Affinage

TCIRG1

V-type proton ATPase 116 kDa subunit a 3 · UniProt Q13488

Length
830 aa
Mass
93.0 kDa
Annotated
2026-06-10
74 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCIRG1 encodes the osteoclast-specific 116-kDa a3 subunit of the vacuolar H+-ATPase (V-ATPase), and is uniquely required for osteoclast-mediated extracellular acidification at the bone-resorption surface while being dispensable for intracellular lysosomal proton-pump activity in other tissues (PMID:10581033). Loss of TCIRG1 causes severe autosomal recessive osteopetrosis in humans: osteoclasts are present in normal or elevated numbers and attach to bone with intact actin rings and podosomes, but lack ruffled borders, fail to acidify their attachment sites, and excavate only shallow pits — establishing the defect as functional rather than developmental (PMID:10888887, PMID:15231021, PMID:12507890). The a3 N-terminal cytoplasmic domain (encoded by exons 5–6) is required for V-ATPase function, as the corresponding truncation fails to complement vacuolar acidification in yeast (PMID:31111556). Beyond proton transport per se, TCIRG1-dependent acidification drives downstream osteoclast biology: it controls lysosome acidification and peripheral lysosome accumulation needed for cell fusion and resorption (PMID:40995561), supports NFATc1 nuclear translocation through IP3R2-dependent calcium signaling during RANKL-induced osteoclastogenesis (PMID:32790690), enables release of matrix TGF-β1 that drives odontoblast differentiation and tooth-root formation via Smad2/3 signaling (PMID:37599332), and is required for matrix mineralization, with TCIRG1 mutation producing osteoid accumulation not seen with CLCN7 or TNFRSF11A defects (PMID:24108692). Restoration of TCIRG1 by lentiviral, transgenic, or CRISPR-corrected approaches rescues resorptive function and downstream enzyme expression (cathepsin K, TRAP) in patient-derived osteoclasts (PMID:23907031, PMID:31567691). The same locus produces an alternative transcript, TIRC7, expressed in activated lymphocytes rather than the osteoclast OC116 form (PMID:10329006); TIRC7 acts as a negative regulator of T and B cell activation, functioning upstream of CTLA-4 to induce its expression and transducing inhibitory signals upon engagement by HLA-DR alpha2 via SHP-1 recruitment and reduced STAT4/ZAP70/TCR-zeta phosphorylation (PMID:15294947, PMID:17082597, PMID:18270567). TCIRG1 mutations also cause severe congenital neutropenia through impaired neutrophil/granulopoiesis function (PMID:24753205, PMID:40964614), and TCIRG1 protein in cancer cells is stabilized by VMA21, which blocks its ubiquitination-mediated degradation (PMID:39267677).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Resolved whether the a3 subunit serves a general or compartment-specific proton-pump role, showing it is uniquely required for osteoclast extracellular acidification but not lysosomal acidification elsewhere.

    Evidence Atp6i knockout mice with extracellular acidification, lysosomal pH, and microsome proton-transport assays

    PMID:10581033

    Open questions at the time
    • Does not identify which alternative a-subunit isoforms maintain lysosomal V-ATPase activity in TCIRG1-null cells
    • Molecular basis for the osteoclast-specific requirement not defined
  2. 2000 High

    Established TCIRG1 as a genetic cause of human autosomal recessive osteopetrosis, localizing the defect to osteoclast acidification capacity rather than osteoclast number.

    Evidence Mutation analysis and genotyping of human osteopetrosis patient cohort

    PMID:10888887

    Open questions at the time
    • Does not establish the structural consequence of individual mutations
    • Fraction of osteopetrosis attributable to TCIRG1 versus other loci not addressed here
  3. 2003 High

    Showed that TCIRG1-deficient osteoclasts complete attachment and fusion but fail to acidify and form ruffled borders, distinguishing the TCIRG1 acidification defect from the matrix-degradation defect of CLCN7.

    Evidence Patient-derived in vitro osteoclasts, bone biopsies, immunohistochemistry, EM, acid-secretion and pit assays, with transplant rescue

    PMID:12507890 PMID:12687885 PMID:15231021

    Open questions at the time
    • Does not define how the a3 subunit is targeted to and assembled at the ruffled border
    • Mechanism linking acidification loss to ruffled-border absence not resolved
  4. 1998 High

    Identified TIRC7 as a lymphocyte-expressed product of the TCIRG1 locus essential for T cell activation, with antibody targeting selectively suppressing Th1 responses and prolonging allograft survival.

    Evidence Anti-TIRC7 antibody modulation in human T cell proliferation/cytokine assays and a rat kidney allograft model

    PMID:9806637

    Open questions at the time
    • Antibody-based readouts do not define the endogenous ligand or receptor partner at this stage
    • Relationship of TIRC7 to the osteoclast a3 protein not yet established
  5. 1999 High

    Demonstrated that TIRC7 and OC116/TCIRG1 are alternative transcripts of one locus with tissue-restricted expression, explaining how a single gene yields both an immune regulator and an osteoclast proton-pump subunit.

    Evidence Genomic cloning, exon-intron mapping, and RT-PCR in alloactivated T lymphocytes

    PMID:10329006

    Open questions at the time
    • Transcriptional control of the isoform switch not defined
    • Whether the two protein products share any functional domains in their respective contexts not addressed
  6. 2004 High

    Established TIRC7 as a negative regulator of both T and B cell responses through loss-of-function genetics, linking it to control of CTLA-4 expression and memory/effector differentiation.

    Evidence TIRC7 knockout mice with proliferation, cytokine, flow-cytometry and delayed-type hypersensitivity assays

    PMID:15294947

    Open questions at the time
    • Does not establish the molecular signaling intermediates downstream of TIRC7
    • Mechanism connecting TIRC7 to CTLA-4 not yet defined
  7. 2006 High

    Placed TIRC7 epistatically upstream of CTLA-4, showing it induces CTLA-4 surface expression and that its inhibitory action requires CTLA-4.

    Evidence Flow cytometry, immunofluorescence co-localization, anti-CTLA-4 blockade rescue, and CTLA-4 knockout splenocytes

    PMID:17082597

    Open questions at the time
    • Does not identify the receptor/ligand that triggers TIRC7 signaling
    • Mechanism of clathrin-coated-vesicle co-trafficking with CTLA-4 not detailed
  8. 2008 High

    Identified HLA-DR alpha2 as a TIRC7 binding partner that triggers an inhibitory signaling cascade, defining the receptor-proximal mechanism of TIRC7-mediated lymphocyte suppression.

    Evidence Co-localization, SHP-1 recruitment, phospho-STAT4/TCR-zeta/ZAP70 assays, apoptosis and cytokine assays

    PMID:18270567

    Open questions at the time
    • Stoichiometry and structural basis of the HLA-DRalpha2–TIRC7 interaction not resolved
    • How a V-ATPase-related transcript transduces a phosphatase-recruiting signal mechanistically unclear
  9. 2013 High

    Demonstrated therapeutic restorability of osteoclast function and showed Atp6i targeting protects against infection-driven bone loss, validating TCIRG1 acidification as both a corrigible defect and a drug target.

    Evidence Lentiviral TCIRG1 gene transfer into patient CD34+ cells with resorption readouts; AAV-RNAi knockdown and haploinsufficiency in periodontal and periapical infection models

    PMID:23166162 PMID:23577057 PMID:23907031

    Open questions at the time
    • Does not define the minimal expression level for durable in vivo correction
    • Whether reduced T-cell infiltration is a direct or secondary consequence of acidification loss not separated
  10. 2014 Medium

    Expanded the TCIRG1 phenotypic spectrum to matrix mineralization and to neutrophil biology, showing TCIRG1 loss causes osteoid accumulation distinct from other osteopetrosis genes and underlies a form of severe congenital neutropenia.

    Evidence Undecalcified bone histomorphometry across gene groups; family segregation with western-blot confirmation of reduced TCIRG1 protein

    PMID:24108692 PMID:24753205

    Open questions at the time
    • Mechanism linking acidification to mineralization versus osteoid build-up not resolved
    • How heterozygous TCIRG1 dysfunction specifically impairs granulopoiesis not mechanistically defined
  11. 2019 High

    Mapped a required functional element to the exon 5–6-encoded N-terminal cytoplasmic domain and confirmed transgenic rescue, connecting a specific splice/structural defect to loss of V-ATPase activity.

    Evidence Splice assay, yeast Vph1p complementation, and TCIRG1 transgenic rescue in iPSC-derived patient osteoclasts with enzyme-expression readouts

    PMID:31111556 PMID:31567691

    Open questions at the time
    • Full domain architecture and assembly requirements of the a3 subunit not delineated
    • Why TCIRG1 loss reduces downstream CTSK/TRAP expression not mechanistically explained
  12. 2020 Medium

    Linked TCIRG1 to an osteoclastogenic signaling axis, showing its loss reduces IP3R2-dependent calcium and NFATc1 nuclear translocation, implicating TCIRG1 in regulation beyond direct proton transport.

    Evidence Lentiviral Tcirg1 knockdown in BMMs with NFATc1/IP3R2 expression, calcium measurement, and nuclear-translocation assays

    PMID:32790690

    Open questions at the time
    • Single-lab study without genetic rescue of the calcium/NFATc1 phenotype
    • Whether the effect is downstream of acidification loss or an independent function unclear
  13. 2023 High

    Established TCIRG1-dependent osteoclast acidification as the upstream event releasing matrix TGF-β1 to drive odontoblast differentiation and tooth-root formation via Smad2/3.

    Evidence Atp6i knockout mice, conditioned-medium experiments, anti-TGF-β1 neutralization, Smad2/3 assays, and in vivo tooth-germ transplant rescue

    PMID:37599332

    Open questions at the time
    • Quantitative contribution of matrix TGF-β1 versus other osteoclast-derived factors not separated
    • Direct demonstration that acidification per se liberates TGF-β1 not provided
  14. 2024 Medium

    Identified a post-translational regulator of TCIRG1, showing VMA21 stabilizes the protein by preventing its ubiquitination-mediated degradation in cancer cells.

    Evidence VMA21-TCIRG1 co-immunoprecipitation, ubiquitination assay, VMA21 knockdown with proliferation/invasion and CD8+ T cell co-culture assays

    PMID:39267677

    Open questions at the time
    • Single-lab Co-IP without reciprocal validation of the interaction interface
    • Ubiquitin ligase responsible for TCIRG1 turnover not identified
  15. 2025 Medium

    Refined the cellular mechanism of TCIRG1 in osteoclast fusion and granulopoiesis, linking it to lysosome acidification/peripheral distribution and to proper TCIRG1 localization within the V-ATPase complex.

    Evidence Tcirg1 knockout mouse OA model with lysosome acidification/distribution assays; CRISPR correction of R736C in patient iPSCs with neutrophil differentiation and localization readouts

    PMID:40964614 PMID:40995561

    Open questions at the time
    • Single-lab studies without orthogonal confirmation of the lysosome-distribution mechanism
    • How mislocalized mutant TCIRG1 disrupts V-ATPase assembly structurally not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single locus coordinates expression of the osteoclast a3 V-ATPase subunit versus the immunoregulatory TIRC7 transcript, and how TIRC7 mechanistically couples to phosphatase-based inhibitory signaling, remains unresolved.
  • No structural model of the a3 subunit within the assembled osteoclast V-ATPase
  • Regulatory logic of the OC116/TIRC7 isoform switch undefined
  • Mechanistic link between V-ATPase function and downstream NFATc1/TGF-β1 signaling not fully separated from acidification

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005764 lysosome 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-382551 Transport of small molecules 3
Partners
CTLA4HLA-DRAIP3R2SHP-1VMA21
Complex memberships
vacuolar H+-ATPase (V-ATPase)

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Targeted disruption of Atp6i (TCIRG1/a3 subunit of vacuolar proton pump) in mice results in severe osteopetrosis. Atp6i-/- osteoclast-like cells lose extracellular acidification function but retain intracellular lysosomal proton pump activity. pH in Atp6i-/- liver lysosomes and proton transport in microsomes of Atp6i-/- kidney are identical to wild-type, demonstrating that Atp6i is uniquely and specifically required for osteoclast-mediated extracellular acidification. Targeted gene disruption (knockout mouse), extracellular acidification assay, lysosomal pH measurement, microsome proton transport assay Nature genetics High 10581033
2000 TCIRG1, encoding the osteoclast-specific 116-kDa subunit (a3) of the vacuolar proton pump, is mutated in human autosomal recessive osteopetrosis patients. Osteoclasts are present in normal or elevated numbers, indicating the defect is in functional capacity (acidification) rather than osteoclast differentiation. Mutation analysis (DNA sequencing), patient cohort genotyping Nature genetics High 10888887
2003 In vitro-differentiated osteoclasts from TCIRG1 compound heterozygous patients attach to bone and undergo cell fusion but fail to acidify attachment sites, consistent with TCIRG1 being essential for H+-ATPase assembly at the ruffled border. CLCN7-deficient osteoclasts, by contrast, do secrete acid but have defective organic matrix removal, distinguishing the two proteins' roles. In vitro osteoclast differentiation from CD14+ monocytes, acid secretion assay, bone pitting assay, enzyme assays, attachment protein assays Journal of bone and mineral research High 15231021
2003 Bone biopsies from TCIRG1-mutant osteopetrosis patients show osteoclasts that are morphologically normal (actin rings, clear zones, podosomes, normal alphavbeta3, c-Src, PYK2) and TRAP-positive, but are a3-subunit-negative and excavate only faint, shallow pits, indicating inefficient bone resorption due to absent proton pump subunit. Post-bone marrow transplant osteoclasts rescue a3 subunit immunoreactivity. Bone biopsy analysis, immunohistochemistry, in vitro osteoclast differentiation, bone resorption pit assay, TRAP activity assay The American journal of pathology High 12507890
2003 Electron microscopy of bone biopsies from a TCIRG1-mutant osteopetrosis infant showed osteoclasts lacking ruffled borders. Post-transplant donor osteoclasts had ruffled borders and intracytoplasmic mineral crystals, demonstrating active bone resorption restored by donor TCIRG1-expressing osteoclasts. Electron microscopy of bone biopsies pre- and post-bone marrow transplantation Pediatric pathology & molecular medicine Medium 12687885
1998 TIRC7 (an alternative transcript product of the TCIRG1 locus) functions as a membrane protein essential for T cell activation. Anti-TIRC7 antibodies prevent human T cell proliferation and IL-2 secretion in vitro, specifically inhibit IFN-gamma (Th1) but not IL-4 (Th2) expression, and prolong kidney allograft survival in vivo via inhibition of rat alloimmune response. In vitro T cell proliferation assay, cytokine secretion assay, rat kidney allograft transplantation model, anti-TIRC7 antibody modulation Immunity High 9806637
1999 TIRC7 and OC116 (TCIRG1) are alternative transcripts of the same gene on chromosome 11q13.4-q13.5, with TIRC7 consisting of 15 exons and OC116 of 20 exons sharing the last 14 introns and exons. In human alloactivated T lymphocytes, only TIRC7 (not OC116) mRNA is expressed, indicating transcript-specific expression patterns. Genomic cloning, exon-intron boundary analysis, RT-PCR in alloactivated T lymphocytes Genomics High 10329006
2004 TIRC7-deficient (knockout) mice exhibit increased T and B cell proliferation, elevated IL-2, IFN-gamma, and IL-4, expansion of memory/effector T cells (decreased CD62L, increased CD11a/CD44), decreased CTLA-4 expression in activated T cells, B cell hyperreactivity, and augmented delayed-type hypersensitivity. This establishes TIRC7 as a negative regulator of both T and B cell responses. Gene targeting (knockout mouse), in vitro T and B cell proliferation assays, cytokine expression assays, flow cytometry, delayed-type hypersensitivity model Journal of immunology High 15294947
2006 Anti-TIRC7 antibody targeting induces early cell surface expression of CTLA-4. TIRC7 co-localizes with CTLA-4 and both accumulate at the site of antigen adhesion upon T cell activation. Both are associated with clathrin-coated vesicles, indicating shared intracellular transport. Anti-TIRC7-mediated inhibition of T cell proliferation is abolished by anti-CTLA-4 antibody blockade, and CTLA-4-deficient mouse splenocytes are not responsive to TIRC7 antibody. Thus TIRC7 acts upstream of CTLA-4. Flow cytometry, immunofluorescence co-localization, CTLA-4 transcription activation assay, anti-CTLA-4 blockade rescue experiments, CTLA-4 knockout mouse splenocytes Journal of immunology High 17082597
2008 HLA-DR alpha2 domain (sHLA-DRalpha2) binds TIRC7 on lymphocytes, inducing negative signaling: inhibition of proliferation, apoptosis of CD4+ and CD8+ T cells via intrinsic pathway, SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-zeta chain and ZAP70, inhibition of IFN-gamma and FasL. HLA-DRalpha2 and TIRC7 co-localize at the APC-T cell interaction site. Co-localization by microscopy, SHP-1 recruitment assay, phosphorylation assays (STAT4, TCR-zeta, ZAP70), cytokine expression assays, apoptosis assays, LPS stimulation in vitro, in vivo apoptosis assay PloS one High 18270567
2010 In Tcirg1-/- (a3-deficient) mice, the a3 subunit accumulates in the choriocapillary meshwork in uveal tissues, while a4 subunit expression is increased in the choriocapillary meshwork of mutant mice (compensatory upregulation). Narrowed foramina in the skull (demonstrated by X-ray microtomography) cause optic nerve compression with increased retinal apoptosis, despite normal retinal architecture. X-ray microtomography, immunohistochemistry for V-ATPase subunit localization, apoptosis assay (retina), Tcirg1-/- mice PloS one Medium 20711468
2012 Murine maturation-stage ameloblasts are immunonegative for Tcirg1 (a3 subunit), despite expressing V-ATPase subunit b (brain isoform). In Tcirg1 null (oc/oc) mice, enamel formation is normal and ameloblasts are unaffected, demonstrating that the a3 subunit is not required for ameloblast proton pump activity and that a different V-ATPase isoform functions there. Immunohistochemistry, Tcirg1 null mouse analysis, enamel mineral content analysis Bone Medium 22245629
2013 Lentiviral gene transfer of TCIRG1 into peripheral blood CD34+ cells from TCIRG1-deficient osteopetrosis patients restored osteoclast resorptive function in vitro, as measured by increased Ca2+ release, CTX-I bone degradation product, and resorption pit formation on bone slices. Non-corrected patient osteoclasts failed to resorb bone. Lentiviral gene transfer, in vitro osteoclast differentiation on bone slices, qPCR, western blot, Ca2+ release assay, CTX-I ELISA, resorption pit assay, NSG mouse engraftment Bone High 23907031
2013 AAV-mediated RNAi knockdown of Atp6i/TIRC7 in periodontal tissues impairs extracellular acidification and osteoclast-mediated bone resorption, protecting mice from P. gingivalis infection-stimulated bone loss (>85% reduction) and decreasing T-cell infiltration. Atp6i haploinsufficient mice (Atp6i+/-) show similar protection from bone resorption and inflammation. AAV-shRNA knockdown in vivo, P. gingivalis infection model, bone resorption measurement, T-cell quantification, cytokine gene expression analysis, Atp6i+/- haploinsufficiency comparison PloS one High 23577057
2013 AAV-mediated Atp6i RNAi knockdown in periapical tissues inhibits osteoclast function in vitro and in vivo, reduces T-cell numbers in periapical lesions, and reduces bacterial infection-stimulated periapical bone resorption by ~80%. Atp6i+/- haploinsufficient mice show similar protection. AAV-shRNA knockdown, endodontic disease mouse model, in vitro osteoclast function assay, T-cell quantification, bone resorption measurement Infection and immunity High 23166162
2014 TCIRG1 mutations cause severe osteoid accumulation (osteomalacia) in osteopetrosis patients, whereas CLCN7 and TNFRSF11A mutations do not. Undecalcified bone biopsies from TCIRG1-mutant patients show pathological osteoid increase and decreased calcium content in mineralized matrix, revealing a specific role of TCIRG1/a3-mediated acidification in bone matrix mineralization. Undecalcified iliac crest bone biopsy histology, quantitative bone histomorphometry, serum calcium measurement Journal of bone and mineral research Medium 24108692
2014 TCIRG1 heterozygous mutations (including R736S, identified in a large pedigree) cause severe congenital neutropenia with reduced TCIRG1 protein levels in affected individuals (western blot). This establishes that TCIRG1 dysfunction impairs not only osteoclast but also neutrophil function. Western blot (reduced protein in affected individuals), family segregation analysis, DNA sequencing Human mutation Medium 24753205
2016 Lentiviral vector-mediated TCIRG1 expression in osteoclasts is post-transcriptionally regulated, being detected only in mature osteoclasts (not precursors or macrophages) despite GFP being expressed in all cell types from the same bicistronic vector. Codon optimization increases mRNA but decreases protein levels and functional rescue. Addition of 30% wild-type CD34+ cells to TCIRG1-deficient cells is sufficient to completely normalize resorptive function in vitro. Lentiviral gene transfer, qPCR, western blot, in vitro osteoclast differentiation, resorption assay, GFP reporter comparison Calcified tissue international Medium 27541021
2019 A novel TCIRG1 mutation (c.G630A) causes aberrant splicing producing exon 5-6 deletion (ΔE56). The ΔE56-truncated protein (lacking part of the cytoplasmic N-terminal domain) fails to complement V-ATPase function in yeast (fails to grow on Zn2+-containing plates requiring vacuolar acidification), while the full-length protein does. This demonstrates the N-terminal cytoplasmic domain (encoded by exons 5-6) is required for V-ATPase function. Splice assay, yeast complementation assay (Vph1p ortholog), in vitro osteoclast differentiation from patient monocytes, bone resorption pit assay, TCIRG1 protein/mRNA expression analysis Journal of cellular biochemistry High 31111556
2019 TCIRG1 transgenic expression in iPSC-derived osteoclasts from a compound heterozygous TCIRG1 patient restored bone-resorbing function (pit formation), and also rescued reduced expression of cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP). This demonstrates that TCIRG1 loss reduces not only proton pump activity but also expression of downstream bone remodeling enzymes. iPSC generation and osteoclast differentiation, transgenic TCIRG1 expression, pit formation assay, gene expression analysis (CTSK, TRAP), western blot The Journal of bone and joint surgery. American volume Medium 31567691
2020 Knockdown of Tcirg1 in mouse bone marrow-derived monocytes inhibits large osteoclast (>100 μm) generation by decreasing expression of NFATc1 and IP3R2. Reduced IP3R2 lowers intracellular calcium levels, which limits nuclear translocation of NFATc1 in RANKL-induced osteoclastogenesis. Lentiviral Tcirg1 knockdown in BMMs, osteoclast differentiation assay, NFATc1/IP3R2 expression analysis, intracellular calcium measurement, nuclear translocation assay PloS one Medium 32790690
2023 Atp6i-/- (TCIRG1-deficient) mice exhibit arrested tooth root formation with truncated Hertwig's epithelial root sheath progression and reduced odontoblast differentiation. Conditioned medium from wild-type osteoclasts (but not Atp6i-/- osteoclasts) promotes odontoblast differentiation via TGF-β1/Smad2/3 signaling. Anti-TGF-β1 neutralization blocks this effect. Ectopic TGF-β1 partially rescues root development in Atp6i-/- tooth germ transplants, establishing TGF-β1 release from bone matrix (dependent on TCIRG1-mediated osteoclast acidification) as a key pathway for odontoblast differentiation and tooth root formation. Atp6i-/- mouse analysis, conditioned medium experiments, anti-TGF-β1 neutralization, Smad2/3 activation assay, RNA-seq, kidney capsule tooth germ transplant rescue, immunohistochemistry International journal of oral science High 37599332
2025 Tcirg1 deficiency in osteoclasts impairs lysosome acidification and peripheral (plasma membrane) accumulation of lysosomes, thereby inhibiting osteoclast fusion and bone resorption. Tcirg1-knockout mice show delayed OA progression with reduced subchondral bone loss and cartilage damage. Tcirg1 knockout mouse OA model (destabilization of medial meniscus), histology, micro-CT, in vitro osteoclast differentiation assay, lysosome acidification assay, lysosome distribution analysis Frontiers in cell and developmental biology Medium 40995561
2025 CRISPR/Cas9-mediated correction of the R736C TCIRG1 mutation in patient-derived iPSCs restored normal neutrophil differentiation. Mutant iPSC lines showed reduced TCIRG1 protein expression and altered intracellular localization (more diffuse cytosolic distribution), suggesting structural and functional disruption of the V-ATPase complex underlies impaired granulopoiesis. iPSC generation from patients, CRISPR/Cas9 correction, in vitro hematopoietic differentiation, immunofluorescence for TCIRG1 localization, proliferation and survival assays Journal of cellular immunology Medium 40964614
2024 VMA21 binds TCIRG1 protein and inhibits its ubiquitination-mediated degradation, thereby stabilizing TCIRG1 protein expression in triple-negative breast cancer cells. VMA21 knockdown reduces TCIRG1 protein levels and impairs TNBC cell proliferation, invasion, and immune evasion. Immunoprecipitation (VMA21-TCIRG1 interaction), ubiquitination assay, VMA21 knockdown, western blot, cell proliferation/invasion/migration assays, CD8+ T cell co-culture assay American journal of cancer research Medium 39267677
2012 The C-terminal extracellular peptide of Tirc7 (the T-cell-expressed TCIRG1 transcript) induces differentiation of RAW264.7 cells and mouse bone marrow CD11b+ cells into osteoclast-like multinucleated TRACP-positive cells, and induces an autocrine/paracrine regulatory loop in osteoclast precursors. Primary monocytes treated with Tirc7-Cter peptide form small multinucleated cells with dendritic cell marker modulation but lacking resorbing activity. Molecular cloning of Tirc7 C-terminal peptide, treatment of RAW264.7 and bone marrow-derived precursor cells, TRACP staining, F4/80 expression analysis, resorption activity assay Journal of cellular physiology Low 22015593

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nature genetics 522 10888887
1999 Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nature genetics 382 10581033
2004 TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA. Human mutation 85 15300850
2003 Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis. The American journal of pathology 83 12507890
1999 Genomic organization of the gene coding for TIRC7, a novel membrane protein essential for T cell activation. Genomics 67 10329006
1998 Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein. Immunity 61 9806637
2003 Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis. Human mutation 47 12552563
2014 CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 24108692
2014 TCIRG1-associated congenital neutropenia. Human mutation 37 24753205
2015 Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 36 25829125
2012 Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 35 22231430
2013 RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease. PloS one 34 23577057
2009 Genetic analysis of autosomal recessive osteopetrosis in Chuvashiya: the unique splice site mutation in TCIRG1 gene spread by the founder effect. European journal of human genetics : EJHG 33 19172990
2013 RNA interference-mediated silencing of Atp6i prevents both periapical bone erosion and inflammation in the mouse model of endodontic disease. Infection and immunity 29 23166162
2001 Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans. Human immunology 29 11295466
2004 In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 28 15231021
2021 Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis. Haematologica 25 31949009
2004 TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response. Journal of immunology (Baltimore, Md. : 1950) 24 15294947
2018 Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. Bone 22 30537558
2003 Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women. Calcified tissue international 22 14523594
2014 As little as needed: the extraordinary case of a mild recessive osteopetrosis owing to a novel splicing hypomorphic mutation in the TCIRG1 gene. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 21 24535816
2010 Optic nerve compression and retinal degeneration in Tcirg1 mutant mice lacking the vacuolar-type H-ATPase a3 subunit. PloS one 21 20711468
2006 TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression. Journal of immunology (Baltimore, Md. : 1950) 21 17082597
2023 Glycolysis-related biomarker TCIRG1 participates in regulation of renal cell carcinoma progression and tumor immune microenvironment by affecting aerobic glycolysis and AKT/mTOR signaling pathway. Cancer cell international 20 37649034
2004 Monoclonal antibody specific for TIRC7 induces donor-specific anergy and prevents rejection of cardiac allografts in mice. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20 15023142
2022 Osteoclast rich osteopetrosis due to defects in the TCIRG1 gene. Bone 18 35981697
2017 Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families. Acta pharmacologica Sinica 18 28816234
2008 Ovocleidin (OC 116) is present in avian skeletal tissues. Poultry science 18 18648057
2022 Novel Disease-Associated Missense Single-Nucleotide Polymorphisms Variants Predication by Algorithms Tools and Molecular Dynamics Simulation of Human TCIRG1 Gene Causing Congenital Neutropenia and Osteopetrosis. Frontiers in molecular biosciences 17 35573728
2013 Lentiviral gene transfer of TCIRG1 into peripheral blood CD34(+) cells restores osteoclast function in infantile malignant osteopetrosis. Bone 17 23907031
2008 Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker. Journal of immunology (Baltimore, Md. : 1950) 17 18424726
2006 Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice. Clinical and experimental immunology 17 16542376
2002 Sibling pair linkage and association studies between peak bone mineral density and the gene locus for the osteoclast-specific subunit (OC116) of the vacuolar proton pump on chromosome 11p12-13. The Journal of clinical endocrinology and metabolism 17 12161516
2012 Murine ameloblasts are immunonegative for Tcirg1, the v-H-ATPase subunit essential for the osteoclast plasma proton pump. Bone 16 22245629
2010 OC-116, the chicken ortholog of mammalian MEPE found in eggshell, is also expressed in bone cells. Journal of experimental zoology. Part B, Molecular and developmental evolution 16 20665709
2016 Regulation and Function of Lentiviral Vector-Mediated TCIRG1 Expression in Osteoclasts from Patients with Infantile Malignant Osteopetrosis: Implications for Gene Therapy. Calcified tissue international 14 27541021
2005 Identification of new alternative splice events in the TCIRG1 gene in different human tissues. Biochemical and biophysical research communications 14 15809087
2019 Novel c.G630A TCIRG1 mutation causes aberrant splicing resulting in an unusually mild form of autosomal recessive osteopetrosis. Journal of cellular biochemistry 13 31111556
2016 Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project. Genetic epidemiology 13 27229898
2020 Generation of an immunodeficient mouse model of tcirg1-deficient autosomal recessive osteopetrosis. Bone reports 12 31938717
2020 Knockdown of Tcirg1 inhibits large-osteoclast generation by down-regulating NFATc1 and IP3R2 expression. PloS one 12 32790690
2013 A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation. Journal of pediatric endocrinology & metabolism : JPEM 12 23412864
2008 HLA-DR alpha 2 mediates negative signalling via binding to Tirc7 leading to anti-inflammatory and apoptotic effects in lymphocytes in vitro and in vivo. PloS one 12 18270567
2006 TIRC7 is induced in rejected human kidneys and anti-TIRC7 mAb with FK506 prolongs survival of kidney allografts in rats. Transplant immunology 12 17138060
2019 TCIRG1 Transgenic Rescue of Osteoclast Function Using Induced Pluripotent Stem Cells Derived from Patients with Infantile Malignant Autosomal Recessive Osteopetrosis. The Journal of bone and joint surgery. American volume 11 31567691
2014 Epiregulin (EREG) and human V-ATPase (TCIRG1): genetic variation, ethnicity and pulmonary tuberculosis susceptibility in Guinea-Bissau and The Gambia. Genes and immunity 10 24898387
2010 Fluid shear stress changes cell morphology and regulates the expression of ATP6V1A and TCIRG1 mRNA in rat osteoclasts. Molecular medicine reports 10 21472218
2019 TCIRG1 and SNX10 gene mutations in the patients with autosomal recessive osteopetrosis. Gene 9 30898715
2018 Autosomal recessive osteopetrosis type I: description of pathogenic variant of TCIRG1 gene. Boletin medico del Hospital Infantil de Mexico 9 30084437
2014 Identification of TCIRG1 and CLCN7 gene mutations in a patient with autosomal recessive osteopetrosis. Molecular medicine reports 9 24535484
2010 Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients. Journal of bone and mineral metabolism 9 21042819
2009 Characterization of a novel Alu-Alu recombination-mediated genomic deletion in the TCIRG1 gene in five osteopetrotic patients. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 9 18715141
2023 Atp6i deficient mouse model uncovers transforming growth factor-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation. International journal of oral science 7 37599332
2017 Eggshell matrix proteins OC-116, OC-17 and OCX36 in hen's sperm storage tubules. Animal reproduction science 7 28844534
2014 A founder mutation in the TCIRG1 gene causes osteopetrosis in the Ashkenazi Jewish population. Clinical genetics 7 24989235
2005 TIRC7 pathway as a target for preventing allograft rejection. Drug news & perspectives 7 15883619
2003 Osteoclast morphology in autosomal recessive malignant osteopetrosis due to a TCIRG1 gene mutation. Pediatric pathology & molecular medicine 7 12687885
2024 Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene. The Journal of clinical endocrinology and metabolism 6 38261998
2019 Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Autosomal Recessive Osteopetrosis due to mutations in TCIRG1 gene. Stem cell research 6 31794943
2018 Ophthalmic phenotype of TCIRG1 gene mutations in Chinese infantile malignant osteopetrosis. BMJ open ophthalmology 6 30539151
2020 TIRC7 inhibits Th1 cells by upregulating the expression of CTLA‑4 and STAT3 in mice with acute graft‑versus‑host disease. Oncology reports 5 32319655
2018 CLCN7 and TCIRG1 mutations in a single family: Evidence for digenic inheritance of osteopetrosis. Molecular medicine reports 5 30431110
2014 TIRC7 and HLA-DR axis contributes to inflammation in multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 4 24526664
2012 A novel TCIRG1 gene mutation leads to severe osteopetrosis with altered content of monocytes/macrophages in several organs. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 4 22280207
2017 [Analysis of TCIRG1 gene mutation in a Chinese family affected with infantile malignant osteopetrosis]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 28604959
2025 Tcirg1 deficiency delays osteoarthritis progression by impairing lysosome acidification and peripheral accumulation in osteoclasts. Frontiers in cell and developmental biology 2 40995561
2018 [Identification of new mutations in TCIRG1 as a cause of infantile malignant osteopetrosis in two Mexican patients]. Revista alergia Mexico (Tecamachalco, Puebla, Mexico : 1993) 2 29723947
2012 Monocytes differentiation upon treatment with a peptide corresponding to the C-terminus of activated T cell-expressed Tirc7 protein. Journal of cellular physiology 2 22015593
2025 Modeling TCIRG1 Neutropenia by Utilizing Patient Derived Induced Pluripotent Stem Cells. Journal of cellular immunology 1 40964614
2023 Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families. Genes 1 37107657
2021 Two novel mutations in TCIRG1 induced infantile malignant osteopetrosis: a case report. BMC pediatrics 1 34210262
2026 Single-Cell Multiomics Decoding of TCIRG1-Mediated Cuproptosis Circuitry Rewiring Immune-Metabolic Landscape in Ischemic Stroke. Translational stroke research 0 41673363
2026 Clinical and Molecular Characterization of TCIRG1-Related Autosomal Recessive Osteopetrosis with Current Therapeutic Approaches. Biomedicines 0 42193285
2024 VMA21: unveiling a novel oncogene that facilitates immune evasion in triple-negative breast cancer through TCIRG1 protein stability regulation. American journal of cancer research 0 39267677

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