Affinage

PLCG2

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

Length
1265 aa
Mass
147.9 kDa
Annotated
2026-04-28
60 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLCγ2 is a phospholipase C that hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate IP3 and diacylglycerol, coupling receptor signaling to intracellular calcium release and activation of PKC, MAPK, NF-κB, and NFAT pathways. Its catalytic activity is restrained by autoinhibitory SH2 and C2 domain interactions; gain-of-function mutations disrupting this autoinhibition cause constitutive or temperature-sensitive hyperactivity that drives NLRP3 inflammasome activation and the PLAID/APLAID spectrum of immune dysregulation, while haploinsufficient loss-of-function variants impair NK cell calcium flux and cytotoxicity (PMID:22236196, PMID:23000145, PMID:25418813, PMID:38965708, PMID:37714437). In microglia, PLCγ2 operates downstream of CSF1R and positively regulates TREM2 expression, inflammatory gene programs, and microglial association with amyloid plaques; the protective P522R hypermorph enhances antigen presentation and CD8⁺ T cell recruitment in Alzheimer's disease models, whereas loss-of-function variants phenocopy PLCG2 knockout with blunted inflammatory responses (PMID:40346446, PMID:35142046, PMID:41066163). A splicing variant (rs1071644-T) promotes nonsense-mediated decay of an aberrant PLCG2 isoform, reducing functional enzyme levels and increasing Alzheimer's disease risk (PMID:41459197).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 Medium

    Establishing that PLCG2 is a distinct gene family member at chromosome 16q22 resolved its genomic identity relative to PLCG1 and enabled subsequent mutation-phenotype studies.

    Evidence Interspecific backcross mapping and somatic cell hybrid panel analysis in mouse and human

    PMID:7774933

    Open questions at the time
    • No functional data from mapping alone
    • Expression pattern across tissues not determined
  2. 2012 High

    Discovery that in-frame deletions in the autoinhibitory cSH2 domain cause constitutive phospholipase activity with temperature-sensitive signaling established the first molecular mechanism for PLAID and identified the autoinhibitory domain as the key regulatory element of PLCγ2.

    Evidence Genomic/cDNA sequencing, enzymatic assays, and lymphocyte signaling in PLAID patient cells

    PMID:22236196

    Open questions at the time
    • Structural basis of temperature sensitivity not resolved
    • Whether other domain mutations can cause similar phenotypes was unknown
  3. 2012 High

    Identification of the p.Ser707Tyr missense mutation as a constitutive gain-of-function at physiological temperature distinguished APLAID from the cold-sensitive PLAID mechanism, showing that different classes of autoinhibitory disruption produce distinct clinical syndromes.

    Evidence Whole-exome sequencing, overexpression in heterologous cells, and ex vivo leukocyte signaling

    PMID:23000145

    Open questions at the time
    • Structural mechanism by which S707Y disrupts autoinhibition not defined
    • Downstream inflammatory consequences not yet explored
  4. 2015 High

    Linking the PLCγ2 S707Y gain-of-function to NLRP3 inflammasome activation via elevated basal Ca²⁺ established the signaling chain from PLCγ2 hyperactivity to IL-1β-mediated sterile inflammation, explaining APLAID pathogenesis.

    Evidence FLIPR calcium flux, inflammasome western blot, and pharmacological rescue (PLC inhibitors, Ca²⁺ blockers) in patient PBMCs

    PMID:25418813

    Open questions at the time
    • Whether canonical vs. alternative inflammasome pathway is engaged was unresolved
    • Contribution of DAG/PKC arm to inflammasome activation not dissected
  5. 2018 Medium

    Expanding the mutational spectrum to include p.Leu848Pro in the cSH2 domain confirmed that multiple positions within the autoinhibitory region regulate PLCγ2 basal activity.

    Evidence In vitro PLC activity assay and whole blood cytokine assays

    PMID:30619256

    Open questions at the time
    • Only a single variant tested
    • No structural modeling of how L848P disrupts autoinhibition
  6. 2019 High

    Demonstrating that the AD-protective P522R variant is a weak enzymatic hypermorph connected PLCγ2 gain-of-function to neuroprotection and positioned PLCγ2 as a modulator of microglial function in neurodegeneration.

    Evidence Radioactive phospholipase assay, IP-One ELISA, and calcium assay in transfected COS7/HEK293T cells

    PMID:30711010

    Open questions at the time
    • Mechanism of P522R-mediated neuroprotection in microglia not yet characterized
    • Whether enzymatic hyperactivity alone explains the protective effect was unclear
  7. 2019 Medium

    Discovery that the C2 domain mutation p.Met1141Lys causes gain-of-function revealed a second autoinhibitory surface beyond the cSH2 domain, broadening understanding of PLCγ2 regulation.

    Evidence Calcium flux and ERK phosphorylation in PLCγ2-knockout DT40 cell reconstitution system

    PMID:31853824

    Open questions at the time
    • Only one C2-domain variant tested
    • No direct biophysical evidence of C2–catalytic domain interaction
  8. 2020 Medium

    Placing PLCγ2 downstream of CSF1R in a CSF1R/PLCγ2/PKA/UCP2 and CSF1R/PLCγ2/PKCε/CREB signaling axis in neonatal brain defined PLCγ2's role in anti-oxidative and anti-inflammatory neuroprotection.

    Evidence Pharmacological epistasis (U73122, BLZ945) with western blot pathway readouts in rat hypoxic-ischemic injury model

    PMID:32522286 PMID:33101590

    Open questions at the time
    • Reliance on U73122, a non-specific PLC inhibitor
    • No genetic confirmation in PLCγ2-deficient animals
    • Single lab, single model system
  9. 2020 Medium

    Showing that novel APLAID variants activate the alternative (not canonical) NLRP3 inflammasome pathway refined the inflammatory mechanism downstream of PLCγ2 hyperactivity.

    Evidence Ex vivo B cell calcium flux and in vitro PLC activity assays in patient cells

    PMID:32671674

    Open questions at the time
    • Distinction between canonical and alternative inflammasome activation requires further biochemical dissection
    • Single lab
  10. 2022 High

    Demonstrating that P522R microglia transplanted into AD mice upregulate HLA, antigen presentation, and CD8⁺ T cell recruitment established a cell-autonomous immune-enhancing mechanism for the protective PLCγ2 variant in Alzheimer's disease.

    Evidence iPSC-derived microglia chimeric mouse model with scRNA-seq and histological analysis

    PMID:35142046

    Open questions at the time
    • Whether enhanced antigen presentation is sufficient for neuroprotection not tested
    • Chimeric model may not fully recapitulate endogenous microglial function
  11. 2022 Medium

    Showing that PLCγ2 expression in microglia is induced by amyloid plaques in a progression-dependent manner and that inactivation alters immune gene expression linked PLCγ2 to disease-stage-specific microglial inflammatory programs.

    Evidence Bulk and single-cell RNA-seq in human AD brain and 5xFAD mice, Plcg2-inactivated mouse model

    PMID:35180881

    Open questions at the time
    • Transcriptomic changes without demonstration of phagocytic or clearance phenotype
    • Mechanism of plaque-dependent induction of PLCG2 not identified
  12. 2023 High

    Systematic functional classification of GOF and LOF PLCG2 variants in DT40 reconstitution and patient cells revealed that monoallelic LOF defines a new class of immune deficiency, establishing a bidirectional genotype-phenotype framework.

    Evidence Mutagenesis, Plcg2-deficient DT40 overexpression, flow cytometry for calcium/ERK, primary patient cell stimulation

    PMID:37769878

    Open questions at the time
    • Not all variants tested in primary human cells
    • In vivo consequences of LOF variants in adaptive immunity not fully explored
  13. 2023 High

    Establishing that PLCγ2 haploinsufficiency selectively impairs NK cell calcium flux and cytotoxicity (but not B cell function) identified a cell-type-specific dependency and a distinct NK cell immunodeficiency phenotype, replicated in Plcg2⁺/⁻ mice.

    Evidence Whole-exome sequencing, mass cytometry, functional assays, Plcg2⁺/⁻ mouse model

    PMID:37714437

    Open questions at the time
    • Mechanism of selective NK cell vulnerability versus B cell resilience not explained
    • Threshold of PLCγ2 activity required for NK function unknown
  14. 2024 High

    Structural-functional analysis of the D993Y variant demonstrated direct disruption of catalytic-autoinhibitory domain interaction, causing autoactivation of IP3/Ca²⁺/MAPK/NF-κB/NFAT, providing the most detailed intramolecular mechanism for PLCγ2 autoinhibition relief.

    Evidence Co-IP of domain interactions, IP1 ELISA, calcium flux, NF-κB/NFAT luciferase reporters in THP-1 KO and HEK293T cells

    PMID:38965708

    Open questions at the time
    • No crystal structure of autoinhibited vs. activated PLCγ2
    • Mechanism applicable to all GOF variants not confirmed
  15. 2024 Medium

    Splice-site mutations causing in-frame exon skipping produced dominant-negative PLCγ2 proteins that failed to activate ERK upon BCR crosslinking, expanding the LOF variant class beyond point mutations.

    Evidence Full-length cDNA RNA-seq, WGS, DT40 Plcg2-KO reconstitution with flow cytometry

    PMID:39667583

    Open questions at the time
    • Dominant-negative mechanism (e.g., competition for scaffolding) not biochemically defined
    • Limited number of splice variants tested
  16. 2025 High

    Genetic epistasis in 5xFAD mice showed PLCγ2 deficiency reduces TREM2 expression and microglial plaque association while TREM2 deficiency increases PLCγ2, establishing PLCγ2 as an upstream positive regulator of TREM2 with a feedback loop.

    Evidence 5xFAD × PLCG2-KO × TREM2-KO crosses, RNA-seq (mouse and human), immunostaining

    PMID:40346446

    Open questions at the time
    • Direct biochemical mechanism linking PLCγ2 activity to TREM2 transcription unknown
    • Whether the feedback loop operates in non-AD contexts not tested
  17. 2025 High

    Isogenic iPSC-microglia carrying P522R versus M28L versus KO demonstrated bidirectional modulation of microglial immune state: P522R enhances cytokine secretion and resists apoptosis while M28L/KO show blunted responses and reduced TREM2, consolidating the variant-function spectrum in a disease-relevant cell type.

    Evidence Isogenic iPSC-derived microglia, bulk transcriptomics, flow cytometry, cytokine and apoptosis assays

    PMID:41066163

    Open questions at the time
    • In vivo validation of M28L variant in mouse brain not performed
    • Downstream effectors mediating apoptosis resistance not identified
  18. 2025 Medium

    A functional splicing variant (rs1071644-T) promoting nonsense-mediated decay of an aberrant PLCG2 isoform demonstrated a non-coding mechanism by which PLCγ2 levels are reduced to increase AD risk.

    Evidence Minigene splicing assay in BV-2 cells, NMD cycloheximide chase, HEK293 calcium assay, qRT-PCR in human brain

    PMID:41459197

    Open questions at the time
    • Effect size of splicing variant on total PLCγ2 protein in microglia in vivo not quantified
    • Single lab, not yet independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of autoinhibited PLCγ2 and the precise molecular mechanism by which it transitions to the active state remain undefined; furthermore, how PLCγ2 enzymatic activity is mechanistically linked to TREM2 transcriptional regulation in microglia is unknown.
  • No crystal or cryo-EM structure of full-length autoinhibited PLCγ2
  • Biochemical intermediates connecting PLCγ2/Ca²⁺/IP3 to TREM2 promoter activity not identified
  • Cell-type-specific thresholds of PLCγ2 activity required for immune function (NK vs. B cell vs. microglia) not quantitatively defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0008289 lipid binding 3
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1643685 Disease 6 R-HSA-168256 Immune System 5
Partners
CSF1RNLRP3RASA4TREM2

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 In-frame genomic deletions within a region encoding an autoinhibitory domain of PLCγ2 result in protein products with constitutive phospholipase activity; these deletion proteins show diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures, establishing a temperature-sensitive gain-of-function mechanism underlying PLAID. Genomic sequencing, cDNA sequencing, enzymatic assays, flow cytometry, lymphocyte stimulation assays The New England journal of medicine High 22236196
2012 The p.Ser707Tyr substitution in the autoinhibitory SH2 domain of PLCγ2 causes a hypermorphic gain-of-function, leading to enhanced PLCγ2 activity and increased intracellular signaling at physiological temperatures, distinct from the cold-sensitive PLAID deletions. Whole-exome sequencing, overexpression of mutant protein in heterologous cells, ex vivo leukocyte signaling assays American journal of human genetics High 23000145
2015 The APLAID-causing hypermorphic PLCγ2 p.Ser707Tyr mutation causes elevated basal intracellular Ca2+ and enhanced Ca2+ flux, which activates the NLRP3 inflammasome, linking PLCγ2-mediated Ca2+ signaling to IL-1β secretion and sterile inflammation; this effect was attenuated by PLC inhibitors, intracellular Ca2+ blockers, or adenylate cyclase activators. Western blotting (inflammasome activation), FLIPR calcium flux assay, pharmacological inhibition in patient PBMCs Arthritis & rheumatology (Hoboken, N.J.) High 25418813
2019 The PLCG2 p.P522R (Pro522Arg) variant is a functional hypermorph that weakly increases PLCγ2 enzymatic activity, as demonstrated by radioactive phospholipase assay, IP-One ELISA, and calcium assays in heterologous COS7 and HEK293T cells. Radioactive enzymatic assay, IP-One ELISA, calcium assay in transfected COS7 and HEK293T cells Alzheimer's research & therapy High 30711010
2019 A novel gain-of-function mutation in the C2 domain of PLCγ2 (p.Met1141Lys) causes platelet hyper-reactivity, increased BCR-triggered calcium influx and ERK phosphorylation, and enhanced BCR-triggered influx of external calcium in a PLCγ2-knockout DT40 cell line, demonstrating that the C2 domain can regulate PLCγ2 autoinhibition. Flow cytometry (calcium flux, ERK phosphorylation), DT40 knockout cell overexpression system, platelet function assay Journal of clinical immunology Medium 31853824
2020 Novel APLAID-causing PLCG2 variants (p.Ala708Pro and p.Leu845_Leu848del) activate the NLRP3 inflammasome through the alternative pathway (not the canonical pathway), as demonstrated by ex vivo calcium responses of patient B cells and in vitro PLC activity assays. Ex vivo B cell calcium flux assay, in vitro PLC activity assay, inflammasome pathway analysis Journal of clinical immunology Medium 32671674
2018 The novel APLAID-causing p.Leu848Pro mutation in PLCγ2 (located in the cSH2 domain) leads to increased basal and EGF-stimulated PLCγ2 activity in vitro, expanding the spectrum of gain-of-function PLCG2 mutations affecting the autoinhibitory domain. In vitro PLC activity assay, whole blood cytokine assays Frontiers in immunology Medium 30619256
2023 PLCG2 variants functionally classified as gain-of-function (GOF) or monoallelic loss-of-function (LOF) alter B-cell activation (BCR-induced calcium flux and ERK phosphorylation) in opposite directions; monoallelic LOF variants define a new class associated with humoral immune deficiency, autoinflammation, herpesvirus susceptibility, and NK cell dysfunction. Mutagenesis of EGFP-PLCG2 plasmid, overexpression in Plcg2-deficient DT40 B cells, flow cytometry (calcium flux, ERK phosphorylation), primary patient cell stimulation The Journal of allergy and clinical immunology High 37769878
2023 PLCγ2 haploinsufficiency (loss-of-function heterozygous PLCG2 variants) impairs NK cell calcium flux and cytotoxicity while preserving B-cell function, establishing a distinct NK cell immunodeficiency syndrome; this phenotype was recapitulated in Plcg2+/- mice. Whole-exome sequencing, mass cytometry, functional assays (calcium flux, cytotoxicity), Plcg2+/- mouse model The Journal of allergy and clinical immunology High 37714437
2020 Rh-CSF1 activates a CSF1R/PLCG2/PKA/UCP2 signaling pathway in neonatal rat brain after hypoxic-ischemic injury, reducing oxidative stress and neuronal apoptosis; pharmacological inhibition of PLCG2 with U73122 abolished the neuroprotective effects of rh-CSF1. Western blot (p-PLCG2, p-PKA, UCP2), pharmacological inhibition (BLZ945, U73122), immunofluorescence, behavioral tests, TUNEL/Fluoro-Jade staining in rat HI model Oxidative medicine and cellular longevity Medium 33101590
2020 Rh-CSF1 activates a CSF1R/PLCG2/PKCε/CREB signaling axis that attenuates neuroinflammation after hypoxic-ischemia; inhibition of PLCG2 with U73122 blocked the anti-inflammatory effects including IL-1β and TNF-α downregulation. Western blot (p-PLCG2, p-PKCε, p-CREB), pharmacological inhibition, immunofluorescence, rat HI model Journal of neuroinflammation Medium 32522286
2025 PLCG2 deficiency in 5xFAD mice reduces TREM2 expression and impairs microglial association with amyloid-beta plaques, while TREM2 deficiency increases PLCG2 expression; human transcriptomics confirmed a positive correlation between PLCG2 and TREM2 expression independent of pathological scores, indicating PLCG2 acts upstream to regulate TREM2-mediated immune responses. 5xFAD x PLCG2-KO x TREM2-KO mouse crosses, RNA-sequencing (mouse and human bulk), immunostaining Alzheimer's & dementia : the journal of the Alzheimer's Association High 40346446
2024 The novel PLCγ2 D993Y variant (APLAID-associated) disrupts the interaction between the catalytic and autoinhibitory domains of PLCγ2, causing autoactivation with heightened PLCγ2 phosphorylation, elevated IP3 production, increased intracellular Ca2+ release, and activation of MAPK, NF-κB, and NFAT signaling pathways. Immunoblotting, luciferase assay (NF-κB/NFAT), inositol monophosphate ELISA, calcium flux assay, immunoprecipitation (domain interaction), overexpression in HEK293T/COS-7/THP-1 KO cells Arthritis & rheumatology (Hoboken, N.J.) High 38965708
2022 The protective PLCG2-P522R variant in human iPSC-derived microglia transplanted into chimeric AD mice induces significant upregulation of HLA expression and antigen presentation, chemokine signaling, and T cell proliferation pathways, and promotes CD8+ T cell recruitment to the brain. Chimeric mouse model with iPSC-microglia transplantation, single-cell and bulk RNA sequencing, histological analysis Alzheimer's & dementia : the journal of the Alzheimer's Association High 35142046
2022 PLCG2 expression in microglia is induced by amyloid plaques in a disease progression-dependent manner in 5xFAD mice, and PLCG2 co-expression network analysis links PLCG2 to inflammatory pathways including NF-κB signaling and response to LPS; inactivation of Plcg2 in mice altered immune-related gene expression without changing microglial cell coverage or morphology. Bulk RNA-seq (human AD brain, 5xFAD mice), single-cell RNA-seq, microglia depletion, immunostaining, differential expression analysis in Plcg2-inactivated mice Genome medicine Medium 35180881
2025 Risk-conferring PLCG2-M28L microglia (iPSC-derived) share transcriptomic similarity with PLCG2-KO microglia, showing reduced TREM2 expression, blunted inflammatory responses, and increased proliferation/cell death, whereas protective PLCG2-P522R microglia show elevated cytokine secretion after LPS and resistance to apoptosis, demonstrating that PLCG2 variants bidirectionally modulate microglial immune state and function. iPSC-derived microglia with isogenic PLCG2 variants (P522R, M28L, KO), bulk transcriptomics, flow cytometry, cytokine assays, apoptosis assays Alzheimer's & dementia : the journal of the Alzheimer's Association High 41066163
2024 The DNMT3B methyltransferase inhibits PLCG2 transcription by methylating the PLCG2 promoter region in colorectal cancer cells; overexpression of PLCG2 suppresses colorectal cancer xenograft tumor growth in vivo. Methylation-specific PCR (MSP), bisulfite-sequencing PCR (BSP), DNMT3B overexpression/knockdown, PLCG2 overexpression, xenograft mouse model Acta biochimica et biophysica Sinica Medium 39108206
2025 A novel PLCG2 mRNA isoform (D65-PLCG2) lacking 65 bp from exon 28 is susceptible to nonsense-mediated decay and lacks Ca2+ responsiveness (demonstrated in transfected HEK293 cells); the rs1071644-T allele promotes increased exon 28 skipping via a functional splicing variant, thereby reducing functional PLCγ2 and increasing AD risk. Minigene splicing assay in BV-2 microglial cells, cycloheximide NMD assay, HEK293 transfection calcium assay, qRT-PCR in human brain/buffy coat Molecular neurodegeneration advances Medium 41459197
2025 PLCγ2 mediates spontaneous calcium oscillation and chemoattractant-induced calcium response in neutrophils; PLCγ2 knockdown impairs spontaneous Ca2+ oscillation, reduces membrane targeting of CAPRI (a RasGAP), causes increased Ras/PI3Kγ activation and actin polymerization, and alters the chemoattractant concentration range for neutrophil chemotaxis. plcg2 knockdown neutrophils, calcium imaging, membrane targeting assays, PI3K activity, actin polymerization assays, chemotaxis assays bioRxivpreprint Medium bio_10.1101_2025.04.07.647573
2024 PLCG2 in colorectal cancer cells promotes proliferation, invasion, metastasis, EMT, and cell cycle progression while inhibiting apoptosis via Akt-mTOR pathway activation; PLCG2 knockdown also suppresses CD8+ T cell infiltration, promotes Treg infiltration, and upregulates PD-1/PD-L1 expression, potentiating immune checkpoint blockade therapy. RNA-seq, western blotting, qRT-PCR, in vivo xenograft models, flow cytometry, multiplex immunohistochemistry International journal of biological sciences Medium 39494327
2024 Splice site mutations and de novo deletions in PLCG2 can cause in-frame exon skipping (e.g., loss of exons 18-19 or 19-22); overexpression of these deletion transcripts in Plcg2-deficient DT40 cells failed to phosphorylate ERK in response to BCR crosslinking, confirming dominant-negative function at physiological temperature. Full-length PLCG2 cDNA RNA sequencing, whole genome sequencing, DT40 Plcg2-KO overexpression, flow cytometry (ERK phosphorylation) The Journal of allergy and clinical immunology Medium 39667583
1995 The PLCG2 gene was mapped to chromosome 16q22-qter in humans and to the central region of mouse chromosome 8, establishing that PLCG2 and PLCG1 are members of a dispersed gene family mapping to distinct chromosomal regions. Interspecific backcross mapping (mouse), rodent/human somatic cell hybrid panel (human) Genomics Medium 7774933

Source papers

Stage 0 corpus · 60 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 770 28714976
2012 Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. The New England journal of medicine 305 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 109 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 106 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 105 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 80 30326945
2022 PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease. Genome medicine 73 35180881
2015 Connecting two pathways through Ca 2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation. Arthritis & rheumatology (Hoboken, N.J.) 66 25418813
2023 BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. Blood advances 64 36696464
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 45 32166339
2015 Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated With PLCG2 Mutations. JAMA dermatology 45 25760457
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 42 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 40 35142046
2020 Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations. Journal of clinical immunology 40 32671674
2023 PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration. Cell death & disease 38 37031207
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 37 37955424
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 30 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
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
2022 Plcg2 Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer's Disease-Relevant Phenotypes in Mice. Frontiers in aging neuroscience 19 35813947
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 18 39494327
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 16 36530083
1995 Phospholipase C gamma-2 (Plcg2) and phospholipase C gamma-1 (Plcg1) map to distinct regions in the human and mouse genomes. Genomics 14 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 6 39487477
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
2024 The PLCG2 Inhibits Tumor Progression and Mediates Angiogenesis by VEGF Signaling Pathway in Clear Cell Renal Cell Carcinoma. Frontiers in bioscience (Landmark edition) 4 39614428
2023 Clinical and immunological features of an APLAID patient caused by a novel mutation in PLCG2. Frontiers in immunology 4 36776842
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
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
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 1 41066163
2024 Characterization of a Novel Pathogenic PLCG2 Variant Leading to APLAID Syndrome Responsive to a TNF Inhibitor. Arthritis & rheumatology (Hoboken, N.J.) 1 38965708
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 Non-microglial downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease-related hallmarks. bioRxiv : the preprint server for biology 0 41928929
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