Affinage

PRKAG2

5'-AMP-activated protein kinase subunit gamma-2 · UniProt Q9UGJ0

Length
569 aa
Mass
63.1 kDa
Annotated
2026-06-10
82 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 Medium

    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

    PMID:11112354

    Open questions at the time
    • Did not address nucleotide-binding function of individual CBS domains
    • No functional consequence of splice variants tested
  2. 2003 High

    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

    PMID:12782567

    Open questions at the time
    • Overexpression model may not reflect endogenous mutant dosage
    • Molecular driver of glycogen accumulation not yet defined
  3. 2005 High

    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

    PMID:15877279

    Open questions at the time
    • Done in vitro; cardiac cellular context not addressed
    • Did not test which catalytic α subunit mediates the effect
  4. 2005 High

    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

    PMID:16275868

    Open questions at the time
    • Residual α1 contribution not fully excluded
    • Downstream metabolic effectors still unidentified
  5. 2007 Medium

    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

    PMID:17597581

    Open questions at the time
    • Single lab
    • Mechanism of the biphasic activity transition unresolved
  6. 2009 High

    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

    PMID:20031621

    Open questions at the time
    • Transcriptional basis of compensation not defined
    • Glucose entry pathway not yet identified
  7. 2009 Medium

    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

    PMID:19808419

    Open questions at the time
    • Single case histopathology
    • Link between AMPK activity and tract formation mechanistic only by inference
  8. 2009 Medium

    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

    PMID:20005292

    Open questions at the time
    • Single lab
    • Direct AMPK-to-NF-κB link not biochemically mapped
  9. 2010 High

    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

    PMID:20600102

    Open questions at the time
    • Single lab
    • Necessity/sufficiency of SGLT1 not yet genetically proven
  10. 2013 Low

    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

    PMID:23741347 PMID:23778007 PMID:23992123

    Open questions at the time
    • K485E salt-bridge disruption awaits in vitro/in vivo functional validation
    • Reconciling loss-of-activity variants with the dominant gain-of-function model unresolved
  11. 2013 Medium

    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

    PMID:23829931

    Open questions at the time
    • Mechanism of insulin unresponsiveness downstream of receptor not defined
    • Single lab
  12. 2014 High

    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

    PMID:25092788

    Open questions at the time
    • SGLT1-independent residual phenotype not quantified
    • Transcriptional control in human hearts not directly shown
  13. 2016 Medium

    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

    PMID:28009297

    Open questions at the time
    • Post-transcriptional TGFβ mechanism not detailed
    • Single lab
  14. 2017 High

    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

    PMID:28550180 PMID:28917552

    Open questions at the time
    • mTOR contribution relative to SGLT1/glycogen axis not weighted
    • In vivo confirmation of K475E lacking
  15. 2018 High

    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

    PMID:29452156

    Open questions at the time
    • Specific AMPK inhibitor selectivity in vivo not addressed
    • Effect on arrhythmic substrate formation not modeled
  16. 2022 Medium

    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

    PMID:35360035 PMID:35787834 PMID:35800350

    Open questions at the time
    • Why atrial and ventricular AMPK responses differ is unexplained
    • Adrenergic/PKA link to AMPK activity mechanistically incomplete
  17. 2023 Medium

    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

    PMID:38117896

    Open questions at the time
    • Isoform-specific regulation of AMPK not structurally explained
    • Cardiac versus immune isoform usage not compared
  18. 2026 Medium

    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

    PMID:42039356

    Open questions at the time
    • Mechanism connecting AMPK mutation to mitochondrial biogenesis unresolved
    • Metformin efficacy not validated clinically

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 1
Partners
BNIP3PRKAA2PRKAB1ULK1
Complex memberships
AMPK heterotrimeric complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Transgenic mouse overexpression of mutant PRKAG2 N488I; histopathology; electrophysiological testing; cardiac glycogen quantification Circulation High 12782567
2005 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. Biochemical characterization of recombinant R531Q mutant protein; nucleotide binding affinity assays; AMPK activity assays; alpha-subunit phosphorylation measurement American journal of human genetics High 15877279
2005 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. Genetic epistasis using compound-heterozygous transgenic mice (TGgamma2N488I × TGalpha2DN); AMPK activity assays; ECG; cardiac morphology; exercise testing Circulation High 16275868
2009 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. 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 Circulation. Cardiovascular genetics High 20031621
2010 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. 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 of molecular and cellular cardiology High 20600102
2007 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. Transgenic mouse model (TGT400N); AMPK activity assays; ischemia-reperfusion protocol; infarct size measurement; apoptosis assays; genetic cross with TGalpha2DN Biochemical and biophysical research communications Medium 17597581
2009 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. Transgenic mouse model (TGT400N); NF-κB activity assay; nuclear fractionation; phospho-Akt and phospho-p70S6K Western blot; genetic epistasis with TGalpha2DN Biochimica et biophysica acta Medium 20005292
2014 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. Double-transgenic mice (TGT400N × TGSGLT1-DOWN); conditional Tet-off SGLT1 overexpression transgenic mice; echocardiography; cardiac morphometry; glycogen content; hypertrophy marker expression Journal of the American Heart Association High 25092788
2016 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. Human iPSC-derived cardiomyocytes combined with 3D cardiac microtissues; RNA sequencing; metabolomics; TGFβ signaling analysis; mouse models Cell reports Medium 28009297
2013 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. Direct sequencing; computational electrostatic modeling; conservation analysis PloS one Low 23741347
2013 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. Lentiviral transfection of CCL13 cells; Western blot; immunofluorescence localization; ELISA for AMPK activity; PAS staining for glycogen; MTT proliferation assay Journal of cardiology Medium 23778007
2013 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. Zebrafish overexpression model; AMPK kinase activity colorimetric assay; PAS staining for glycogen; cardiac wall thickness measurement Clinical genetics Medium 23992123
2017 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. Patient-derived iPSC-CMs; CRISPR correction generating isogenic lines; patch clamp electrophysiology; microelectrode array; transmission electron microscopy; glycogen quantification Heart rhythm High 28917552
2018 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. Patient-derived hiPSC-CMs; CRISPR-Cas9 genome correction; small molecule AMPK inhibition; AMPK activity assays; glycogen quantification; cell size measurement Journal of molecular and cellular cardiology High 29452156
2017 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. 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 American journal of physiology. Heart and circulatory physiology Medium 28550180
2022 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. In vitro mutagenesis in HEK293 cells; quantitative RT-PCR; immunofluorescence staining; ELISA for AMPK activity; PAS staining for glycogen Archives of biochemistry and biophysics Medium 35787834
2022 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. 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 Frontiers in cardiovascular medicine Medium 35360035
2009 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. Histopathological examination of cardiac tissue from suddenly deceased R302Q mutation carrier; electrophysiological studies in living carriers showing AV node-like bypass properties Circulation. Arrhythmia and electrophysiology Medium 19808419
2013 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. 18F-FDG PET imaging in transgenic R302Q mice; euglycemic hyperinsulinemic clamp; phospho-AMPK alpha Western blot; glycogen quantification; insulin receptor expression EJNMMI research Medium 23829931
2022 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. 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 Cardiovascular diagnosis and therapy Medium 35800350
2023 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. 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 Science advances Medium 38117896
2000 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. cDNA cloning; Northern blot tissue expression analysis; radiation hybrid mapping; genomic organization determination by cDNA-genomic sequence comparison Genomics Medium 11112354
2026 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. iPSC-CMs from WPW/PRKAG2 patient; Seahorse metabolic flux assay; lipidomics; metabolomics; RNA-seq; murine PRKAG2 mutant hearts; metformin pharmacological treatment Frontiers in cardiovascular medicine Medium 42039356

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation 252 12782567
2001 Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Circulation 215 11748095
2005 Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. American journal of human genetics 108 15877279
2016 Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell research 102 27573176
2005 Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation 80 16275868
2010 Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1. Carcinogenesis 79 20622004
2010 SGLT1, a novel cardiac glucose transporter, mediates increased glucose uptake in PRKAG2 cardiomyopathy. Journal of molecular and cellular cardiology 78 20600102
2002 PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy. Current opinion in cardiology 72 12015471
2014 Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice. Journal of the American Heart Association 69 25092788
2010 Clinical, electrocardiographic, and electrophysiologic characteristics of patients with a fasciculoventricular pathway: the role of PRKAG2 mutation. Heart rhythm 69 20888928
2016 Integrative Analysis of PRKAG2 Cardiomyopathy iPS and Microtissue Models Identifies AMPK as a Regulator of Metabolism, Survival, and Fibrosis. Cell reports 66 28009297
2020 Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis. Journal of the American College of Cardiology 65 32646569
2017 CRISPR correction of the PRKAG2 gene mutation in the patient's induced pluripotent stem cell-derived cardiomyocytes eliminates electrophysiological and structural abnormalities. Heart rhythm 51 28917552
2000 Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant gamma2 subunit of 5'-AMP-activated protein kinase, to human chromosome 7q36. Genomics 47 11112354
2003 Glycogen storage disease as a unifying mechanism of disease in the PRKAG2 cardiac syndrome. Biochemical Society transactions 45 12546691
2006 A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis. Neuromuscular disorders : NMD 44 16487706
2015 Cardiovascular magnetic resonance findings in patients with PRKAG2 gene mutations. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance 41 26496977
2017 High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 39 28431061
2007 A PRKAG2 mutation causes biphasic changes in myocardial AMPK activity and does not protect against ischemia. Biochemical and biophysical research communications 32 17597581
2003 Molecular genetic analysis of PRKAG2 in sporadic Wolff-Parkinson-White syndrome. Journal of cardiovascular electrophysiology 32 12716108
2009 Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen. Circulation. Cardiovascular genetics 30 20031621
2013 Identification of a novel de novo mutation associated with PRKAG2 cardiac syndrome and early onset of heart failure. PloS one 27 23741347
2009 Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation. Biochimica et biophysica acta 27 20005292
2008 Nodoventricular accessory pathways in PRKAG2-dependent familial preexcitation syndrome reveal a disorder in cardiac development. Circulation. Arrhythmia and electrophysiology 27 19808419
2006 Ventricular pre-excitation and cardiac hypertrophy mimicking hypertrophic cardiomyopathy in a Turkish family with a novel PRKAG2 mutation. European journal of heart failure 27 16716659
2018 Establishment of a PRKAG2 cardiac syndrome disease model and mechanism study using human induced pluripotent stem cells. Journal of molecular and cellular cardiology 26 29452156
2011 AMPK γ2 subunit gene PRKAG2 polymorphism associated with cognitive impairment as well as diabetes in old age. Psychoneuroendocrinology 26 21813245
2009 Severe hypertrophic cardiomyopathy in an infant with a novel PRKAG2 gene mutation: potential differences between infantile and adult onset presentation. Pediatric cardiology 25 19787389
2018 Cardiac manifestations of PRKAG2 mutation. BMC medical genetics 24 29298659
2013 Identification and functional analysis of a novel PRKAG2 mutation responsible for Chinese PRKAG2 cardiac syndrome reveal an important role of non-CBS domains in regulating the AMPK pathway. Journal of cardiology 21 23778007
2015 PRKAG2 mutation: An easily missed cardiac specific non-lysosomal glycogenosis. Annals of pediatric cardiology 20 26085771
2020 Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort. Scientific reports 19 33244021
2017 A novel, de novo mutation in the PRKAG2 gene: infantile-onset phenotype and the signaling pathway involved. American journal of physiology. Heart and circulatory physiology 19 28550180
2010 High risk of sudden death associated with a PRKAG2-related familial Wolff-Parkinson-White syndrome. Journal of electrocardiology 19 20381067
2009 In vivo assessment of myocardial glucose uptake by positron emission tomography in adults with the PRKAG2 cardiac syndrome. Circulation. Cardiovascular imaging 14 19920047
2017 A novel PRKAG2 mutation in a Chinese family with cardiac hypertrophy and ventricular pre-excitation. Scientific reports 13 28546535
2016 Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation. Molecular genetics and metabolism 12 27692944
2013 Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model. EJNMMI research 10 23829931
2009 A rare connection: fasciculoventricular pathway in PRKAG2 disease. Journal of cardiovascular electrophysiology 10 19732236
2007 A familial form of conduction defect related to a mutation in the PRKAG2 gene. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 10 17483151
2004 Determination of PRKAG1 coding sequence and mapping of PRKAG1 and PRKAG2 relatively to porcine back fat thickness QTL. Animal genetics 9 15025572
2022 Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem cell research 8 35413566
2021 Targeting Antisense lncRNA PRKAG2-AS1, as a Therapeutic Target, Suppresses Malignant Behaviors of Hepatocellular Carcinoma Cells. Frontiers in medicine 8 33928106
2021 A Two-Stage Study Identifies Two Novel Polymorphisms in PRKAG2 Affecting Metformin Response in Chinese Type 2 Diabetes Patients. Pharmacogenomics and personalized medicine 8 34188521
2020 Familial Atrial Enlargement, Conduction Disorder and Symmetric Cardiac Hypertrophy Are Early Signs of PRKAG2 R302Q. Current medical science 8 32681253
2022 Atrial Lesions in a Pedigree With PRKAG2 Cardiomyopathy: Involvement of Disrupted AMP-Activated Protein Kinase Signaling. Frontiers in cardiovascular medicine 7 35360035
2022 Echocardiographic characteristics of PRKAG2 syndrome: a research using three-dimensional speckle tracking echocardiography compared with sarcomeric hypertrophic cardiomyopathy. Cardiovascular ultrasound 7 35509080
2022 AKT-mTOR signaling-mediated rescue of PRKAG2 R302Q mutant-induced familial hypertrophic cardiomyopathy by treatment with β-adrenergic receptor (β-AR) blocker metoprolol. Cardiovascular diagnosis and therapy 7 35800350
2019 A Case Series on Cardiac and Skeletal Involvement in Two Families with PRKAG2 Mutations. Case reports in pediatrics 7 31049239
2017 PRKAG2 mutations presenting in infancy. Journal of inherited metabolic disease 7 28801758
2013 Overexpression of G100S mutation in PRKAG2 causes Wolff-Parkinson-White syndrome in zebrafish. Clinical genetics 7 23992123
2022 Left ventricular non-compaction cardiomyopathy associated with the PRKAG2 mutation. BMC medical genomics 6 36221081
2014 DNA polymorphisms and transcript abundance of PRKAG2 and phosphorylated AMP-activated protein kinase in the rumen are associated with gain and feed intake in beef steers. Animal genetics 6 24730749
2022 Intrafamilial Phenotypical Variability Linked to PRKAG2 Mutation-Family Case Report and Review of the Literature. Life (Basel, Switzerland) 5 36556501
2022 Controversial molecular functions of CBS versus non-CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review. Molecular genetics & genomic medicine 4 35588295
2022 Identification of the pathogenic effects of missense variants causing PRKAG2 cardiomyopathy. Archives of biochemistry and biophysics 4 35787834
2022 Atrial Flutter in PRKAG2 Syndrome: Clinical and Electrophysiological Characteristics. Arquivos brasileiros de cardiologia 4 36102422
2021 Novel PRKAG2 variant presenting as liver cirrhosis: report of a family with 2 cases and review of literature. BMC medical genomics 4 33509202
2019 Patient with a PRKAG2 mutation who developed Immunoglobulin A nephropathy: a case report. European heart journal. Case reports 4 31449595
2024 PRKAG2 -Related Lethal Congenital Glycogen Storage Disease of the Heart as Rare Cause of Fetal Hydrops With Bradycardia and Cardiomyopathy: Clinical Report and Literature Review. American journal of medical genetics. Part A 3 39215506
2015 Novel polymorphisms of the PRKAG2 gene and their association with body measurement and meat quality traits in Qinchuan cattle. Genetics and molecular research : GMR 3 25966135
2009 Identification of two novel variants in PRKAG2 gene in Tunisian type 2 diabetic patients with family history of cardiovascular disease. Diabetes research and clinical practice 3 20022652
2025 Genome-Wide Association Study of Age-Related Hearing Loss in CFW Mice Identifies Multiple Genes and Loci, Including Prkag2. Journal of the Association for Research in Otolaryngology : JARO 2 40399499
2024 PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders. Einstein (Sao Paulo, Brazil) 2 39082507
2023 Abnormal expression of PRKAG2-AS results in dysfunction of cardiomyocytes through regulating PRKAG2 transcription by interacting with PPARG. Clinical epigenetics 2 37932845
2023 PRKAG2.2 is essential for FoxA1+ regulatory T cell differentiation and metabolic rewiring distinct from FoxP3+ regulatory T cells. Science advances 2 38117896
2020 Cardiac MR manifestations in two cases of PRKAG2 mutations in a Chinese family. The international journal of cardiovascular imaging 2 32314121
2019 Novel PRKAG2 Variant Manifesting with a Cardiac Arrest in a Child. Pediatric cardiology 2 31720784
2026 PRKAG2 Cardiomyopathy: A Case-Control Study on the Diagnostic Yield Of Histopathology and Ultrastructural Analysis from Endomyocardial Biopsy. Arquivos brasileiros de cardiologia 1 41849454
2025 Identifying PRKAG2 syndrome-a rare cause of wolff-Parkinson-white syndrome and left ventricular hypertrophy: a case report. European heart journal. Case reports 1 40671717
2024 Abnormal expression of PRKAG2-AS1 in endothelial cells induced inflammation and apoptosis by reducing PRKAG2 expression. Non-coding RNA research 1 38511052
2024 Fasciculoventricular accessory pathway masked extensive atrioventricular conduction system disease in a patient with PRKAG2 syndrome. Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc 1 38937983
2024 When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review. International journal of molecular sciences 1 39273120
2026 Radiofrequency ablation of atrial flutter with 1:1 accessory pathway conduction improved cardiac function in a patent with PRKAG2 Cardiomyopathy. Insights with 68Ga-FAPI PET/CT imaging. The international journal of cardiovascular imaging 0 41989697
2026 Bioenergetic and metabolic aberrations in induced pluripotent stem cell-derived cardiomyocytes generated from a patient with Wolff-Parkinson-White syndrome caused a PRKAG2 mutation. Frontiers in cardiovascular medicine 0 42039356
2026 Generation of gene-corrected human isogenic iPSC lines from hypertrophic cardiomyopathy patients harboring PRKAG2 mutation (c.2084A>G, p.His530Arg) using prime editing. Stem cell research 0 42096740
2025 A South Asian Indian PRKAG2 patient-derived induced pluripotent stem cell (iPSC) line to model glycogen storage-associated hypertrophic cardiomyopathy. Stem cell research 0 40516147
2025 Temporal dysregulation of PPARG-PRKAG2 co-expression in gray matter: Implications for cognitive decline and intervention targets in type 2 diabetes. Research square 0 41282094
2024 Severe Hypertrophic Cardiomyopathy Caused by a Protein Kinase Adenosine Monophosphate-Activated Non-catalytic Subunit Gamma 2 (PRKAG2) Mutation With Refractory Chylous Effusions in a Neonate: A Case Report and Literature Review. Cureus 0 39569283
2024 PRKAG2 Variant, Motor Neuron Disease, and Parkinsonism: Fortuitous Association or a Potentially Underestimated Pathophysiological Mechanism? Muscles (Basel, Switzerland) 0 40757593
2007 [Same genotype and different phenotypes in a family with PRKAG2 gene mutation]. Zhonghua xin xue guan bing za zhi 0 17711718
2007 [A familial form of conduction defects associated with a PRKAG2 gene mutation]. Archives des maladies du coeur et des vaisseaux 0 18033003

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