Affinage

GNAS

Protein ALEX · UniProt P84996

Length
626 aa
Mass
67.9 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 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

GNAS is a complex imprinted locus that produces multiple, oppositely imprinted gene products from alternative first exons within a single transcription unit, including the signaling protein Gsα, the paternally expressed XLαs, the maternally expressed neuroendocrine protein NESP55, and the paternally expressed antisense macroRNA Nespas (PMID:10097123). Gsα couples seven-transmembrane receptors to adenylyl cyclase to generate cAMP through a GTPase cycle; somatic activating mutations at R201 and Q227 impair GTP hydrolysis to cause constitutive cAMP elevation in fibrous dysplasia, McCune-Albright syndrome, and endocrine tumors, while inactivating mutations produce Albright hereditary osteodystrophy with hormone resistance restricted to maternal inheritance owing to tissue-specific maternal-predominant Gsα expression (PMID:15331575). Beyond canonical cAMP output, oncogenic Gsα signaling engages Wnt/β-catenin (via Lrp6) in fibrous dysplasia and colorectal cancer, modulates BMP-Smad-dependent osteoblast versus adipocyte fate, and a splicing-driven long isoform (Gsα-L) additionally activates ERK/MAPK signaling (PMID:29158412, PMID:22903279, PMID:34620690, PMID:35879396). Gsα-dependent cAMP is required for β-cell insulin secretion and for melanocortin-4 receptor signaling, and receptor-selective signaling defects underlie GNAS-associated obesity (PMID:34614324, PMID:31374326). The locus also exerts antagonistic metabolic control: Gsα and the paternal XLαs product have opposite effects on energy and glucose homeostasis (PMID:15883378, PMID:23822972). NESP55 is a chromogranin-like acidic protein of neuroendocrine dense-core secretory granules, processed to bioactive peptides and functionally linked to noradrenergic and serotonergic neuronal systems and behavior (PMID:9111083, PMID:15798190). Imprinting across the cluster is governed hierarchically by germline differentially methylated regions—the Nespas/Nesp DMRs act as principal imprinting control regions, with the antisense Nespas transcript silencing Nesp in cis through histone modification that can precede and is separable from DNA methylation (PMID:16462745, PMID:20427744, PMID:21455290).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Established that the GNAS locus encodes more than Gsα by characterizing NESP55 as a neuroendocrine secretory protein, expanding the locus beyond a single signaling product.

    Evidence Molecular cloning, immunoblot, and gel electrophoresis of chromaffin granule secretory proteins

    PMID:9111083

    Open questions at the time
    • Physiological role of NESP55-derived peptides in vivo not established
    • Relationship to Gsα-encoding transcripts not yet defined at this stage
  2. 1999 High

    Revealed that the locus is a single transcription unit producing oppositely imprinted transcripts, defining GNAS as a reciprocally imprinted cluster rather than a simple gene.

    Evidence Representational difference analysis, RT-PCR, and Northern blot in interspecific mouse crosses; plus cell-type-specific NESP55 localization in adrenergic chromaffin cells

    PMID:10097123 PMID:10218899

    Open questions at the time
    • Mechanism enforcing parent-of-origin methylation not addressed
    • Functional consequences of each isoform not yet tested
  3. 2000 High

    Identified the paternal antisense Nespas transcript and allele-specific epigenetic features, pointing to a cis-regulatory architecture controlling imprinting.

    Evidence Strand-specific RT-PCR and Northern blot in uniparental disomy embryos; tissue-specific NESP55 splicing and PTM analysis

    PMID:10716699 PMID:10729789

    Open questions at the time
    • Causal role of Nespas in silencing not yet demonstrated by perturbation
    • Hierarchy among DMRs unknown
  4. 2003 High

    Mapped allele-specific methylation and DNase I hypersensitivity to germline marks over Nespas/Gnasxl, separating their control from the Gnas promoter.

    Evidence Bisulfite sequencing and DNase I hypersensitivity across gametes, ES cells, and tissues

    PMID:12897124

    Open questions at the time
    • Which DMR is the principal control region not resolved
    • Mechanism linking methylation to expression switching not shown
  5. 2004 High

    Defined the enzymatic basis of disease by showing R201/Q227 mutations impair GTPase turn-off to cause constitutive cAMP, unifying activating and inactivating phenotypes with imprinting.

    Evidence Biochemical GTPase assays, genetic analysis, and mouse knockout models

    PMID:15331575

    Open questions at the time
    • Tissue-specific effectors downstream of cAMP not enumerated
    • Non-cAMP effector branches not yet identified
  6. 2005 High

    Demonstrated that Gsα and XLαs exert opposite effects on energy and glucose metabolism, dissociating metabolic phenotypes from a single gene product.

    Evidence Allele-specific Gnas exon deletions in mice with metabolic phenotyping; Nesp55 knockout with behavioral assays

    PMID:15798190 PMID:15883378

    Open questions at the time
    • Molecular basis of XLαs antagonism of Gsα not defined
    • Neural circuit mediating Nesp55 behavioral phenotype unresolved
  7. 2006 High

    Identified the Nespas DMR as the principal bidirectional imprinting control region governing the entire cluster, establishing locus-wide hierarchical control.

    Evidence Paternal targeted DMR deletion in mice with allele-specific expression and methylation analysis

    PMID:16462745

    Open questions at the time
    • Molecular mechanism of bidirectional switching not detailed
    • Role of antisense transcription versus the DNA element itself not separated
  8. 2010 High

    Established a second principal ICR (Nesp55 DMR) directing maternal Gnas methylation and downstream calcium/phosphate homeostasis, refining the imprinting hierarchy.

    Evidence Maternal-allele deletion mouse model with methylation, RT-PCR, and serum biochemistry

    PMID:20427744

    Open questions at the time
    • Interaction between the two principal ICRs not mapped
    • Human relevance of mouse DMR hierarchy not directly tested here
  9. 2011 High

    Separated chromatin-based silencing from DNA methylation by showing Nespas silences Nesp via histone modification independent of and preceding DNA methylation.

    Evidence Nespas hypomorph knock-in with ChIP for histone marks, bisulfite analysis, and allele-specific RT-PCR

    PMID:21455290

    Open questions at the time
    • Histone-modifying machinery recruited by Nespas not identified
    • Order of events in human cells not established
  10. 2012 Medium

    Linked cAMP level to cell-fate decisions by showing elevated cAMP inhibits osteoblast differentiation and enhances adipogenesis via BMP-Smad blockade, connecting GNAS signaling to bone disease mechanism.

    Evidence Pluripotent mouse ES cell osteogenic differentiation with pharmacological cAMP modulation and BMP-Smad readouts

    PMID:22903279

    Open questions at the time
    • In vitro pharmacological model; in vivo relevance to fibrous dysplasia not tested here
    • Single lab
  11. 2013 High

    Used gene-dosage genetics to formally demonstrate antagonistic Gsα/XLαs actions across tissues, separating edema from the full lethal phenotype.

    Evidence Targeted mutations combined with uniparental disomy and metabolic/behavioral phenotyping

    PMID:23822972

    Open questions at the time
    • Tissue-specific molecular targets of XLαs not identified
    • Mechanism of dose-dependent phenotype combination unresolved
  12. 2015 Medium

    Showed that Nespas transcription is necessary and sufficient for Nesp DMR methylation and that transcription can drive somatic de novo CpG methylation, defining a transcription-coupled methylation mechanism.

    Evidence Truncating and ectopic-transcription knock-in mouse alleles with bisulfite and allele-specific RT-PCR

    PMID:25659103 PMID:29861426

    Open questions at the time
    • Methyltransferase complex coupling transcription to methylation not identified
    • Single-lab genetic models
  13. 2017 High

    Demonstrated in vivo that activating GNAS R201H drives fibrous dysplasia through Wnt/β-catenin via Lrp6, providing a genetically validated effector branch and rescue target.

    Evidence Conditional knock-in mouse with histology, Western blot, and Lrp6 heterozygosity rescue

    PMID:29158412

    Open questions at the time
    • Direct molecular link from cAMP/PKA to Wnt activation not fully defined
    • Generality across other GNAS-driven tissues not tested here
  14. 2019 Medium

    Expanded GNAS signaling to context-specific tumor behavior and β-cell function, showing PKA-dependent NOTCH regulation in pancreatic cancer and cAMP-dependent insulin secretion.

    Evidence CRISPR R201H manipulation with xenografts and NICD analysis; siRNA knockdown in INS-1 β-cells with secretion and transcription factor readouts

    PMID:31374326 PMID:35018527

    Open questions at the time
    • Single-lab models for each context
    • Direct PKA-NOTCH and PKA-β-cell transcription factor links not biochemically reconstituted
  15. 2021 High

    Explained clinical heterogeneity of GNAS-associated obesity by showing mutations differentially impair MC4R, GHRHR, and TSHR signaling, linking receptor-selective cAMP defects to phenotype.

    Evidence Exome sequencing with receptor-specific cAMP signaling assays and genotype-phenotype correlation in a patient cohort

    PMID:34614324

    Open questions at the time
    • Structural basis for receptor-selective coupling defects not resolved
    • Tissue-level integration of multiple receptor defects not modeled
  16. 2022 High

    Revealed non-cAMP and isoform-specific oncogenic mechanisms: splicing-driven Gsα-L activates ERK/MAPK, and R201 mutations drive β-catenin in colorectal cancer with oncogene addiction.

    Evidence RNA-seq/eCLIP in isogenic iPSC-derived HSPCs with biochemical assays and MEK inhibitor sensitivity; CRISPR GNAS knockout in CRC with organoid/xenograft and PKA/β-catenin inhibition

    PMID:34620690 PMID:35879396

    Open questions at the time
    • Switch determining cAMP versus ERK output not defined
    • Relative contribution of Wnt versus PKA in CRC growth not separated
  17. 2023 High

    Defined human imprinting architecture by showing the NESP-ICR controls A/B silencing and the STX16-ICR acts as a pluripotency-factor-dependent long-range enhancer of NESP55, and identified GPR176 as an intracellular Gsα-recruiting receptor controlling mitophagy.

    Evidence CRISPR ICR deletions in hESCs with allele-specific methylation/expression and ChIP; Co-IP and domain modeling with cAMP/mitophagy assays and CRC mouse models

    PMID:36853809 PMID:36905238

    Open questions at the time
    • Conservation of STX16-ICR enhancer mechanism in non-embryonic tissues unclear
    • GPR176/GNAS interaction validated by single-lab Co-IP and modeling
  18. 2024 Medium

    Connected GNAS protein stability to chemoresistance by showing a PRKDC-GDE2 axis stabilizes GNAS to drive AKT activation and doxorubicin resistance in osteosarcoma.

    Evidence CRISPR kinome screen, Co-IP of PRKDC/GDE2/GNAS, stability assays, xenografts, and organoids

    PMID:38900943

    Open questions at the time
    • Mechanism by which PRKDC/GDE2 stabilizes GNAS not defined
    • Single lab; interaction not reciprocally validated across systems

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Gsα output is partitioned between cAMP/PKA, Wnt/β-catenin, and ERK/MAPK branches across tissues, and how the imprinting hierarchy and isoform antagonism are integrated into human disease, remains incompletely resolved.
  • No unified model linking receptor identity to effector branch selection
  • Molecular machinery coupling Nespas transcription to methylation not identified
  • Mechanistic basis of Gsα/XLαs metabolic antagonism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2 GO:0003924 GTPase activity 1
Localization
GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2
Partners
GDE2GPR176LRP6PRKDC

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 The Gnas locus encodes multiple oppositely imprinted transcripts (Gnasxl, Nesp/NESP55, and Gnas) within a single transcription unit; Gnasxl and Nesp transcripts are alternatively spliced onto exon 2 of Gnas. Gnasxl is maternally methylated and paternally expressed, whereas Nesp is paternally methylated and maternally expressed. Representational difference analysis based on parent-of-origin methylation differences; RT-PCR and Northern blot in interspecific mouse crosses Proceedings of the National Academy of Sciences of the United States of America High 10097123
1997 NESP55 (encoded by the GNAS locus, maternally expressed) is a chromogranin-like acidic protein localized to large dense-core secretory vesicles in neuroendocrine tissues; it is proteolytically processed within chromaffin granules to smaller peptides, including the tetrapeptide LSAL (flanked by prohormone convertase cleavage sites), which acts as an endogenous 5-HT1B receptor antagonist. Molecular cloning; immunoblot; immunofluorescence; 1D/2D gel electrophoresis of secretory proteins from chromaffin granules The Journal of biological chemistry High 9111083
2000 A paternal-allele-specific antisense transcript (Nespas/Gnas-as) originates ~2.2 kb upstream of the Gnasxl promoter and spans the Nesp region; it is expressed exclusively from the paternal allele in most tissues, suggesting a cis-regulatory role in imprinting of the Nesp sense transcript. Strand-specific RT-PCR; Northern blot analysis in embryos carrying uniparental disomy for distal Chr 2 Proceedings of the National Academy of Sciences of the United States of America High 10716699
2000 NESP55 mRNA is alternatively spliced in a tissue-specific manner onto Gsα exons 2–13 (adrenal, pituitary, brain) or onto exons 2, 3, N1 (pituitary); the protein is posttranslationally modified by keratan sulfate glycosaminoglycan addition and differentially processed by endopeptidases in various tissues. cDNA cloning, RT-PCR, Northern blot, protein sequencing Neuroendocrinology Medium 10729789
2002 NESP55 undergoes fast anterograde axonal transport in peripheral neurons and is slowly proteolytically processed to smaller peptides (including GAIPIRRH) during transport; it is not retrogradely transported and is absent from terminal regions. Crush-operated sciatic nerve experiments; immunohistochemistry; HPLC-radioimmunoassay Neuroscience Medium 11934480
2003 The Nesp and Gnasxl promoter regions are embedded in extensive CpG islands with allele-specific methylation (paternal methylation at Nesp; maternal methylation at Gnasxl). Parental allele-specific DNase I-hypersensitive sites correlate with the hypomethylated (active) allele. A germline methylation mark covering Gnasxl and Nespas promoters was identified, suggesting separate control from the Gnas promoter. Bisulfite sequencing; DNase I hypersensitivity assay in gametes, ES cells, and tissues Molecular and cellular biology High 12897124
2004 Gsα (encoded by GNAS) couples seven-transmembrane receptors to adenylyl cyclase to generate cAMP. Somatic activating mutations at residues R201 and Q227 (which impair the GTPase turn-off reaction) cause constitutive adenylyl cyclase activation, found in endocrine tumors, fibrous dysplasia, and McCune-Albright syndrome. Heterozygous inactivating mutations cause Albright hereditary osteodystrophy, with hormone resistance only on maternal inheritance due to tissue-specific maternal-allele-predominant expression. Biochemical characterization of GTPase activity; genetic analysis; mouse knockout models Endocrinology High 15331575
2005 Gsα deficiency from maternal allele (via exon 1 deletion) causes obesity and insulin resistance, phenotypically distinct from paternal exon 2 deletion. The lean, hypermetabolic, insulin-sensitive phenotype of paternal exon 2 deletion mice results from XLαs (Gnasxl product) deficiency, not Gsα loss. Thus, Gsα and XLαs have opposite effects on energy/glucose metabolism. Targeted gene deletion of Gnas exon 1 in mice; metabolic phenotyping; comparison with exon 2 mutants Proceedings of the National Academy of Sciences of the United States of America High 15883378
2005 Knockout of Nesp55 in mice produces no metabolic or developmental defect but causes abnormal reactivity to novel environments (hyperreactivity in three behavioral tasks) independent of general locomotion and anxiety, associated with prominent Nesp55 expression in the noradrenergic locus coeruleus. Gene targeting knockout; behavioral assays (open field, elevated plus maze, light-dark box) Molecular and cellular biology High 15798190
2006 A paternally derived targeted deletion of the germline differentially methylated region (DMR) associated with the antisense Nespas transcript (Nespas DMR) unexpectedly abolishes expression of all transcripts in the Gnas cluster and methylation of two downstream DMRs, establishing the Nespas DMR as the principal imprinting control region (ICR) that acts bidirectionally to switch expression between Gnasxl and Gnas. Targeted deletion in mice; allele-specific RT-PCR; bisulfite methylation analysis Nature genetics High 16462745
2010 Targeted deletion of the region equivalent to the NESP55 DMR (delNesp55) on the maternal allele causes loss of all maternal Gnas methylation imprints; in kidney this leads to increased 1A transcription, decreased Gsα mRNA, and hypocalcemia/hyperphosphatemia/secondary hyperparathyroidism, establishing the Nesp55 DMR as an additional principal ICR directing Gnas methylation. Mouse knock-in/deletion model; bisulfite methylation analysis; quantitative RT-PCR; serum calcium/phosphate measurements Proceedings of the National Academy of Sciences of the United States of America High 20427744
2011 The paternally expressed macroRNA Nespas silences Nesp in cis via chromatin modification (reduced H3K4me3 demethylation and H3K36me3 depletion at the Nesp promoter), independent of DNA methylation, demonstrating that Nespas-mediated silencing can precede and is mechanistically separable from somatic DNA methylation. Nespas hypomorph knock-in allele; ChIP for histone modifications; bisulfite methylation analysis; allele-specific RT-PCR PLoS genetics High 21455290
2015 Nespas transcript/transcription across the ~2.6 kb region encompassing the Nesp promoter is necessary and sufficient for DNA methylation of the Nesp DMR; higher levels of Nespas are required for methylation than for transcriptional downregulation of Nesp. Nespas is strictly cis-acting even at supraphysiological levels. Knock-in alleles truncating Nespas upstream and downstream of Nesp promoter; bisulfite methylation; allele-specific RT-PCR Non-coding RNA Medium 29861426
2015 On the paternal allele, ectopic transcription of Nesp traversing the intragenic Exon1A DMR causes somatic de novo methylation of that DMR and de-repression of Gnas, demonstrating that transcription-driven de novo CpG methylation of an intragenic island can occur in somatic (non-germline) tissues. Mutant mouse models with ectopic Nesp expression on paternal allele; bisulfite methylation; allele-specific RT-PCR; phenotypic analysis PloS one Medium 25659103
2013 Gene dosage analysis in PatDp(dist2) mice shows that oedema is caused by loss of imprinted Gnas expression alone, while the full hyperactive/chunky/lethal phenotype requires combination of double-dose Gnasxl and absent imprinted Gnas, demonstrating antagonistic actions of Gsα and XLαs in multiple tissues including glucose homeostasis. Targeted mutations combined with uniparental disomy; metabolic/behavioral phenotyping; glucose measurements PloS one High 23822972
2017 Conditional knock-in of the activating GNAS R201H (fibrous dysplasia) mutation in osteochondral progenitors, osteoblasts, or bone marrow stromal cells (BMSCs) causes fibrous dysplasia features; the mechanism involves up-regulation of Wnt/β-catenin signaling, and removal of one Lrp6 copy significantly rescues the phenotype. Conditional knock-in mouse model; histology; Western blot; genetic rescue (Lrp6 heterozygosity) Proceedings of the National Academy of Sciences of the United States of America High 29158412
2012 At early stages of osteogenesis, increased cAMP signaling (mimicking activating GNAS mutation as in fibrous dysplasia) inhibits osteoblast differentiation and enhances adipogenesis partly by blocking BMP-Smad pathway signaling; inhibition of cAMP (as in inactivating GNAS mutations/POH) enhances osteoblast differentiation by stimulating BMP signaling. Pluripotent mouse ES cell osteogenic differentiation assay; pharmacological cAMP modulation (forskolin, 2',5'-dideoxyadenosine); BMP-Smad pathway readouts Hormone and metabolic research Medium 22903279
2021 GNAS mutations that cause obesity differentially impair MC4R (melanocortin 4 receptor) signaling, growth hormone-releasing hormone receptor signaling, and thyrotropin receptor signaling, explaining clinical heterogeneity; the obesity phenotype is mechanistically linked to defective MC4R/Gsα-mediated cAMP generation. Exome sequencing; functional GPCR signaling assays (cAMP production) for each mutation; clinical correlation with receptor-specific signaling The New England journal of medicine High 34614324
2022 Splicing factor mutations (U2AF1 and SRSF2) in MDS promote a long isoform of GNAS (GNAS-L) that encodes a hyperactive Gαs-L protein. GNAS-L activates ERK/MAPK signaling (not only cAMP), and MDS cells with SF mutations are sensitive to MEK inhibitors. RNA-seq; eCLIP in isogenic iPSC-derived hematopoietic stem/progenitor cells; biochemical cAMP/ERK assays; MEK inhibitor sensitivity assays Cancer discovery High 34620690
2023 The NESP55 imprinting control region (NESP-ICR) is required for DNA methylation and transcriptional silencing of the GNAS A/B region on the maternal allele; the STX16-ICR acts as a long-range enhancer of NESP55 transcription from the maternal allele, and this enhancer activity is enabled by direct binding of pluripotency factors in an embryonic stage-specific manner. CRISPR/Cas9 ICR deletions in human embryonic stem cells; allele-specific methylation and expression analysis; chromatin immunoprecipitation for pluripotency factor binding The Journal of clinical investigation High 36853809
2023 GPR176 recruits GNAS intracellularly via its transmembrane helix 3-intracellular loop 2 domain; the GPR176/GNAS complex activates cAMP/PKA signaling and inhibits mitophagy through the cAMP/PKA/BNIP3L axis in colorectal cancer cells. Co-immunoprecipitation; homology modeling; cAMP measurements; mitophagy assays; genetic mouse models of CRC with Gpr176-deficiency Advanced science Medium 36905238
2016 Nesp55 protein is co-localized with serotonin in midbrain neurons; mice lacking Nesp55 show impulsive choice behavior and reduced mRNA expression of serotonergic genes (Tph2, Slc6a4) in midbrain regions, implicating Nesp55 in regulation of the serotonin system and impulse control. Nesp55 knockout mouse (Nespm/+); delayed reinforcement task; stop-signal reaction time task; immunofluorescence co-localization; qPCR Genes, brain, and behavior Medium 27509352
2022 Oncogenic GNAS R201C/H mutations drive cAMP/PKA signaling and activate β-catenin phosphorylation and Wnt/β-catenin target genes in colorectal cancer cells; GNAS knockout reduces tumor growth in peritoneal models, and chemical inhibition of PKA or β-catenin reduces organoid growth, demonstrating oncogene addiction. CRISPR/Cas9 GNAS knockout in CRC cell lines; 2D/3D organoid growth assays; xenograft mouse models; cAMP measurements; molecular profiling (western blot, PKA/β-catenin inhibitors) Oncogene Medium 35879396
2019 Mutant GNAS R201H in IPMN-associated pancreatic cancer cells promotes mucin production (MUC2, MUC5AC/B) and limits tumor aggressiveness by negatively regulating NOTCH signaling via the GNAS-PKA pathway; PKA inhibition induces NOTCH intracellular domain (NICD) in GNAS-mutant cells, while GNAS wild-type cells show higher NICD levels and invasive capacity. CRISPR/Cas9 GNAS R201H silencing; xenograft experiments; western blot; transcriptome analysis; nuclear fractionation for NICD; PKA inhibitor treatment Journal of gastroenterology Medium 35018527
2020 GNAS knockdown in HCC cells inhibits LPS-induced IL-6 expression by suppressing STAT3 activation; mechanistically, GNAS promotes STAT3 activation by inhibiting the long non-coding RNA TPTEP1 which interacts with STAT3. LPS stimulation increases GNAS expression through increased m6A methylation of GNAS mRNA. siRNA knockdown; ELISA; RNA-binding protein immunoprecipitation (RIP) for m6A; transcription factor profiling array; subcutaneous xenograft mouse model Cellular & molecular biology letters Low 32123532
2024 PRKDC recruits and binds GDE2 to enhance the stability of GNAS protein; elevated GNAS subsequently activates AKT phosphorylation and confers doxorubicin resistance in osteosarcoma. Combined PRKDC inhibition (AZD7648) and doxorubicin synergistically suppresses osteosarcoma growth. CRISPR kinome screen; Co-IP of PRKDC/GDE2/GNAS; protein stability assays; xenograft mouse models; human organoids Cancer research Medium 38900943
1999 NESP55 is preferentially localized in adrenaline-synthesizing (adrenergic) chromaffin cells of the adrenal medulla, co-localizing with phenylethanolamine-N-methyltransferase; noradrenergic cells contain ~5-fold lower levels. NESP55 mRNA distribution mirrors preproenkephalin mRNA, restricted to adrenergic cells. Immunohistochemistry of consecutive sections; radioimmunoassay; in situ hybridization Neuroscience letters Medium 10218899
2002 The Oed-Sml ENU point mutation (V159E in Gnas exon 6) causes opposite parent-of-origin phenotypes: maternally transmitted mutation (via Gnas/Gsα) causes microcardia with gross edema, while paternally transmitted mutation (via Gnasxl) causes postnatal growth retardation, revealing distinct roles for Gsα in cardiac growth and XLαs in postnatal body growth. ENU mutagenesis; genetic mapping; sequencing of point mutation; uniparental transmission phenotyping Genomics Medium 12376090
2019 GNAS knockdown in INS-1 β-cells reduces insulin secretion, insulin content, and cAMP production; expression of Insulin, PDX1, and MAFA is significantly downregulated, demonstrating that Gsα/cAMP signaling is required for normal β-cell insulin secretory capacity. siRNA knockdown in INS-1 cells; insulin secretion assay; cAMP measurement; RT-PCR for β-cell transcription factors Gene Medium 31374326

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Development and characterization of novel erythropoiesis stimulating protein (NESP). British journal of cancer 401 11308268
2004 Minireview: GNAS: normal and abnormal functions. Endocrinology 242 15331575
1999 A cluster of oppositely imprinted transcripts at the Gnas locus in the distal imprinting region of mouse chromosome 2. Proceedings of the National Academy of Sciences of the United States of America 215 10097123
2001 Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 190 11402085
1997 Molecular cloning and characterization of NESP55, a novel chromogranin-like precursor of a peptide with 5-HT1B receptor antagonist activity. The Journal of biological chemistry 172 9111083
2014 Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clinical cancer research : an official journal of the American Association for Cancer Research 164 24938521
2006 Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nature genetics 163 16462745
2005 Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proceedings of the National Academy of Sciences of the United States of America 151 15883378
2015 GNAS Spectrum of Disorders. Current osteoporosis reports 138 25851935
2005 GNAS locus and pseudohypoparathyroidism. Hormone research 132 15711092
2000 An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proceedings of the National Academy of Sciences of the United States of America 131 10716699
2009 Immunohistochemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinal carcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors. The American journal of surgical pathology 125 19065104
2005 Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). The Journal of biological chemistry 111 16286456
2013 KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer 103 23335286
2005 Imprinted Nesp55 influences behavioral reactivity to novel environments. Molecular and cellular biology 100 15798190
2003 Epigenetic properties and identification of an imprint mark in the Nesp-Gnasxl domain of the mouse Gnas imprinted locus. Molecular and cellular biology 95 12897124
2014 GNAS mutations in Pseudohypoparathyroidism type 1a and related disorders. Human mutation 94 25219572
2008 Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. The Journal of endocrinology 90 18252944
2002 The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of the recombinant drugs rhEpo and NESP. European journal of haematology 88 12460230
2016 KRAS, GNAS, and RNF43 mutations in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. SpringerPlus 83 27512631
2011 Uncoupling antisense-mediated silencing and DNA methylation in the imprinted Gnas cluster. PLoS genetics 76 21455290
2008 The GNAS locus and pseudohypoparathyroidism. Advances in experimental medicine and biology 76 18372789
2001 An overview of the efficacy and safety of novel erythropoiesis stimulating protein (NESP). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 76 11402086
2019 GNAS-AS1/miR-4319/NECAB3 axis promotes migration and invasion of non-small cell lung cancer cells by altering macrophage polarization. Functional & integrative genomics 75 31267263
2012 A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib. The Journal of clinical endocrinology and metabolism 75 22378814
2021 Obesity-Associated GNAS Mutations and the Melanocortin Pathway. The New England journal of medicine 70 34614324
2020 GNAS promotes inflammation-related hepatocellular carcinoma progression by promoting STAT3 activation. Cellular & molecular biology letters 70 32123532
2009 The role of GNAS and other imprinted genes in the development of obesity. International journal of obesity (2005) 70 19844212
2007 Studies of the regulation and function of the Gs alpha gene Gnas using gene targeting technology. Pharmacology & therapeutics 65 17588669
2013 The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Hormone research in paediatrics 62 24107509
2005 Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties. European journal of human genetics : EJHG 62 15915160
2000 Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus. Genomics 60 11056047
2001 Novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia of chronic disease associated with cancer. British journal of cancer 59 11308271
2019 Elevated expression of GNAS promotes breast cancer cell proliferation and migration via the PI3K/AKT/Snail1/E-cadherin axis. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 58 30767161
2017 Induced Gnas expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling. Proceedings of the National Academy of Sciences of the United States of America 58 29158412
2010 Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells. Journal of molecular endocrinology 58 20841428
2015 Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum. British journal of cancer 55 25867268
2001 Pharmacokinetics of novel erythropoiesis stimulating protein (NESP) in cancer patients: preliminary report. British journal of cancer 55 11308269
2023 GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 54 36905238
2010 Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus. American journal of medical genetics. Part C, Seminars in medical genetics 53 20803660
2001 A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy. British journal of cancer 52 11308270
2022 Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms. Cancer discovery 50 34620690
2010 Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib. Proceedings of the National Academy of Sciences of the United States of America 50 20427744
2012 Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 48 22903279
2007 The GNAS Locus: Quintessential Complex Gene Encoding Gsalpha, XLalphas, and other Imprinted Transcripts. Current genomics 48 19412439
1997 Expression of gpsA encoding biosynthetic sn-glycerol 3-phosphate dehydrogenase suppresses both the LB- phenotype of a secB null mutant and the cold-sensitive phenotype of a secG null mutant. Molecular microbiology 47 9426138
2015 DNA methylation in imprinted genes IGF2 and GNASXL is associated with prenatal maternal stress. Genes, brain, and behavior 46 26333472
2018 GNAS, GNAQ, and GNA11 alterations in patients with diverse cancers. Cancer 43 30204251
2017 GNAS mutations in primary mucinous and non-mucinous lung adenocarcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 43 28776576
2002 The imprinted oedematous-small mutation on mouse chromosome 2 identifies new roles for Gnas and Gnasxl in development. Genomics 43 12376090
2007 Control of imprinting at the Gnas cluster. Epigenetics 39 18094621
2019 hsa_circRNA_100533 regulates GNAS by sponging hsa_miR_933 to prevent oral squamous cell carcinoma. Journal of cellular biochemistry 38 31297884
2013 GNAS -Related Loss-of-Function Disorders and the Role of Imprinting. Hormone research in paediatrics 37 23548772
2015 GNAS mutations are not detected in parosteal and low-grade central osteosarcomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 36 26248895
2019 Hypermethylator Phenotype and Ectopic GIP Receptor in GNAS Mutation-Negative Somatotropinomas. The Journal of clinical endocrinology and metabolism 34 30376114
2017 Mechanical stress affects methylation pattern of GNAS isoforms and osteogenic differentiation of hAT-MSCs. Biochimica et biophysica acta. Molecular cell research 33 28483487
1999 Relative amounts and molecular forms of NESP55 in various bovine tissues. Brain research 33 10350534
2017 GNAS mutations and heterotopic ossification. Bone 32 28889026
2004 Neuroendocrine secretory protein-55 (NESP-55) expression discriminates pancreatic endocrine tumors and pheochromocytomas from gastrointestinal and pulmonary carcinoids. The American journal of surgical pathology 31 15371954
2003 NESP55, a novel chromogranin-like peptide, is expressed in endocrine tumours of the pancreas and adrenal medulla but not in ileal carcinoids. British journal of cancer 31 12771991
2000 Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein. Neuroendocrinology 31 10729789
2020 GNAS mutation detection in circulating cell-free DNA is a specific predictor for intraductal papillary mucinous neoplasms of the pancreas, especially for intestinal subtype. Scientific reports 30 33082481
2010 GNAS imprinting and pituitary tumors. Molecular and cellular endocrinology 30 20398730
2005 Capillary electrophoresis and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry for analysis of the novel erythropoiesis-stimulating protein (NESP). Electrophoresis 30 15759304
2002 Alternative non-coding splice variants of Nespas, an imprinted gene antisense to Nesp in the Gnas imprinting cluster. Mammalian genome : official journal of the International Mammalian Genome Society 30 11889554
2012 GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification? Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 29 22674477
2006 Imprinting the Gnas locus. Cytogenetic and genome research 29 16575178
2024 PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT. Cancer research 28 38900943
2017 RNF43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct. Histopathology 28 27864998
2014 Activating GNAS mutations in parosteal osteosarcoma. The American journal of surgical pathology 27 24525511
2006 Different mutations within or upstream of the GNAS locus cause distinct forms of pseudohypoparathyroidism. Journal of pediatric endocrinology & metabolism : JPEM 25 16789629
1999 The new chromogranin-like protein NESP55 is preferentially localized in adrenaline-synthesizing cells of the bovine and rat adrenal medulla. Neuroscience letters 25 10218899
2021 Peptide vaccine targeting mutated GNAS: a potential novel treatment for pseudomyxoma peritonei. Journal for immunotherapy of cancer 24 34711663
2019 Clinical assessment of the GNAS mutation status in patients with intraductal papillary mucinous neoplasm of the pancreas. Surgery today 24 30879148
2016 GNAS mutations in adrenal aldosterone-producing adenomas. Endocrine journal 24 26743443
2020 The biological basis and function of GNAS mutation in pseudomyxoma peritonei: a review. Journal of cancer research and clinical oncology 23 32700107
2011 DNA sequence polymorphisms within the bovine guanine nucleotide-binding protein Gs subunit alpha (Gsα)-encoding (GNAS) genomic imprinting domain are associated with performance traits. BMC genetics 23 21214909
2022 Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway. Journal of gastroenterology 22 35018527
2008 Control of imprinting at the Gnas cluster. Advances in experimental medicine and biology 22 18372788
2022 Oncogene addiction to GNAS in GNASR201 mutant tumors. Oncogene 21 35879396
2019 GNAS gene is an important regulator of insulin secretory capacity in pancreatic β-cells. Gene 21 31374326
2014 Differential expression of GNAS and KRAS mutations in pancreatic cysts. JOP : Journal of the pancreas 21 25435574
2023 The long-range interaction between two GNAS imprinting control regions delineates pseudohypoparathyroidism type 1B pathogenesis. The Journal of clinical investigation 20 36853809
2022 The glycerol-3-phosphate dehydrogenases GpsA and GlpD constitute the oxidoreductive metabolic linchpin for Lyme disease spirochete host infectivity and persistence in the tick. PLoS pathogens 20 35255112
2016 Impulsive choices in mice lacking imprinted Nesp55. Genes, brain, and behavior 20 27509352
2004 Imprinting of Nesp55 gene in cattle. Mammalian genome : official journal of the International Mammalian Genome Society 20 15457345
2023 Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS -Mutant and GNAS -Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas. Annals of surgery 19 33914475
2023 Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia/McCune Albright Syndrome. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 18 36593655
2022 A GNAS Gene Mutation's Independent Expression in the Growth of Colorectal Cancer: A Systematic Review and Meta-Analysis. Cancers 18 36428574
2015 Transcription driven somatic DNA methylation within the imprinted Gnas cluster. PloS one 18 25659103
2014 Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b. European journal of human genetics : EJHG 18 25005734
1977 Further mapping of several membrane lipid biosynthetic genes (fabC, fabB, gpsA, plsB) of Escherichia coli. Journal of bacteriology 17 334747
2013 Brain-expressed imprinted genes and adult behaviour: the example of Nesp and Grb10. Mammalian genome : official journal of the International Mammalian Genome Society 16 23974804
2024 Quercetin-primed BMSC-derived extracellular vesicles ameliorate chronic liver damage through miR-136-5p and GNAS/STAT3 signaling pathways. International immunopharmacology 15 39340996
2022 Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation. Cold Spring Harbor molecular case studies 14 35012940
2020 Long non-coding RNA GNAS-AS1 promotes cell migration and invasion via regulating Wnt/β-catenin pathway in nasopharyngeal carcinoma. European review for medical and pharmacological sciences 14 32271425
2016 GNAS gene mutation may be present only transiently during colorectal tumorigenesis. International journal of molecular epidemiology and genetics 14 27186325
2015 Antisense Activity across the Nesp Promoter is Required for Nespas-Mediated Silencing in the Imprinted Gnas Cluster. Non-coding RNA 14 29861426
2013 Gene Dosage Effects at the Imprinted Gnas Cluster. PloS one 14 23822972
2002 Distribution and intraneuronal trafficking of a novel member of the chromogranin family, NESP55, in the rat peripheral nervous system. Neuroscience 14 11934480

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