Affinage

PLCG2

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 · UniProt P16885

Length
1265 aa
Mass
147.9 kDa
Annotated
2026-06-10
61 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLCG2 encodes phospholipase Cγ2, a signaling enzyme whose catalytic hydrolysis of phosphoinositides generates IP3 and triggers intracellular Ca2+ release downstream of immune receptors, and whose activity is held in check by an intramolecular autoinhibitory domain (PMID:22236196, PMID:38965708). The enzyme is normally restrained through contacts between its catalytic core and autoinhibitory regions, including the cSH2 and C2 domains; missense substitutions (S707Y, M1141K, D993Y) and in-frame genomic deletions in these regions relieve autoinhibition to produce constitutive or temperature-sensitive hyperactivity, with the deleted autoinhibitory domain conferring temperature-dependent regulation (PMID:22236196, PMID:23000145, PMID:31853824, PMID:38965708). Disruption of the catalytic–autoinhibitory interface drives heightened PLCγ2 phosphorylation, elevated IP3, Ca2+ release, and downstream MAPK, NF-κB, and NFAT signaling (PMID:38965708), and the resulting elevated Ca2+ flux engages the NLRP3 inflammasome to drive IL-1β secretion (PMID:25418813). Gain-of-function variants in PLCG2 cause autoinflammatory and immune-dysregulation disease, while a broad class of monoallelic loss-of-function variants and haploinsufficiency impair NK cell calcium flux and cytotoxicity with relatively preserved B cell function (PMID:37769878, PMID:37714437). In the immune-receptor pathway, PLCG2 acts downstream of the B cell receptor to drive Ca2+ flux and ERK phosphorylation, and downstream of CSF1R via PKA/UCP2 and PKCε/CREB branches in microglial and neuronal contexts (PMID:31853824, PMID:33101590, PMID:32522286). PLCG2 is a component of TREM2 signal transduction in microglia, where its expression is induced by amyloid pathology and supports microglial association with plaques; the Alzheimer's-protective P522R variant is mildly hypermorphic and enhances microglial antigen presentation, T cell recruitment, and cytokine responses, whereas risk variants phenocopy PLCG2 loss (PMID:30711010, PMID:40346446, PMID:35142046, PMID:41066163).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2012 High

    Established that a discrete region of PLCG2 functions as an autoinhibitory domain whose loss produces constitutive, temperature-sensitive enzyme hyperactivity, defining the regulatory logic of the enzyme.

    Evidence Sequencing of patient cDNA/genomic DNA with enzymatic phospholipase assays and temperature-dependent leukocyte signaling assays

    PMID:22236196

    Open questions at the time
    • Did not resolve the structural basis of the temperature-sensitive conformational switch
    • Did not map all autoinhibitory contacts within the enzyme
  2. 2012 High

    Identified the cSH2 domain as a specific autoinhibitory element by showing a single missense substitution there is hypermorphic at physiological temperature, refining which domain restrains activity.

    Evidence Overexpression of mutant in heterologous cells plus ex vivo patient leukocyte signaling and whole-exome sequencing

    PMID:23000145

    Open questions at the time
    • Did not establish the downstream effector consequences of the hypermorphic state
    • Mechanism of cSH2-mediated autoinhibition not structurally defined
  3. 2015 High

    Connected PLCγ2 hyperactivity to a defined inflammatory effector by showing elevated Ca2+ drives NLRP3 inflammasome activation and IL-1β secretion, placing PLCG2 upstream of the inflammasome.

    Evidence Caspase-1/IL-1β immunoblotting and FLIPR Ca2+ assays in patient PBMCs with pharmacological PLC, Ca2+, and adenylate cyclase modulation

    PMID:25418813

    Open questions at the time
    • Did not establish whether all GOF variants signal through the same canonical inflammasome route
    • Molecular link between Ca2+ flux and NLRP3 assembly not detailed
  4. 2018 Medium

    Demonstrated that gain-of-function variants can act through inflammasome-independent inflammatory mechanisms, showing the disease pathway is variant-dependent.

    Evidence In vitro PLC activity assay and whole-blood cytokine assays with IL-1 blockade

    PMID:30619256

    Open questions at the time
    • Single lab
    • Alternative inflammatory effector pathway for L848P not identified
  5. 2019 Medium

    Extended the autoinhibitory map beyond the SH2 domains by showing a C2-domain GOF variant enhances BCR-triggered Ca2+ and ERK signaling.

    Evidence BCR-triggered Ca2+ flux and ERK phosphorylation by flow cytometry in patient cells and Plcg2-deficient DT40 reconstitution

    PMID:31853824

    Open questions at the time
    • Single lab
    • Structural contribution of C2 domain to autoinhibition not resolved
  6. 2019 High

    Showed the Alzheimer's-protective P522R variant is a mild gain-of-function allele, linking PLCγ2 enzymatic tuning to reduced disease risk.

    Evidence Radioactive phospholipase, IP-One ELISA, and Ca2+ assays in transfected COS7/HEK293T cells

    PMID:30711010

    Open questions at the time
    • Heterologous system did not establish the cell type relevant to protection
    • Did not link enzyme activity to a microglial phenotype
  7. 2020 Medium

    Placed PLCG2 downstream of CSF1R in microglial/neuronal protective signaling, defining CSF1R/PLCG2/PKA/UCP2 and CSF1R/PLCG2/PKCε/CREB branches.

    Evidence Pharmacological epistasis (BLZ945, U73122) with phospho-pathway immunoblotting and functional readouts in a rat hypoxic-ischemic model

    PMID:32522286 PMID:33101590

    Open questions at the time
    • Single lab, animal model
    • Direct PLCγ2 substrate-to-PKA/PKCε link not biochemically demonstrated
  8. 2022 Medium

    Positioned PLCG2 within TREM2 signal transduction in microglia and showed its requirement for amyloid-responsive microglial behavior.

    Evidence PLCG2-deficient and TREM2-deficient crosses into 5xFAD mice with bulk RNA-seq, immunostaining, and human transcriptomic correlation

    PMID:40346446

    Open questions at the time
    • Directionality of PLCG2-TREM2 regulatory relationship not fully resolved
    • Single lab
  9. 2022 Medium

    Linked the protective P522R allele to a specific microglial gain-of-function — enhanced antigen presentation and T cell engagement — providing a cellular mechanism for AD protection.

    Evidence P522R vs WT iPSC-microglia transplanted into chimeric AD mice with single-cell/bulk RNA-seq and CD8+ T cell histology

    PMID:35142046

    Open questions at the time
    • Single lab
    • Causal link between enzymatic hypermorphism and antigen-presentation phenotype not isolated
  10. 2023 High

    Systematically classified PLCG2 variants, revealing a dominant class of monoallelic loss-of-function alleles alongside gain-of-function alleles with distinct immune phenotypes including NK cell dysfunction.

    Evidence Mutagenesis and reconstitution in Plcg2-deficient DT40 cells with BCR Ca2+/ERK readouts and primary patient cell assays

    PMID:37769878

    Open questions at the time
    • Mechanistic basis of cell-type-selective phenotypes not resolved
    • Did not define why NK cells are more sensitive than B cells
  11. 2023 High

    Established that full PLCG2 gene dosage is specifically required for NK cell function, showing haploinsufficiency causes NK immunodeficiency with preserved B cells.

    Evidence Whole-exome sequencing, mass cytometry, NK cytotoxicity/Ca2+ assays, and a Plcg2+/- mouse phenocopy

    PMID:37714437

    Open questions at the time
    • Molecular basis for NK-specific dosage sensitivity not identified
  12. 2024 High

    Provided direct biochemical evidence that autoinhibition operates through a catalytic–autoinhibitory domain interaction, disrupted by D993Y to drive Ca2+/MAPK/NF-κB/NFAT signaling.

    Evidence IP3 ELISA, Ca2+ flux, phospho-immunoblotting, NF-κB/NFAT luciferase reporters, and co-immunoprecipitation of domain interaction across HEK293T/COS-7/PLCG2-KO THP-1 cells

    PMID:38965708

    Open questions at the time
    • Structural detail of the interdomain interface not solved
    • Did not test whether other GOF variants disrupt the same contact
  13. 2024 Medium

    Demonstrated a dominant-negative class of PLCG2 alleles, where in-frame deletion proteins fail to transmit BCR signaling, expanding the spectrum of pathogenic mechanisms beyond simple GOF/LOF.

    Evidence cDNA/whole-genome sequencing and reconstitution of deletion transcripts in Plcg2-deficient DT40 cells with BCR-triggered ERK readout

    PMID:39667583

    Open questions at the time
    • Single lab
    • Mechanism by which deletion protein interferes with wild-type enzyme not defined
  14. 2024 Medium

    Identified epigenetic silencing of PLCG2 in cancer and a tumor-suppressive role, broadening its functional contexts beyond immune signaling.

    Evidence Methylation-specific/bisulfite PCR linking DNMT3B to PLCG2 promoter methylation, with xenograft tumor growth assays

    PMID:39108206

    Open questions at the time
    • Single lab
    • Effector pathway downstream of PLCG2 in colorectal cancer not defined
  15. 2025 Medium

    Defined a chemotaxis-gating function for PLCγ2 in neutrophils via control of CAPRI membrane recruitment and Ras/PI3Kγ activity.

    Evidence Ca2+ imaging, CAPRI membrane localization, Ras/PI3Kγ activity, actin and chemotaxis assays in plcg2-knockdown neutrophils (preprint)

    PMID:bio_10.1101_2025.04.07.647573

    Open questions at the time
    • Preprint, single lab
    • Direct PLCγ2-CAPRI biochemical link not established
  16. 2025 Medium

    Identified splice-based loss-of-function mechanisms, including an NMD-susceptible isoform lacking the Ca2+-binding domain generated by a risk allele.

    Evidence Minigene splicing in BV-2 cells, cycloheximide NMD assessment, and Ca2+ response comparison in transfected HEK293 cells

    PMID:41459197

    Open questions at the time
    • Single lab
    • Endogenous in vivo abundance of the isoform not quantified
  17. 2025 Medium

    Resolved allele-specific microglial consequences, with risk M28L phenocopying PLCG2 knockout and protective P522R enhancing cytokine responses and apoptosis resistance.

    Evidence Isogenic iPSC-derived microglia (P522R/M28L/KO) with bulk RNA-seq, cytokine, proliferation, apoptosis, and TREM2 expression assays

    PMID:41066163

    Open questions at the time
    • Single lab
    • Mechanism connecting M28L to TREM2 downregulation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PLCγ2 dosage and activity translate into cell-type-selective phenotypes (NK vs B cells, microglia vs neurons) and the structural basis of its temperature-sensitive autoinhibition remain unresolved.
  • No high-resolution structure of the autoinhibited and activated states reported in the corpus
  • Cell-type-specific effector wiring not mechanistically dissected
  • Neuronal role of PLCG2 rests on preprint-level evidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0060089 molecular transducer activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CAPRICSF1RTREM2VCP

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 In-frame genomic deletions within the autoinhibitory domain of PLCG2 result in protein products with constitutive phospholipase activity. Cells expressing these deletion proteins show diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures, establishing that the deleted region encodes an autoinhibitory domain critical for temperature-dependent regulation. Sequencing of cDNA and genomic DNA from patients; enzymatic assays measuring phospholipase activity; flow cytometry-based signaling assays in patient leukocytes at different temperatures The New England journal of medicine High 22236196
2012 The p.Ser707Tyr missense substitution in the autoinhibitory cSH2 domain of PLCγ2 causes enhanced PLCγ2 activity (hypermorphic effect) with increased intracellular signaling at physiological temperatures, establishing that the cSH2 domain normally restrains enzyme activity. Overexpression of altered protein in heterologous cells; ex vivo leukocyte signaling assays from affected patients; whole-exome sequencing to identify the de novo variant American journal of human genetics High 23000145
2015 The hypermorphic p.Ser707Tyr PLCγ2 mutation causes elevated basal intracellular Ca2+ and enhanced Ca2+ flux, which drives NLRP3 inflammasome activation and IL-1β secretion in response to LPS alone; this effect is blocked by PLC inhibitors, intracellular Ca2+ blockers, or adenylate cyclase activators, placing PLCG2 upstream of the NLRP3 inflammasome via Ca2+ signaling. Western blotting for caspase-1 cleavage and IL-1β; FLIPR calcium flux assay in patient PBMCs; pharmacological inhibition with U73122 (PLC inhibitor), Ca2+ blockers, and forskolin Arthritis & rheumatology (Hoboken, N.J.) High 25418813
2019 The Alzheimer's disease-protective p.P522R variant of PLCG2 produces a small hypermorphic (gain-of-function) effect on enzyme activity, as measured by multiple orthogonal assays in transfected heterologous cells. Radioactive phospholipase assay; IP-One ELISA; calcium assay in transfected COS7 and HEK293T cells Alzheimer's research & therapy High 30711010
2019 The p.Met1141Lys gain-of-function mutation in the C2 domain of PLCγ2 causes increased B cell receptor-triggered calcium influx and ERK phosphorylation, as demonstrated in primary patient cells and by overexpression in a PLCγ2-knockout DT40 cell line, expanding the functional domains required for autoinhibition beyond the SH2 domains. BCR-triggered calcium flux and ERK phosphorylation assays by flow cytometry in primary cells; overexpression of mutant in Plcg2-deficient DT40 B cells Journal of clinical immunology Medium 31853824
2018 A novel p.L848P missense mutation in PLCG2 causes increased basal and EGF-stimulated PLCγ2 activity in vitro, establishing this as a gain-of-function variant; unlike S707Y, it does not appear to activate the NLRP3 inflammasome as the primary inflammatory mechanism. In vitro PLC activity assay; whole blood cytokine assays; negative result for IL-1β response to IL-1 blockade Frontiers in immunology Medium 30619256
2020 Two novel PLCG2 variants (p.Ala708Pro and p.Leu845_Leu848del) cause enhanced PLCγ2 enzymatic activity as measured by ex vivo calcium responses in patient B cells stimulated via IgM and by in vitro PLC activity assays; additionally, both variants activate the NLRP3 inflammasome through the alternative rather than the canonical pathway. Ex vivo calcium flux assay in patient B cells; in vitro PLC activity assay; Western blotting for inflammasome components Journal of clinical immunology Medium 32671674
2020 CSF1R activation by rh-CSF1 increases phosphorylation of PLCG2, and pharmacological inhibition of PLCG2 (U73122) abolishes neuroprotective effects of rh-CSF1 in a rat hypoxic-ischemic model, placing PLCG2 downstream of CSF1R in a CSF1R/PLCG2/PKA/UCP2 signaling pathway that reduces oxidative stress and neuronal apoptosis. Western blot for p-PLCG2, p-PKA, UCP2; pharmacological inhibition with CSF1R inhibitor BLZ945 and PLCG2 inhibitor U73122; brain infarct volume, TUNEL staining, immunofluorescence in rat pups Oxidative medicine and cellular longevity Medium 33101590
2020 CSF1R activation by rh-CSF1 increases p-PLCG2, p-PKCε, and p-CREB; inhibition of PLCG2 by U73122 abolishes anti-inflammatory effects, establishing a CSF1R/PLCG2/PKCε/CREB signaling pathway downstream of CSF1R in microglial neuroinflammation regulation. Western blot for pathway components; pharmacological inhibition with BLZ945 and U73122; brain edema, infarct area, and cytokine measurements in rat HIE model Journal of neuroinflammation Medium 32522286
2022 PLCG2 deficiency in 5xFAD mice abolishes the increase in Plcg2 expression driven by amyloid pathology, reduces microglial association with amyloid plaques, and perturbs immune-related transcriptional pathways; PLCG2 deficiency also reduces TREM2 expression, while TREM2 deficiency increases PLCG2 expression, placing PLCG2 as a component of TREM2 signal transduction that may play an upstream regulatory role. PLCG2-deficient × 5xFAD mouse crosses; TREM2-deficient × 5xFAD crosses; bulk RNA-sequencing transcriptomics; immunostaining; correlation with human bulk RNA-seq data Alzheimer's & dementia : the journal of the Alzheimer's Association Medium 40346446
2022 PLCG2 P522R variant in human iPSC-derived microglia transplanted into chimeric AD mice induces increased HLA/antigen presentation gene expression, chemokine signaling, and T cell proliferation pathways, and promotes CD8+ T cell recruitment to the brain, demonstrating a functional role for PLCG2 in microglial antigen presentation and T cell engagement. iPSC-derived microglia (P522R vs. wild-type) transplanted into chimeric AD mice; single-cell and bulk RNA-sequencing; histological analysis of CD8+ T cell infiltration Alzheimer's & dementia : the journal of the Alzheimer's Association Medium 35142046
2023 Functional classification of numerous PLCG2 variants in Plcg2-deficient DT40 B cells revealed that most functional variants define a class of monoallelic loss-of-function (LOF) mutations, while 13 variants are gain-of-function (GOF); LOF and GOF variants cause overlapping but distinct immune phenotypes, including NK cell dysfunction that can exceed B cell effects. Mutagenesis of EGFP-PLCG2 plasmid; overexpression in Plcg2-deficient DT40 cells; BCR-induced calcium flux and ERK phosphorylation by flow cytometry; primary patient cell calcium flux assays The Journal of allergy and clinical immunology High 37769878
2023 PLCG2 haploinsufficiency (heterozygous loss-of-function) causes impaired NK cell calcium flux and cytotoxicity with preserved B cell function; Plcg2+/- mice phenocopy this human NK cell immunodeficiency, establishing that full PLCG2 dosage is required for normal NK cell—but not B cell—function. Whole-exome sequencing; mass cytometry; functional NK cell cytotoxicity assays; calcium flux assays; Plcg2+/- mouse model The Journal of allergy and clinical immunology High 37714437
2024 The PLCG2 p.D993Y variant disrupts the interaction between catalytic and autoinhibitory domains of PLCγ2, causing autoactivation with heightened PLCγ2 phosphorylation, elevated IP3 production, intracellular Ca2+ release, and activation of MAPK, NF-κB, and NFAT signaling pathways. IP3 (inositol monophosphate) ELISA; calcium flux assay; immunoblotting for pPLCγ2; luciferase reporter assays for NF-κB/NFAT; immunoprecipitation for domain interaction; expression in HEK293T, COS-7, and PLCG2-KO THP-1 cells Arthritis & rheumatology (Hoboken, N.J.) High 38965708
2024 In-frame deletions of exons 18-19 or 19-22 in PLCG2 (caused by splice site or de novo mutations) produce proteins that fail to phosphorylate ERK in response to B cell receptor crosslinking at physiological conditions, consistent with dominant-negative function. cDNA sequencing of full-length PLCG2; whole genome sequencing; overexpression of deletion transcripts in Plcg2-deficient DT40 cells; ERK phosphorylation by flow cytometry with/without BCR crosslinking The Journal of allergy and clinical immunology Medium 39667583
2025 PLCG2 downregulation in neurons (non-microglial) disrupts dendritic morphology, impairs synaptic function, and increases Aβ levels and tau phosphorylation in rat primary neuronal cultures and human neuronal cultures; a loss-of-function PLCG2 variant (R953*) recapitulates these synaptic and AD-related phenotypes, suggesting a neuronal role for PLCG2 in synaptic maintenance. High-content screening in rat primary neuronal cultures; PLCG2 knockdown; human neuronal culture experiments; Aβ measurement; tau phosphorylation assay; single-nuclei RNA-seq bioRxiv : the preprint server for biologypreprint Medium 41928929
2025 PLCγ2 mediates spontaneous calcium oscillation in neutrophils and contributes to chemoattractant-triggered calcium response; PLCγ2-deficient (plcg2 kd) neutrophils show impaired Ca2+ oscillation, decreased membrane targeting of the RasGAP CAPRI, and increased Ras/PI3Kγ activation and actin polymerization, demonstrating that PLCγ2 gates chemoattractant concentration range for chemotaxis by controlling CAPRI membrane recruitment. Ca2+ imaging; membrane localization assays for CAPRI; Ras activation assay; PI3Kγ activity; actin polymerization assay; chemotaxis assay in plcg2 knockdown neutrophils bioRxivpreprint Medium bio_10.1101_2025.04.07.647573
2025 A PLCG2 splice isoform lacking 65 bp from exon 28 (D65-PLCG2), generated by the rs1071644-T allele, lacks the Ca2+-binding domain and does not respond to cytosolic Ca2+ increase in the same manner as canonical PLCG2; D65-PLCG2 is susceptible to nonsense-mediated RNA decay, representing a loss-of-function mechanism. Minigene splicing assay in BV-2 microglial cells; cycloheximide treatment for NMD assessment; Ca2+ response assay comparing D65-PLCG2-GFP vs. PLCG2-GFP in transfected HEK293 cells; qRT-PCR Molecular neurodegeneration advances Medium 41459197
1995 PLCG2 maps to the long arm of human chromosome 16 (region q22-qter) and to the central region of mouse chromosome 8, distinct from the chromosomal location of the paralog PLCG1, establishing that the mammalian Plcg genes constitute a dispersed family. Interspecific backcross mapping in mice (AEJ/Gn × M. spretus); rodent/human somatic cell hybrid panel mapping Genomics Medium 7774933
2019 PLCG2 knockdown in rat liver BRL-3A cells reduces cell viability, proliferation, and G2/M cell cycle progression, with downregulation of NF-κB, FOS, JUN, ELK, BCL2, CCNB1, and CCND1, placing PLCG2 upstream of ERK and NF-κB pathways in hepatocyte proliferation. siRNA knockdown; MTT and BrdU proliferation assays; flow cytometry cell cycle analysis; qRT-PCR and Western blot for pathway components Artificial cells, nanomedicine, and biotechnology Low 31549850
2024 DNMT3B methylates the PLCG2 promoter to suppress PLCG2 transcription in colorectal cancer cells; overexpression of PLCG2 inhibits colorectal cancer xenograft tumor growth in vivo. Methylation-specific PCR; bisulfite-sequencing PCR; qRT-PCR and Western blot; CCK-8 and colony formation assays; in vivo xenograft model Acta biochimica et biophysica Sinica Medium 39108206
2025 PLCG2 interacts with VCP (valosin-containing protein) and promotes mitophagy and cell survival in small cell lung cancer cells; VCP overexpression rescues the inhibitory effects of PLCG2 silencing on mitophagy. RNA immunoprecipitation; dual-luciferase reporter assay; Western blot for mitophagy markers; CCK-8, colony formation, apoptosis assays; xenograft mouse model Anti-cancer drugs Low 41176779
2025 In iPSC-derived microglia, the risk-conferring PLCG2-M28L variant reduces TREM2 expression and blunts inflammatory responses while increasing proliferation and cell death, phenotypically resembling PLCG2-knockout microglia; the protective PLCG2-P522R variant shows elevated cytokine secretion after LPS stimulation and resistance to apoptosis, demonstrating allele-specific effects on microglial function. iPSC-derived microglia with PLCG2P522R, PLCG2M28L, or PLCG2KO; bulk RNA-sequencing; cytokine secretion assays; proliferation and apoptosis assays; TREM2 expression analysis Alzheimer's & dementia : the journal of the Alzheimer's Association Medium 41066163

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature genetics 778 28714976
2012 Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. The New England journal of medicine 307 22236196
2012 A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. American journal of human genetics 268 23000145
2019 Alzheimer's disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimer's research & therapy 112 30711010
2019 Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood 109 31243043
2014 HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome. Journal of the American Society of Nephrology : JASN 107 25349203
2019 A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta neuropathologica 94 31131421
2018 ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans. Molecular neurodegeneration 81 30326945
2022 PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome medicine 75 35180881
2023 BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. Blood advances 67 36696464
2015 Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation. Arthritis & rheumatology (Hoboken, N.J.) 66 25418813
2018 Novel PLCG2 Mutation in a Patient With APLAID and Cutis Laxa. Frontiers in immunology 54 30619256
2020 PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta neuropathologica 46 32166339
2015 Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations. JAMA dermatology 45 25760457
2024 Absence of BTK, BCL2, and PLCG2 Mutations in Chronic Lymphocytic Leukemia Relapsing after First-Line Treatment with Fixed-Duration Ibrutinib plus Venetoclax. Clinical cancer research : an official journal of the American Association for Cancer Research 43 37955424
2023 PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants. The Journal of allergy and clinical immunology 43 37769878
2022 The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model. Alzheimer's & dementia : the journal of the Alzheimer's Association 42 35142046
2023 PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration. Cell death & disease 41 37031207
2020 Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations. Journal of clinical immunology 40 32671674
2020 Examination of the Effect of Rare Variants in TREM2, ABI3, and PLCG2 in LOAD Through Multiple Phenotypes. Journal of Alzheimer's disease : JAD 31 32894242
2020 Rh-CSF1 Attenuates Oxidative Stress and Neuronal Apoptosis via the CSF1R/PLCG2/PKA/UCP2 Signaling Pathway in a Rat Model of Neonatal HIE. Oxidative medicine and cellular longevity 31 33101590
2019 A Germline Mutation in the C2 Domain of PLCγ2 Associated with Gain-of-Function Expands the Phenotype for PLCG2-Related Diseases. Journal of clinical immunology 29 31853824
2018 Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: NOD2, PLCG2 and LACC1. International immunology 26 29538758
2020 Rh-CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE. Journal of neuroinflammation 24 32522286
2024 Targeting PLCG2 Suppresses Tumor Progression, Orchestrates the Tumor Immune Microenvironment and Potentiates Immune Checkpoint Blockade Therapy for Colorectal Cancer. International journal of biological sciences 21 39494327
2022 Plcg2 Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer's Disease-Relevant Phenotypes in Mice. Frontiers in aging neuroscience 21 35813947
2019 PLCG2 promotes hepatocyte proliferation in vitro via NF-κB and ERK pathway by targeting bcl2, myc and ccnd1. Artificial cells, nanomedicine, and biotechnology 20 31549850
2021 PLCG2 as a potential indicator of tumor microenvironment remodeling in soft tissue sarcoma. Medicine 18 33725976
2023 Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer's Disease. Journal of Alzheimer's disease : JAD 17 36530083
1995 Phospholipase C gamma-2 (Plcg2) and phospholipase C gamma-1 (Plcg1) map to distinct regions in the human and mouse genomes. Genomics 15 7774933
2024 Methyltransferase DNMT3B promotes colorectal cancer cell proliferation by inhibiting PLCG2. Acta biochimica et biophysica Sinica 11 39108206
2022 Variant in the PLCG2 Gene May Cause a Phenotypic Overlap of APLAID/PLAID: Case Series and Literature Review. Journal of clinical medicine 10 35955991
2020 A new report of autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) with a homozygous pattern from Iran. Immunology letters 10 32014489
2016 A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma. PloS one 10 26966907
2021 Four diseases, PLAID, APLAID, FCAS3 and CVID and one gene (PHOSPHOLIPASE C, GAMMA-2; PLCG2): Striking clinical phenotypic overlap and difference. Clinical case reports 9 33936634
2019 Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration. Investigative ophthalmology & visual science 9 31560769
2023 Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency. The Journal of allergy and clinical immunology 8 37714437
2025 PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology. Alzheimer's & dementia : the journal of the Alzheimer's Association 7 40346446
2024 Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner. Journal of neuroinflammation 7 39487477
2024 The PLCG2 Inhibits Tumor Progression and Mediates Angiogenesis by VEGF Signaling Pathway in Clear Cell Renal Cell Carcinoma. Frontiers in bioscience (Landmark edition) 6 39614428
2021 A novel likely pathogenic PLCG2 variant in a patient with a recurrent skin blistering disease and B-cell lymphopenia. European journal of medical genetics 6 34768012
2025 Overexpression of PLCG2 and TMEM38A inhibit tumor progression in clear cell renal cell carcinoma. Scientific reports 5 39863641
2023 Clinical and immunological features of an APLAID patient caused by a novel mutation in PLCG2. Frontiers in immunology 4 36776842
2025 Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells. Alzheimer's & dementia : the journal of the Alzheimer's Association 2 41066163
2024 Characterization of a Novel Pathogenic PLCG2 Variant Leading to APLAID Syndrome Responsive to a TNF Inhibitor. Arthritis & rheumatology (Hoboken, N.J.) 2 38965708
2024 Splice site and de novo variants can cause PLCG2-associated immune dysregulation with cold urticaria. The Journal of allergy and clinical immunology 2 39667583
2020 Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta neuropathologica 2 31955222
2016 Construction of recombinant adenovirus Ad-rat PLCg2-shRNA and successful suppression of PLCg2 expression in BRL-3A cells. Genetics and molecular research : GMR 2 27323081
2026 Non-microglial downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease-related hallmarks. bioRxiv : the preprint server for biology 1 41928929
2025 Case Report: de novo in-frame deletion in PLCG2 gene: a case report of B-cell lymphopenia, pulmonary bullae, and cutis laxa. Frontiers in immunology 1 40170866
2024 PLCG2 variants in cherubism. The Journal of allergy and clinical immunology 1 39197752
2020 A novel somatic PLCG2 variant associated with resistance to BTK and SYK inhibition in chronic lymphocytic leukemia. European journal of haematology 1 33089525
2026 PLCG2 across human disease: genetic variants, signaling mechanisms, and clinical implications. Journal of translational medicine 0 41507916
2026 Protective PLCG2 variants associate with a delayed onset of Alzheimer's disease among heterozygous APOE ε4 carriers. Alzheimer's research & therapy 0 41620758
2026 PLCG2 signaling and genetic resilience in Alzheimer's disease. Molecular neurodegeneration 0 41888907
2026 Potentially Functional Variants in FCER1A and PLCG2, Two B Cell-Related Immune Genes Predict the Survival of Chinese Gastric Cancer Patients. Molecular carcinogenesis 0 42138601
2025 Genetics of PLCG2 expression and splicing relative to Alzheimer's disease risk. Research square 0 40585241
2025 PLCG2 promotes cell survival and mitophagy of small cell lung cancer via regulating VCP. Anti-cancer drugs 0 41176779
2025 Genetics of PLCG2 expression and splicing relative to Alzheimer's disease risk. Molecular neurodegeneration advances 0 41459197
2025 Early-onset bibasilar emphysema in a patient with PLCG2-related immune dysregulation. Respiratory medicine case reports 0 41537131
2024 Splice site and de novo mutations can cause mixed dominant negative/gain of function PLCG2-associated immune dysregulation with cold urticaria (CU-PLAID). medRxiv : the preprint server for health sciences 0 38562814

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