhythmic substrate formation not modeled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed tissue- and chamber-specific divergence: R302Q downregulates AMPK activity in atrial cardiomyocytes, and additional CBS4 variants reduce activity, complicating the uniform gain-of-function model.\",\n      \"evidence\": \"Human atrial tissue plus HL-1 and hiPSC-atrial CM models; HEK293 CBS4 variant assays; NRCM AKT-mTOR rescue with metoprolol/H89\",\n      \"pmids\": [\"35360035\", \"35787834\", \"35800350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why atrial and ventricular AMPK responses differ is unexplained\", \"Adrenergic/PKA link to AMPK activity mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a non-cardiac role, showing the PRKAG2.2 isoform is IFNβ/FoxA1-induced in FoxA1+ Tregs to drive AMPK-dependent mitophagy via ULK1-BNIP3 for immunosuppressive function.\",\n      \"evidence\": \"IFNβ stimulation, isoform-specific transcript analysis, mitochondrial respiration and mitophagy assays in T cells\",\n      \"pmids\": [\"38117896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific regulation of AMPK not structurally explained\", \"Cardiac versus immune isoform usage not compared\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Characterized the metabolic rewiring of mutant cardiomyocytes toward mitochondrial respiration and lipid storage and showed metformin attenuates respiration and arrhythmia, pointing to a metabolic therapeutic strategy.\",\n      \"evidence\": \"Patient iPSC-CMs and mutant mouse hearts with Seahorse flux, lipidomics, metabolomics and metformin treatment\",\n      \"pmids\": [\"42039356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting AMPK mutation to mitochondrial biogenesis unresolved\", \"Metformin efficacy not validated clinically\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the same mutations produce gain-of-AMPK-activity in ventricular models yet loss-of-activity in atrial tissue and several CBS variants, and how this reconciles with the unified glycogen-storage phenotype.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical model for context-dependent AMPK activity\", \"Structural basis of CBS-domain mutation effects on the holoenzyme incompletely defined\", \"Therapeutic node (AMPK vs SGLT1 vs mTOR vs metabolism) not prioritized in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 8, 22]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 14, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\"AMPK heterotrimeric complex\"],\n    \"partners\": [\"PRKAA2\", \"PRKAB1\", \"ULK1\", \"BNIP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}