{"gene":"IL2RG","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1993,"finding":"IL2RG maps to Xq13.1 and encodes the gamma chain of the IL-2 receptor; point mutations in IL2RG (including splice-donor site ablation, premature chain termination, and amino acid changes) are causally associated with X-linked SCID, establishing IL2RG as the SCIDX1 gene. The gamma chain was shown to be required to associate with the beta chain for IL-2 internalization and cell activation.","method":"Fluorescence in situ hybridization, somatic cell hybrid PCR mapping, genomic sequencing, mRNA expression analysis in patient B-cell lines, mutation analysis in SCID pedigrees","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (FISH, sequencing, mRNA expression, functional correlation) in a focused gene identification study, independently replicated by Noguchi et al.","pmids":["8401490"],"is_preprint":false},{"year":2000,"finding":"IL2RG encodes the gamma-c cytokine receptor subunit shared by IL-2, IL-4, IL-7, IL-9, and IL-15 receptors; mutations cause an early block in T and NK lymphocyte differentiation by impairing delivery of growth, survival, and differentiation signals to early lymphoid progenitors. Retroviral transfer of IL2RG cDNA into CD34+ cells restored T and NK cell development and function in SCID-X1 patients.","method":"Retrovirus-mediated gene transfer into autologous CD34+ cells, patient follow-up with T/NK/B cell counts and functional assays including antigen-specific responses","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clinical gene correction with functional immune reconstitution, directly demonstrating the role of IL2RG in lymphoid development and cytokine signaling","pmids":["10784449"],"is_preprint":false},{"year":1997,"finding":"Sixty-two different mutations spanning all eight IL2RG exons were found in 87 SCID cases; abnormal gamma-c chains are expressed in up to two-thirds of patients. Mutations disrupt conserved cytokine receptor family motifs or alter the intracellular domain critical for interaction with signal-transducing molecules including JAK3.","method":"DNA sequencing, SSCP, mRNA expression analysis, cell-surface staining with anti-gamma-c antibodies, X-chromosome inactivation analysis in 103 unrelated SCID males","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — large cohort with multiple orthogonal molecular methods establishing mutation-function correlations across the full gene","pmids":["9058718"],"is_preprint":false},{"year":2012,"finding":"The Cys183–Cys232 disulfide bond in CD132 (IL2RG) is labile and can be reduced by thioredoxin, gamma-interferon-inducible lysosomal thiolreductase, and protein disulfide isomerase. Reduction of this disulfide bond inhibits IL-2-dependent T cell proliferation and STAT-5 signaling, and is proposed to impair IL-2 binding to the receptor complex. The bond is also reduced in vivo in an LPS-induced acute inflammation model.","method":"In vitro reduction assays with recombinant enzymes, T-cell proliferation assay, STAT-5 phosphorylation analysis, LPS-induced in vivo inflammation model, structural analysis of published receptor complex data","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays (proliferation, STAT-5 signaling) combined with in vivo model, single lab but multiple orthogonal methods","pmids":["22645657"],"is_preprint":false},{"year":2006,"finding":"Retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of LMO2 leads to severe abnormalities. IL2RG restoration of normal IL-7 receptor signaling in SCID precursor cells allows T-cell progression to stages permissive for pro-leukemic LMO2 effects, but IL2RG itself is not directly oncogenic.","method":"Retroviral overexpression of IL2RG or LMO2 in human CD34+ cells, in vitro T-cell development assay, comparison of developmental outcomes","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional experiment in human CD34+ cells with two orthogonal comparators (IL2RG vs. LMO2), single lab","pmids":["16988660"],"is_preprint":false},{"year":2001,"finding":"Functional IL-2 receptor beta (CD122) and gamma (CD132) chains are expressed on fibroblast-like synoviocytes (FLS). IL-2 stimulation of FLS via these receptors induces MCP-1 production and increased tyrosine phosphorylation, an effect partially blocked by anti-CD122 neutralizing antibody.","method":"Western blot and RT-PCR for CD122 and CD132 protein/mRNA, receptor quantification (binding sites), ELISA for MCP-1, anti-CD122 blocking antibody, tyrosine phosphorylation assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional receptor signaling demonstrated by ligand stimulation, antibody blockade, and downstream signaling readout in non-lymphoid cells, single lab","pmids":["11238664"],"is_preprint":false},{"year":2002,"finding":"Retroviral transduction of IL2RG into XSCID patient CD34+ cells restores cell-surface gamma-c expression and permits development of T and B cells (but not myeloid-only differentiation seen with untransduced cells) in the chimeric sheep fetal model, demonstrating that gamma-c expression is specifically required for lymphoid (T and B cell) differentiation from hematopoietic progenitors.","method":"Retroviral gene transfer, surface gamma-c expression analysis, chimeric sheep fetal transplantation model, lineage differentiation analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue experiment with patient-derived cells in a large-animal model, direct demonstration of lineage-specific requirement, single lab","pmids":["12070011"],"is_preprint":false},{"year":2017,"finding":"CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth and reduced JAK3 expression in vivo, indicating that IL2RG/JAK3 signaling contributes to pancreatic cancer cell-autonomous growth.","method":"CRISPR/Cas9 knockout of IL2RG in pancreatic cancer cells, orthotopic implantation in mice, tumor growth measurement, JAK3 expression analysis in tumors","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vivo loss-of-function with defined molecular readout (JAK3 expression), single lab, single method approach","pmids":["29137350"],"is_preprint":false},{"year":2019,"finding":"siRNA-specific knockdown of IL2RG in Jurkat cells expressing the ITK-SYK fusion gene showed the same suppression of cell growth, apoptosis induction, and G1/S cell cycle arrest as the JAK3-selective inhibitor tofacitinib, demonstrating that the IL2RG/JAK3/STAT5 signaling axis is required for ITK-SYK-driven oncogenic growth.","method":"siRNA knockdown of IL2RG, cell proliferation assay, apoptosis assay, cell cycle analysis, comparison with pharmacological JAK3 inhibition (tofacitinib) in Jurkat cells","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA) and pharmacological (tofacitinib) convergent approaches confirm IL2RG/JAK3/STAT5 pathway requirement, single lab","pmids":["31545408"],"is_preprint":false},{"year":2020,"finding":"A hypomorphic IL2RG p.Pro58Ser mutation impairs surface expression of IL2RG on lymphocytes. BioID proximity labeling showed aberrant interactions between the mutated IL2RG and ER/Golgi proteins, causing mislocalization of the mutated protein to the ER/Golgi interface rather than the plasma membrane, leading to impaired STAT5 phosphorylation in response to IL-2 and IL-21 and reduced T-cell proliferation.","method":"Flow cytometry for surface IL2RG expression, BioID proximity labeling, STAT5 phosphorylation assay, T-cell proliferation assay, IL-2 target gene expression analysis","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (BioID, phosphorylation, proliferation, gene expression) in a single lab establishing both localization and functional consequence","pmids":["32072341"],"is_preprint":false},{"year":2020,"finding":"The IL2RG R328X nonsense mutation allows partial STAT-5 phosphorylation through a JAK3-independent pathway. Co-immunoprecipitation demonstrated that the R328X mutant protein has impaired JAK3 binding. A critical three-amino-acid region in the gamma-c intracellular domain was identified as necessary for receptor stabilization and JAK3-dependent signaling.","method":"Co-immunoprecipitation of mutant IL2RG with JAK3, STAT-5 phosphorylation assays, CD132 surface expression analysis, functional lymphocyte assays in patients","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction assay (Co-IP) combined with functional signaling readout, single lab, patient-derived material","pmids":["31799703"],"is_preprint":false},{"year":2013,"finding":"An IL2RG reversion mutation to normal sequence occurred specifically in committed T-cell progenitors and conferred selective outgrowth advantage to CD8+ T cells. Only revertant cells showed normal CD132 surface expression and normal cytokine-dependent proliferative responses, demonstrating that gamma-c expression is required for T-cell competitive fitness in vivo.","method":"IL2RG mutation and reversion analysis by sequencing, flow cytometry for CD132 surface expression and T-cell subset analysis, TCR repertoire analysis, longitudinal follow-up","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural experiment with isogenic revertant cells providing direct evidence of IL2RG requirement for T-cell fitness, single patient but multiple orthogonal analyses","pmids":["23403317"],"is_preprint":false},{"year":2004,"finding":"A novel splice-site mutation (c.468+3A>C in intron 3 of IL2RG) produces two aberrantly spliced gamma-c mRNA species with reduction of correctly spliced message to trace levels, resulting in failure to detect gamma-c on the surface of B and NK cells. The NK+ (but not T+) phenotype supports the hypothesis that IL-15 receptor-mediated signaling is preferentially retained as cell-surface gamma-c becomes limiting.","method":"Sequencing, RT-PCR for splice variant analysis, FACS for surface gamma-c expression on lymphocyte subsets","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient, single lab, limited mechanistic follow-up beyond mRNA and surface expression analysis","pmids":["15108287"],"is_preprint":false},{"year":2022,"finding":"Tim-3+ decidual macrophages with higher CD132 expression induced Th2 and Treg bias in decidual CD4+ T cells; blockade of the CD132 pathway led to dysfunction of maternal-fetal tolerance and increased fetal loss, demonstrating a functional role for CD132 signaling in decidual macrophage-mediated immune regulation during pregnancy.","method":"Flow cytometry, adoptive transfer of Tim-3+ vs. Tim-3- macrophages into macrophage-depleted mice, CD132 pathway blockade with functional pregnancy outcome readout, microarray analysis","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo blockade and adoptive transfer establish a functional role, but the mechanistic link to CD132 specifically is indirect (pathway blockade), single lab","pmids":["35550500"],"is_preprint":false}],"current_model":"IL2RG encodes the common gamma chain (γc/CD132), a shared signaling subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; it is required for T and NK lymphocyte development by delivering growth, survival, and differentiation signals through recruitment of JAK3 and downstream STAT5 phosphorylation. Loss-of-function mutations cause X-linked SCID, while hypomorphic mutations reduce surface expression or impair JAK3 binding (via a critical intracellular domain region), yielding partial signaling and attenuated phenotypes. A labile Cys183–Cys232 disulfide bond modulates IL-2 binding and receptor function under inflammatory redox conditions. Beyond lymphocytes, γc/JAK3/STAT5 signaling is also active in fibroblast-like synoviocytes and contributes to pancreatic cancer and T-cell lymphoma cell growth."},"narrative":{"mechanistic_narrative":"IL2RG encodes the common gamma chain (γc/CD132), a shared signal-transducing subunit used by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and its loss produces an early block in T and NK lymphocyte differentiation by depriving early lymphoid progenitors of growth, survival, and differentiation signals [PMID:10784449]. Point mutations spanning all eight exons—splice-site disruptions, premature terminations, and amino acid substitutions—cause X-linked SCID (SCIDX1), the gene mapping to Xq13.1, with γc required to associate with the IL-2 receptor beta chain for ligand internalization and cell activation [PMID:8401490, PMID:9058718]. Signaling proceeds through the γc intracellular domain, which recruits JAK3 to drive STAT5 phosphorylation; a critical three-residue region of this domain is required for receptor stabilization and JAK3-dependent signaling, and mutations such as R328X impair JAK3 binding while permitting partial JAK3-independent STAT5 phosphorylation [PMID:31799703]. The lymphoid requirement is direct and cell-autonomous: retroviral restoration of γc in patient CD34+ cells rescues T and NK (and B) cell development and function [PMID:10784449, PMID:12070011], and a spontaneous reversion to normal sequence in committed T-cell progenitors conferred selective outgrowth, establishing γc as necessary for T-cell competitive fitness [PMID:23403317]. Hypomorphic lesions act largely by limiting surface receptor: the p.Pro58Ser mutation traps γc at the ER/Golgi interface through aberrant interactions, impairing IL-2/IL-21-driven STAT5 phosphorylation and proliferation [PMID:32072341]. A labile Cys183–Cys232 disulfide bond, reducible by thioredoxin, GILT, and protein disulfide isomerase, modulates IL-2-dependent proliferation and STAT5 signaling, linking receptor function to redox state during inflammation [PMID:22645657]. Beyond lymphocytes, functional γc/JAK3/STAT5 signaling operates in fibroblast-like synoviocytes and contributes to the growth of pancreatic cancer cells and ITK-SYK-driven T-cell lymphoma cells [PMID:11238664, PMID:29137350, PMID:31545408].","teleology":[{"year":1993,"claim":"Established the molecular cause of X-linked SCID by mapping IL2RG and showing its mutations ablate the IL-2 receptor gamma chain required for receptor assembly and activation.","evidence":"FISH/somatic-cell-hybrid mapping, genomic sequencing, and mutation analysis in SCID pedigrees","pmids":["8401490"],"confidence":"High","gaps":["Did not resolve which downstream signaling molecule the gamma chain recruits","Sharing of the chain across multiple cytokine receptors not yet established"]},{"year":1997,"claim":"Defined the mutational landscape across the full gene and linked the intracellular domain to interaction with signal-transducing molecules including JAK3.","evidence":"Sequencing, SSCP, surface anti-γc staining, and X-inactivation analysis in a large SCID cohort","pmids":["9058718"],"confidence":"High","gaps":["Genotype-to-residual-signaling correlations for individual mutations not functionally dissected","JAK3-binding region not mapped to specific residues"]},{"year":2000,"claim":"Demonstrated directly that IL2RG is the shared gamma chain whose restoration rescues lymphoid development, defining its role in delivering signals to early lymphoid progenitors.","evidence":"Retroviral IL2RG transfer into patient CD34+ cells with immune reconstitution and functional assays","pmids":["10784449"],"confidence":"High","gaps":["Did not address insertional/oncogenic risks of the corrective vector","Relative contribution of each cytokine receptor to the rescue not parsed"]},{"year":2001,"claim":"Showed γc signaling is not lymphocyte-restricted by demonstrating functional IL-2Rβ/γc receptors on fibroblast-like synoviocytes driving chemokine production.","evidence":"Receptor detection, IL-2 stimulation, anti-CD122 blockade, and tyrosine phosphorylation/MCP-1 readouts in FLS","pmids":["11238664"],"confidence":"Medium","gaps":["JAK/STAT involvement in FLS not directly tested","In vivo relevance to synovial pathology not established"]},{"year":2002,"claim":"Established that γc expression is specifically required for lymphoid lineage differentiation from progenitors in vivo.","evidence":"Retroviral correction of patient CD34+ cells in a chimeric sheep fetal transplantation model with lineage analysis","pmids":["12070011"],"confidence":"Medium","gaps":["Single large-animal model, not human in vivo","Quantitative thresholds of γc needed per lineage not defined"]},{"year":2004,"claim":"Indicated differential cytokine-receptor sensitivity to limiting γc, with IL-15-mediated NK signaling preferentially retained.","evidence":"Splice-variant RT-PCR and surface γc FACS in a single SCID patient with NK+ phenotype","pmids":["15108287"],"confidence":"Low","gaps":["Single patient, no functional signaling assays to confirm IL-15 retention","Mechanism of preferential retention not tested"]},{"year":2006,"claim":"Distinguished γc restoration from oncogenesis, showing IL2RG itself is not directly transforming but enables developmental progression permissive for LMO2-driven leukemogenesis.","evidence":"Comparative retroviral overexpression of IL2RG vs LMO2 in human CD34+ cells with T-cell development assays","pmids":["16988660"],"confidence":"Medium","gaps":["Did not exclude rare insertional cooperative events with IL2RG vector","Single in vitro developmental system"]},{"year":2012,"claim":"Identified a redox-regulatory mechanism, the labile Cys183–Cys232 disulfide, whose reduction impairs IL-2 binding and STAT5 signaling.","evidence":"In vitro enzymatic reduction, proliferation and STAT5 phosphorylation assays, and an LPS in vivo inflammation model","pmids":["22645657"],"confidence":"Medium","gaps":["Direct structural confirmation of altered IL-2 binding not obtained","Physiological contexts where reduction occurs incompletely defined"]},{"year":2013,"claim":"Provided isogenic in vivo evidence that γc expression confers T-cell competitive fitness via a spontaneous reversion event.","evidence":"Reversion sequencing, surface CD132 and subset flow cytometry, TCR repertoire analysis, longitudinal follow-up in a patient","pmids":["23403317"],"confidence":"Medium","gaps":["Single patient natural experiment","Mechanism of selective CD8+ advantage not dissected"]},{"year":2017,"claim":"Extended γc/JAK3 signaling to cell-autonomous tumor growth in pancreatic cancer.","evidence":"CRISPR knockout of IL2RG in orthotopically implanted pancreatic cancer cells with tumor growth and JAK3 expression readouts","pmids":["29137350"],"confidence":"Medium","gaps":["Single in vivo loss-of-function approach","Ligand/upstream cytokine driving the signaling not identified"]},{"year":2019,"claim":"Showed the IL2RG/JAK3/STAT5 axis is required for ITK-SYK-driven oncogenic growth, converging genetic and pharmacologic evidence.","evidence":"siRNA knockdown vs tofacitinib in ITK-SYK-expressing Jurkat cells with proliferation, apoptosis, and cell-cycle assays","pmids":["31545408"],"confidence":"Medium","gaps":["Single cell-line model","In vivo relevance not tested"]},{"year":2020,"claim":"Defined two hypomorphic mechanisms: mislocalization of γc to the ER/Golgi (p.Pro58Ser) and impaired JAK3 binding with residual JAK3-independent STAT5 signaling (R328X), mapping a critical intracellular three-residue region.","evidence":"BioID proximity labeling, Co-IP with JAK3, surface expression, STAT5 phosphorylation, and proliferation assays on patient mutants","pmids":["32072341","31799703"],"confidence":"Medium","gaps":["Identity of the JAK3-independent STAT5 kinase not established","ER/Golgi retention partners not validated reciprocally"]},{"year":2022,"claim":"Implicated CD132 signaling in decidual macrophage-mediated maternal-fetal tolerance.","evidence":"Adoptive transfer of Tim-3+ vs Tim-3- macrophages, CD132 pathway blockade, and pregnancy-outcome readouts in mice","pmids":["35550500"],"confidence":"Low","gaps":["CD132 involvement inferred from pathway blockade, not gene-specific perturbation","Single lab, indirect mechanistic link"]},{"year":null,"claim":"The molecular identity of the JAK3-independent kinase mediating residual STAT5 phosphorylation, and the structural basis by which the critical intracellular region stabilizes the receptor and recruits JAK3, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the γc intracellular domain bound to JAK3 in the corpus","JAK3-independent STAT5 activation mechanism uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6,9,11]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,6,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,8]}],"complexes":["IL-2 receptor complex"],"partners":["JAK3","IL2RB","STAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31785","full_name":"Cytokine receptor common subunit gamma","aliases":["Interleukin-2 receptor subunit gamma","IL-2 receptor subunit gamma","IL-2R subunit gamma","IL-2RG","gammaC","p64"],"length_aa":369,"mass_kda":42.3,"function":"Common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, involved in the stimulation of neutrophil phagocytosis by IL15 (PubMed:15123770)","subcellular_location":"Cell membrane; Cell surface","url":"https://www.uniprot.org/uniprotkb/P31785/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL2RG","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL2RG","total_profiled":1310},"omim":[{"mim_id":"616243","title":"TRANSMEMBRANE PROTEIN 131-LIKE; TMEM131L","url":"https://www.omim.org/entry/616243"},{"mim_id":"612086","title":"MINOR HISTOCOMPATIBILITY ANTIGEN, SERPIN DOMAIN-CONTAINING; HMSD","url":"https://www.omim.org/entry/612086"},{"mim_id":"608958","title":"ADENOSINE DEAMINASE; ADA","url":"https://www.omim.org/entry/608958"},{"mim_id":"607531","title":"KLF TRANSCRIPTION FACTOR 12; KLF12","url":"https://www.omim.org/entry/607531"},{"mim_id":"607003","title":"THYMIC STROMAL LYMPHOPOIETIN; TSLP","url":"https://www.omim.org/entry/607003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":109.3},{"tissue":"lymphoid tissue","ntpm":317.8}],"url":"https://www.proteinatlas.org/search/IL2RG"},"hgnc":{"alias_symbol":["CD132"],"prev_symbol":["SCIDX1","IMD4","CIDX"]},"alphafold":{"accession":"P31785","domains":[{"cath_id":"2.60.40.10","chopping":"54-153","consensus_level":"high","plddt":92.8873,"start":54,"end":153},{"cath_id":"2.60.40.10","chopping":"155-247","consensus_level":"high","plddt":94.2886,"start":155,"end":247},{"cath_id":"1.20.5","chopping":"255-289","consensus_level":"medium","plddt":82.7274,"start":255,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31785","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31785-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31785-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL2RG","jax_strain_url":"https://www.jax.org/strain/search?query=IL2RG"},"sequence":{"accession":"P31785","fasta_url":"https://rest.uniprot.org/uniprotkb/P31785.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31785/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31785"}},"corpus_meta":[{"pmid":"14564000","id":"PMC_14564000","title":"LMO2-associated 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25670669","citation_count":7,"is_preprint":false},{"pmid":"36311661","id":"PMC_36311661","title":"Allogeneic and xenogeneic lymphoid reconstitution in a RAG2 -/- IL2RG  severe combined immunodeficient pig: A preclinical model for intrauterine hematopoietic transplantation.","date":"2022","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/36311661","citation_count":7,"is_preprint":false},{"pmid":"33964513","id":"PMC_33964513","title":"Reduction of Graft-versus-Host-Disease in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) Mice by Cotransplantation of Syngeneic Human Umbilical Cord-Derived Mesenchymal Stromal Cells.","date":"2021","source":"Transplantation and cellular therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33964513","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49852,"output_tokens":3819,"usd":0.10342,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11714,"output_tokens":4149,"usd":0.081147,"stage2_stop_reason":"end_turn"},"total_usd":0.184567,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"IL2RG maps to Xq13.1 and encodes the gamma chain of the IL-2 receptor; point mutations in IL2RG (including splice-donor site ablation, premature chain termination, and amino acid changes) are causally associated with X-linked SCID, establishing IL2RG as the SCIDX1 gene. The gamma chain was shown to be required to associate with the beta chain for IL-2 internalization and cell activation.\",\n      \"method\": \"Fluorescence in situ hybridization, somatic cell hybrid PCR mapping, genomic sequencing, mRNA expression analysis in patient B-cell lines, mutation analysis in SCID pedigrees\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (FISH, sequencing, mRNA expression, functional correlation) in a focused gene identification study, independently replicated by Noguchi et al.\",\n      \"pmids\": [\"8401490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL2RG encodes the gamma-c cytokine receptor subunit shared by IL-2, IL-4, IL-7, IL-9, and IL-15 receptors; mutations cause an early block in T and NK lymphocyte differentiation by impairing delivery of growth, survival, and differentiation signals to early lymphoid progenitors. Retroviral transfer of IL2RG cDNA into CD34+ cells restored T and NK cell development and function in SCID-X1 patients.\",\n      \"method\": \"Retrovirus-mediated gene transfer into autologous CD34+ cells, patient follow-up with T/NK/B cell counts and functional assays including antigen-specific responses\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clinical gene correction with functional immune reconstitution, directly demonstrating the role of IL2RG in lymphoid development and cytokine signaling\",\n      \"pmids\": [\"10784449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Sixty-two different mutations spanning all eight IL2RG exons were found in 87 SCID cases; abnormal gamma-c chains are expressed in up to two-thirds of patients. Mutations disrupt conserved cytokine receptor family motifs or alter the intracellular domain critical for interaction with signal-transducing molecules including JAK3.\",\n      \"method\": \"DNA sequencing, SSCP, mRNA expression analysis, cell-surface staining with anti-gamma-c antibodies, X-chromosome inactivation analysis in 103 unrelated SCID males\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large cohort with multiple orthogonal molecular methods establishing mutation-function correlations across the full gene\",\n      \"pmids\": [\"9058718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Cys183–Cys232 disulfide bond in CD132 (IL2RG) is labile and can be reduced by thioredoxin, gamma-interferon-inducible lysosomal thiolreductase, and protein disulfide isomerase. Reduction of this disulfide bond inhibits IL-2-dependent T cell proliferation and STAT-5 signaling, and is proposed to impair IL-2 binding to the receptor complex. The bond is also reduced in vivo in an LPS-induced acute inflammation model.\",\n      \"method\": \"In vitro reduction assays with recombinant enzymes, T-cell proliferation assay, STAT-5 phosphorylation analysis, LPS-induced in vivo inflammation model, structural analysis of published receptor complex data\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays (proliferation, STAT-5 signaling) combined with in vivo model, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22645657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of LMO2 leads to severe abnormalities. IL2RG restoration of normal IL-7 receptor signaling in SCID precursor cells allows T-cell progression to stages permissive for pro-leukemic LMO2 effects, but IL2RG itself is not directly oncogenic.\",\n      \"method\": \"Retroviral overexpression of IL2RG or LMO2 in human CD34+ cells, in vitro T-cell development assay, comparison of developmental outcomes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional experiment in human CD34+ cells with two orthogonal comparators (IL2RG vs. LMO2), single lab\",\n      \"pmids\": [\"16988660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Functional IL-2 receptor beta (CD122) and gamma (CD132) chains are expressed on fibroblast-like synoviocytes (FLS). IL-2 stimulation of FLS via these receptors induces MCP-1 production and increased tyrosine phosphorylation, an effect partially blocked by anti-CD122 neutralizing antibody.\",\n      \"method\": \"Western blot and RT-PCR for CD122 and CD132 protein/mRNA, receptor quantification (binding sites), ELISA for MCP-1, anti-CD122 blocking antibody, tyrosine phosphorylation assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional receptor signaling demonstrated by ligand stimulation, antibody blockade, and downstream signaling readout in non-lymphoid cells, single lab\",\n      \"pmids\": [\"11238664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Retroviral transduction of IL2RG into XSCID patient CD34+ cells restores cell-surface gamma-c expression and permits development of T and B cells (but not myeloid-only differentiation seen with untransduced cells) in the chimeric sheep fetal model, demonstrating that gamma-c expression is specifically required for lymphoid (T and B cell) differentiation from hematopoietic progenitors.\",\n      \"method\": \"Retroviral gene transfer, surface gamma-c expression analysis, chimeric sheep fetal transplantation model, lineage differentiation analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue experiment with patient-derived cells in a large-animal model, direct demonstration of lineage-specific requirement, single lab\",\n      \"pmids\": [\"12070011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth and reduced JAK3 expression in vivo, indicating that IL2RG/JAK3 signaling contributes to pancreatic cancer cell-autonomous growth.\",\n      \"method\": \"CRISPR/Cas9 knockout of IL2RG in pancreatic cancer cells, orthotopic implantation in mice, tumor growth measurement, JAK3 expression analysis in tumors\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vivo loss-of-function with defined molecular readout (JAK3 expression), single lab, single method approach\",\n      \"pmids\": [\"29137350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"siRNA-specific knockdown of IL2RG in Jurkat cells expressing the ITK-SYK fusion gene showed the same suppression of cell growth, apoptosis induction, and G1/S cell cycle arrest as the JAK3-selective inhibitor tofacitinib, demonstrating that the IL2RG/JAK3/STAT5 signaling axis is required for ITK-SYK-driven oncogenic growth.\",\n      \"method\": \"siRNA knockdown of IL2RG, cell proliferation assay, apoptosis assay, cell cycle analysis, comparison with pharmacological JAK3 inhibition (tofacitinib) in Jurkat cells\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA) and pharmacological (tofacitinib) convergent approaches confirm IL2RG/JAK3/STAT5 pathway requirement, single lab\",\n      \"pmids\": [\"31545408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A hypomorphic IL2RG p.Pro58Ser mutation impairs surface expression of IL2RG on lymphocytes. BioID proximity labeling showed aberrant interactions between the mutated IL2RG and ER/Golgi proteins, causing mislocalization of the mutated protein to the ER/Golgi interface rather than the plasma membrane, leading to impaired STAT5 phosphorylation in response to IL-2 and IL-21 and reduced T-cell proliferation.\",\n      \"method\": \"Flow cytometry for surface IL2RG expression, BioID proximity labeling, STAT5 phosphorylation assay, T-cell proliferation assay, IL-2 target gene expression analysis\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (BioID, phosphorylation, proliferation, gene expression) in a single lab establishing both localization and functional consequence\",\n      \"pmids\": [\"32072341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The IL2RG R328X nonsense mutation allows partial STAT-5 phosphorylation through a JAK3-independent pathway. Co-immunoprecipitation demonstrated that the R328X mutant protein has impaired JAK3 binding. A critical three-amino-acid region in the gamma-c intracellular domain was identified as necessary for receptor stabilization and JAK3-dependent signaling.\",\n      \"method\": \"Co-immunoprecipitation of mutant IL2RG with JAK3, STAT-5 phosphorylation assays, CD132 surface expression analysis, functional lymphocyte assays in patients\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction assay (Co-IP) combined with functional signaling readout, single lab, patient-derived material\",\n      \"pmids\": [\"31799703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An IL2RG reversion mutation to normal sequence occurred specifically in committed T-cell progenitors and conferred selective outgrowth advantage to CD8+ T cells. Only revertant cells showed normal CD132 surface expression and normal cytokine-dependent proliferative responses, demonstrating that gamma-c expression is required for T-cell competitive fitness in vivo.\",\n      \"method\": \"IL2RG mutation and reversion analysis by sequencing, flow cytometry for CD132 surface expression and T-cell subset analysis, TCR repertoire analysis, longitudinal follow-up\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural experiment with isogenic revertant cells providing direct evidence of IL2RG requirement for T-cell fitness, single patient but multiple orthogonal analyses\",\n      \"pmids\": [\"23403317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel splice-site mutation (c.468+3A>C in intron 3 of IL2RG) produces two aberrantly spliced gamma-c mRNA species with reduction of correctly spliced message to trace levels, resulting in failure to detect gamma-c on the surface of B and NK cells. The NK+ (but not T+) phenotype supports the hypothesis that IL-15 receptor-mediated signaling is preferentially retained as cell-surface gamma-c becomes limiting.\",\n      \"method\": \"Sequencing, RT-PCR for splice variant analysis, FACS for surface gamma-c expression on lymphocyte subsets\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient, single lab, limited mechanistic follow-up beyond mRNA and surface expression analysis\",\n      \"pmids\": [\"15108287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Tim-3+ decidual macrophages with higher CD132 expression induced Th2 and Treg bias in decidual CD4+ T cells; blockade of the CD132 pathway led to dysfunction of maternal-fetal tolerance and increased fetal loss, demonstrating a functional role for CD132 signaling in decidual macrophage-mediated immune regulation during pregnancy.\",\n      \"method\": \"Flow cytometry, adoptive transfer of Tim-3+ vs. Tim-3- macrophages into macrophage-depleted mice, CD132 pathway blockade with functional pregnancy outcome readout, microarray analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo blockade and adoptive transfer establish a functional role, but the mechanistic link to CD132 specifically is indirect (pathway blockade), single lab\",\n      \"pmids\": [\"35550500\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL2RG encodes the common gamma chain (γc/CD132), a shared signaling subunit of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; it is required for T and NK lymphocyte development by delivering growth, survival, and differentiation signals through recruitment of JAK3 and downstream STAT5 phosphorylation. Loss-of-function mutations cause X-linked SCID, while hypomorphic mutations reduce surface expression or impair JAK3 binding (via a critical intracellular domain region), yielding partial signaling and attenuated phenotypes. A labile Cys183–Cys232 disulfide bond modulates IL-2 binding and receptor function under inflammatory redox conditions. Beyond lymphocytes, γc/JAK3/STAT5 signaling is also active in fibroblast-like synoviocytes and contributes to pancreatic cancer and T-cell lymphoma cell growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL2RG encodes the common gamma chain (γc/CD132), a shared signal-transducing subunit used by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and its loss produces an early block in T and NK lymphocyte differentiation by depriving early lymphoid progenitors of growth, survival, and differentiation signals [#1]. Point mutations spanning all eight exons—splice-site disruptions, premature terminations, and amino acid substitutions—cause X-linked SCID (SCIDX1), the gene mapping to Xq13.1, with γc required to associate with the IL-2 receptor beta chain for ligand internalization and cell activation [#0, #2]. Signaling proceeds through the γc intracellular domain, which recruits JAK3 to drive STAT5 phosphorylation; a critical three-residue region of this domain is required for receptor stabilization and JAK3-dependent signaling, and mutations such as R328X impair JAK3 binding while permitting partial JAK3-independent STAT5 phosphorylation [#10]. The lymphoid requirement is direct and cell-autonomous: retroviral restoration of γc in patient CD34+ cells rescues T and NK (and B) cell development and function [#1, #6], and a spontaneous reversion to normal sequence in committed T-cell progenitors conferred selective outgrowth, establishing γc as necessary for T-cell competitive fitness [#11]. Hypomorphic lesions act largely by limiting surface receptor: the p.Pro58Ser mutation traps γc at the ER/Golgi interface through aberrant interactions, impairing IL-2/IL-21-driven STAT5 phosphorylation and proliferation [#9]. A labile Cys183–Cys232 disulfide bond, reducible by thioredoxin, GILT, and protein disulfide isomerase, modulates IL-2-dependent proliferation and STAT5 signaling, linking receptor function to redox state during inflammation [#3]. Beyond lymphocytes, functional γc/JAK3/STAT5 signaling operates in fibroblast-like synoviocytes and contributes to the growth of pancreatic cancer cells and ITK-SYK-driven T-cell lymphoma cells [#5, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the molecular cause of X-linked SCID by mapping IL2RG and showing its mutations ablate the IL-2 receptor gamma chain required for receptor assembly and activation.\",\n      \"evidence\": \"FISH/somatic-cell-hybrid mapping, genomic sequencing, and mutation analysis in SCID pedigrees\",\n      \"pmids\": [\"8401490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which downstream signaling molecule the gamma chain recruits\", \"Sharing of the chain across multiple cytokine receptors not yet established\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the mutational landscape across the full gene and linked the intracellular domain to interaction with signal-transducing molecules including JAK3.\",\n      \"evidence\": \"Sequencing, SSCP, surface anti-γc staining, and X-inactivation analysis in a large SCID cohort\",\n      \"pmids\": [\"9058718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-to-residual-signaling correlations for individual mutations not functionally dissected\", \"JAK3-binding region not mapped to specific residues\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated directly that IL2RG is the shared gamma chain whose restoration rescues lymphoid development, defining its role in delivering signals to early lymphoid progenitors.\",\n      \"evidence\": \"Retroviral IL2RG transfer into patient CD34+ cells with immune reconstitution and functional assays\",\n      \"pmids\": [\"10784449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address insertional/oncogenic risks of the corrective vector\", \"Relative contribution of each cytokine receptor to the rescue not parsed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed γc signaling is not lymphocyte-restricted by demonstrating functional IL-2Rβ/γc receptors on fibroblast-like synoviocytes driving chemokine production.\",\n      \"evidence\": \"Receptor detection, IL-2 stimulation, anti-CD122 blockade, and tyrosine phosphorylation/MCP-1 readouts in FLS\",\n      \"pmids\": [\"11238664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK/STAT involvement in FLS not directly tested\", \"In vivo relevance to synovial pathology not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that γc expression is specifically required for lymphoid lineage differentiation from progenitors in vivo.\",\n      \"evidence\": \"Retroviral correction of patient CD34+ cells in a chimeric sheep fetal transplantation model with lineage analysis\",\n      \"pmids\": [\"12070011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single large-animal model, not human in vivo\", \"Quantitative thresholds of γc needed per lineage not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Indicated differential cytokine-receptor sensitivity to limiting γc, with IL-15-mediated NK signaling preferentially retained.\",\n      \"evidence\": \"Splice-variant RT-PCR and surface γc FACS in a single SCID patient with NK+ phenotype\",\n      \"pmids\": [\"15108287\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single patient, no functional signaling assays to confirm IL-15 retention\", \"Mechanism of preferential retention not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Distinguished γc restoration from oncogenesis, showing IL2RG itself is not directly transforming but enables developmental progression permissive for LMO2-driven leukemogenesis.\",\n      \"evidence\": \"Comparative retroviral overexpression of IL2RG vs LMO2 in human CD34+ cells with T-cell development assays\",\n      \"pmids\": [\"16988660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not exclude rare insertional cooperative events with IL2RG vector\", \"Single in vitro developmental system\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a redox-regulatory mechanism, the labile Cys183–Cys232 disulfide, whose reduction impairs IL-2 binding and STAT5 signaling.\",\n      \"evidence\": \"In vitro enzymatic reduction, proliferation and STAT5 phosphorylation assays, and an LPS in vivo inflammation model\",\n      \"pmids\": [\"22645657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural confirmation of altered IL-2 binding not obtained\", \"Physiological contexts where reduction occurs incompletely defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided isogenic in vivo evidence that γc expression confers T-cell competitive fitness via a spontaneous reversion event.\",\n      \"evidence\": \"Reversion sequencing, surface CD132 and subset flow cytometry, TCR repertoire analysis, longitudinal follow-up in a patient\",\n      \"pmids\": [\"23403317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient natural experiment\", \"Mechanism of selective CD8+ advantage not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended γc/JAK3 signaling to cell-autonomous tumor growth in pancreatic cancer.\",\n      \"evidence\": \"CRISPR knockout of IL2RG in orthotopically implanted pancreatic cancer cells with tumor growth and JAK3 expression readouts\",\n      \"pmids\": [\"29137350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vivo loss-of-function approach\", \"Ligand/upstream cytokine driving the signaling not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed the IL2RG/JAK3/STAT5 axis is required for ITK-SYK-driven oncogenic growth, converging genetic and pharmacologic evidence.\",\n      \"evidence\": \"siRNA knockdown vs tofacitinib in ITK-SYK-expressing Jurkat cells with proliferation, apoptosis, and cell-cycle assays\",\n      \"pmids\": [\"31545408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line model\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined two hypomorphic mechanisms: mislocalization of γc to the ER/Golgi (p.Pro58Ser) and impaired JAK3 binding with residual JAK3-independent STAT5 signaling (R328X), mapping a critical intracellular three-residue region.\",\n      \"evidence\": \"BioID proximity labeling, Co-IP with JAK3, surface expression, STAT5 phosphorylation, and proliferation assays on patient mutants\",\n      \"pmids\": [\"32072341\", \"31799703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the JAK3-independent STAT5 kinase not established\", \"ER/Golgi retention partners not validated reciprocally\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated CD132 signaling in decidual macrophage-mediated maternal-fetal tolerance.\",\n      \"evidence\": \"Adoptive transfer of Tim-3+ vs Tim-3- macrophages, CD132 pathway blockade, and pregnancy-outcome readouts in mice\",\n      \"pmids\": [\"35550500\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"CD132 involvement inferred from pathway blockade, not gene-specific perturbation\", \"Single lab, indirect mechanistic link\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the JAK3-independent kinase mediating residual STAT5 phosphorylation, and the structural basis by which the critical intracellular region stabilizes the receptor and recruits JAK3, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the γc intracellular domain bound to JAK3 in the corpus\", \"JAK3-independent STAT5 activation mechanism uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6, 9, 11]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 6, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"complexes\": [\"IL-2 receptor complex\"],\n    \"partners\": [\"JAK3\", \"IL2RB\", \"STAT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}