Affinage

TCIRG1

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

Length
830 aa
Mass
93.0 kDa
Annotated
2026-04-28
73 papers in source corpus 24 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCIRG1 encodes the a3 subunit of the vacuolar H⁺-ATPase (V-ATPase), a proton pump component that is essential for osteoclast-mediated extracellular acidification at the ruffled border and for lysosomal acidification and peripheral trafficking during bone resorption (PMID:10581033, PMID:15231021, PMID:40995561). Loss-of-function mutations cause autosomal recessive infantile malignant osteopetrosis: TCIRG1-deficient osteoclasts differentiate and polarize normally but fail to acidify the resorption lacuna, and re-expression by lentiviral gene transfer rescues bone resorption to near-normal levels (PMID:10888887, PMID:12507890, PMID:23907031). An alternative transcript (TIRC7) produces a T-cell co-inhibitory receptor that binds HLA-DRα2, recruits SHP-1, suppresses TCR-proximal signaling (ZAP70, TCR-ζ, STAT4 phosphorylation), and acts upstream of CTLA-4 surface expression to limit lymphocyte activation (PMID:9806637, PMID:15294947, PMID:17082597, PMID:18270567). TCIRG1 also influences osteoclast fusion through an IP3R2–NFATc1 calcium-signaling axis, promotes downstream expression of bone-remodeling enzymes cathepsin K and TRAP, and its protein stability is regulated by VMA21-mediated protection from ubiquitin-dependent degradation (PMID:32790690, PMID:31567691, PMID:39267677).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 Medium

    Whether the TIRC7 gene product had any functional role in T cells was unknown; antibody-blocking experiments revealed that TIRC7 is a membrane protein required for T cell proliferation, IL-2 secretion, and Th1-skewed cytokine production, and that anti-TIRC7 antibody prolongs allograft survival, establishing the first evidence of an immune-regulatory function at this locus.

    Evidence In vitro T cell proliferation/cytokine assays and rat kidney allograft model with anti-TIRC7 antibody

    PMID:9806637

    Open questions at the time
    • Single lab; mechanism of TIRC7 signaling undefined
    • Relationship between TIRC7 and the osteoclast isoform not yet clarified
  2. 1999 High

    The molecular identity of the osteoclast-specific V-ATPase a-subunit and its relationship to TIRC7 were unresolved; genomic analysis demonstrated that TCIRG1 and TIRC7 are alternative transcripts of the same gene at 11q13, with the osteoclast isoform (OC116/TV1) and the T-cell isoform (TV2) arising from tissue-specific alternative splicing, and knockout of the mouse ortholog Atp6i caused severe osteopetrosis with loss of extracellular but not lysosomal acidification.

    Evidence Genomic exon-intron mapping; RT-PCR; Atp6i knockout mice with pH and proton transport assays

    PMID:10329006 PMID:10581033

    Open questions at the time
    • Whether a3 loss affects V-ATPase assembly versus membrane targeting unclear
    • Mechanism of isoform-specific plasma membrane versus lysosome localization not defined
  3. 2000 High

    Whether human osteopetrosis was caused by TCIRG1 mutations was unknown; mutation analysis across patient cohorts identified loss-of-function TCIRG1 mutations as the most common cause of autosomal recessive osteopetrosis, confirming that osteoclasts are present but functionally impaired.

    Evidence Mutation screening in osteopetrosis patient cohorts with genotype-phenotype correlation

    PMID:10888887

    Open questions at the time
    • Molecular basis of individual mutations not characterized
    • Whether haploinsufficiency causes disease unclear
  4. 2004 High

    Whether TCIRG1-deficient osteoclasts had broader cytoskeletal or differentiation defects was unknown; detailed phenotyping showed that mutant osteoclasts form normal actin rings, clear zones, and podosomes but specifically fail to acidify the resorption compartment, while bone marrow transplant rescued a3 expression, confirming a cell-autonomous acidification defect.

    Evidence Patient-derived osteoclast differentiation, resorption pit assays, immunostaining for cytoskeletal markers, post-transplant biopsy immunohistochemistry

    PMID:12507890 PMID:15231021

    Open questions at the time
    • Whether mutant V-ATPase complexes assemble but mislocalize versus fail to assemble not resolved
    • Effect on osteoclast secretory pathway not examined
  5. 2004 High

    Whether TIRC7 was necessary for immune homeostasis in vivo was unresolved; TIRC7-knockout mice showed hyperproliferation of T and B cells, augmented cytokine production, reduced CTLA-4 expression, and enhanced delayed-type hypersensitivity, establishing TIRC7 as a non-redundant negative regulator of lymphocyte activation.

    Evidence Gene-targeted TIRC7 knockout mice; proliferation assays; flow cytometry; DTH assay

    PMID:15294947

    Open questions at the time
    • Signaling pathway downstream of TIRC7 not yet defined
    • Whether the T-cell phenotype contributes to osteopetrosis pathology unknown
  6. 2006 High

    How TIRC7 inhibits T cell activation mechanistically was unknown; epistasis experiments showed that TIRC7 promotes early CTLA-4 surface expression, the two proteins colocalize in clathrin-coated vesicles, and TIRC7-mediated inhibition requires intact CTLA-4, placing TIRC7 upstream of CTLA-4 in the co-inhibitory pathway.

    Evidence Immunofluorescence colocalization; CTLA-4 antibody blockade; CTLA-4-deficient splenocyte experiments

    PMID:17082597

    Open questions at the time
    • Direct physical interaction between TIRC7 and CTLA-4 not demonstrated
    • Molecular basis of CTLA-4 mobilization by TIRC7 unclear
  7. 2008 High

    The ligand for TIRC7 and its proximal signaling events were unknown; HLA-DRα2 was identified as a direct binding partner that delivers negative signals recruiting SHP-1, suppressing phosphorylation of ZAP70, TCR-ζ, and STAT4, and inducing apoptosis via the intrinsic pathway.

    Evidence Pulldown, co-localization at APC–T cell contacts, SHP-1 recruitment assay, phospho-signaling assays, apoptosis assay

    PMID:18270567

    Open questions at the time
    • Structure of the TIRC7–HLA-DRα2 interface unresolved
    • Whether SHP-1 directly dephosphorylates TCR-ζ/ZAP70 or acts indirectly not tested
  8. 2013 High

    Whether TCIRG1 gene transfer could functionally correct patient osteoclasts was untested; lentiviral delivery of TCIRG1 cDNA into patient CD34⁺ cells restored bone resorption to 70–80% of normal, establishing proof-of-concept for gene therapy of TCIRG1-dependent osteopetrosis.

    Evidence Lentiviral transduction of patient CD34⁺ cells; Ca²⁺ release, CTX-I ELISA, pit assay; NSG mouse engraftment

    PMID:23907031

    Open questions at the time
    • Long-term in vivo engraftment and correction not demonstrated
    • Optimal vector design for clinical translation undefined
  9. 2014 High

    Whether TCIRG1 loss affected bone matrix quality beyond resorption was unknown; genotype-specific histological analysis revealed that TCIRG1 mutations uniquely cause severe osteoid accumulation and decreased calcium content (osteomalacia), separating this from CLCN7 or TNFRSF11A mutation phenotypes.

    Evidence Undecalcified iliac crest biopsy histology and calcium content analysis across genotyped osteopetrosis subtypes

    PMID:24108692

    Open questions at the time
    • Whether the mineralization defect is secondary to impaired acidification or an independent function of a3 unknown
  10. 2019 Medium

    How TCIRG1 expression is controlled at the protein level was unclear; studies revealed that TCIRG1 protein accumulates only in mature osteoclasts despite constitutive mRNA expression, and that specific exon-encoded domains (exons 5–6) are essential for V-ATPase function as demonstrated by yeast complementation.

    Evidence Lentiviral vector expression at different differentiation stages; codon optimization analysis; yeast Vph1p complementation assay

    PMID:27541021 PMID:31111556

    Open questions at the time
    • Identity of factors controlling post-transcriptional regulation unknown
    • Structure–function mapping of the N-terminal cytoplasmic domain incomplete
  11. 2020 Medium

    Whether TCIRG1 influences osteoclast fusion and differentiation signaling beyond its proton-pumping role was unresolved; knockdown revealed that Tcirg1 promotes large osteoclast formation by sustaining IP3R2 expression and intracellular calcium levels required for NFATc1 nuclear translocation during RANKL-induced osteoclastogenesis.

    Evidence Lentiviral shRNA knockdown in bone marrow monocytes; NFATc1/IP3R2 expression; calcium imaging; nuclear translocation assay

    PMID:32790690

    Open questions at the time
    • Whether IP3R2 regulation is direct or secondary to acidification defect not tested
    • Single lab, not independently confirmed
  12. 2023 Medium

    Whether osteoclast dysfunction from Tcirg1 loss impacts neighboring non-osteoclast cell types was unknown; in Atp6i⁻/⁻ mice, failure to release TGF-β1 from bone matrix impaired Smad2/3 signaling in odontoblasts, arresting tooth root formation, and ectopic TGF-β1 partially rescued the phenotype, placing Tcirg1-dependent resorption upstream of paracrine growth factor signaling.

    Evidence Atp6i⁻/⁻ mouse; RNA-seq; Smad2/3 phosphorylation; TGF-β1 neutralization; kidney capsule transplant rescue

    PMID:37599332

    Open questions at the time
    • Whether other resorption-released growth factors are similarly affected not examined
    • Relevance to human dental phenotype not confirmed
  13. 2025 Medium

    Whether TCIRG1 controls lysosomal positioning during osteoclast activation and whether heterozygous mutations affect myeloid lineage beyond osteoclasts were open questions; new studies showed that Tcirg1 loss impairs lysosome acidification and peripheral lysosome accumulation during resorption, and that heterozygous TCIRG1 missense mutations cause congenital neutropenia correctable by CRISPR repair.

    Evidence Tcirg1-KO OA mouse model with lysosome distribution assays; iPSC-derived neutrophil differentiation with CRISPR/Cas9 correction of R736C

    PMID:40964614 PMID:40995561

    Open questions at the time
    • Mechanism linking a3 to peripheral lysosome trafficking not defined
    • Whether heterozygous mutations cause neutropenia via V-ATPase assembly defects versus dominant-negative effects unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of a3-subunit integration into V₀ and its isoform-specific targeting to ruffled border versus lysosomes remains undefined; the molecular mechanism by which TIRC7 mobilizes CTLA-4 to the cell surface and the physiological interplay between the osteoclast and T-cell isoforms in vivo have not been resolved.
  • No structural model of human a3 in the V₀ complex
  • Mechanism of isoform-specific membrane targeting unresolved
  • Whether TIRC7 immune function contributes to osteopetrosis clinical phenotype unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 3 GO:0140657 ATP-dependent activity 3
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2 GO:0005764 lysosome 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 3 GO:0005215 transporter activity 1 R-HSA-1266738 Developmental Biology 1
Partners
CTLA4HLA-DRANFATC1PTPN6VMA21
Complex memberships
V-ATPase (V₀ sector)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TCIRG1 encodes the osteoclast-specific 116-kDa subunit (a3) of the vacuolar proton pump (V-ATPase), and loss-of-function mutations in TCIRG1 cause autosomal recessive osteopetrosis by impairing osteoclast function (not differentiation), establishing TCIRG1 as essential for mature osteoclast resorptive activity. Mutation analysis in osteopetrosis patients; functional correlation with osteoclast presence/absence Nature genetics High 10888887
1999 Targeted disruption of Atp6i (mouse ortholog of TCIRG1) results in severe osteopetrosis; Atp6i-/- osteoclasts lose extracellular acidification function but retain intracellular lysosomal proton pump activity, demonstrating that the a3 subunit is specifically required for plasma membrane-directed extracellular acidification by osteoclasts. Gene knockout mouse model; pH measurement in lysosomes; proton transport assay in kidney microsomes; acid-base balance measurement Nature genetics High 10581033
2004 In vitro-differentiated osteoclasts from patients with TCIRG1 compound heterozygous mutations can fuse and attach to bone but fail to acidify the resorption compartment, consistent with TCIRG1 being essential for H+-ATPase assembly at the ruffled border; by contrast, CLCN7 defects impair organic matrix removal rather than acidification. CD14+ monocyte differentiation into osteoclasts; acid secretion assay; bone pit assay; genotype correlation Journal of bone and mineral research High 15231021
2004 TCIRG1 (ATP6i/a3) mutations cause osteopetrosis with osteoclasts that are morphologically normal (normal actin rings, clear zones, podosomes, αVβ3, c-Src, PYK2) but excavate only faint, shallow pits, confirming the specific role of the a3 subunit in bone acidification rather than osteoclast cytoskeletal organization. Bone biopsy histology; in vitro osteoclast differentiation from patient CD14+ cells; TRAP activity; bone resorption pit assay; immunostaining The American journal of pathology High 12507890
2003 Post-transplant osteoclasts in TCIRG1-deficient patients rescue a3 subunit immunoreactivity, demonstrating that donor-derived osteoclasts restore V-ATPase a3 expression and function, confirming the cell-autonomous nature of the TCIRG1 defect. Bone marrow transplantation with post-transplant immunostaining for a3 subunit The American journal of pathology Medium 12507890
1999 TCIRG1/TIRC7 are alternative transcripts of the same gene located on chromosome 11q13.4-q13.5; TIRC7 (TV2, 7-transmembrane domain isoform) is expressed in alloactivated T lymphocytes while OC116 (TV1) is the osteoclast-specific V-ATPase subunit, establishing tissue-specific alternative splicing of the locus. Genomic organization analysis; RT-PCR in human T lymphocytes; exon-intron mapping Genomics Medium 10329006
1998 TIRC7 (the T-cell isoform of TCIRG1) functions as a membrane protein essential for T cell activation; anti-TIRC7 antibodies inhibit human T cell proliferation and IL-2 secretion in vitro, and specifically suppress IFN-γ (Th1) but not IL-4 (Th2) expression; cross-reactive antibody prolonged rat kidney allograft survival in vivo. In vitro T cell proliferation assay; cytokine ELISA; rat kidney allograft model with anti-TIRC7 antibody treatment Immunity Medium 9806637
2004 TIRC7-deficient mice exhibit increased T and B cell proliferation and cytokine production (IL-2, IFN-γ, IL-4), reduced CTLA-4 expression on activated T cells, expanded memory/effector T cells (CD62L↓, CD11a↑, CD44↑), B cell hyperreactivity, and augmented delayed-type hypersensitivity, establishing TIRC7 as a negative regulator of lymphocyte activation. Gene-targeted TIRC7 knockout mice; in vitro T and B cell proliferation assays; cytokine measurement; flow cytometry; delayed-type hypersensitivity assay Journal of immunology High 15294947
2006 Anti-TIRC7 antibody induces early surface expression of CTLA-4; TIRC7 and CTLA-4 colocalize in T cells and both associate with clathrin-coated vesicles sharing intracellular transport systems; TIRC7-mediated inhibition of T cell proliferation is abolished by CTLA-4 blockade or in CTLA-4-deficient mouse splenocytes, placing TIRC7 upstream of CTLA-4 in the T cell inhibitory pathway. Immunofluorescence colocalization; flow cytometry; CTLA-4 antibody blockade; CTLA-4 knockout splenocyte experiments; transcription activation assay Journal of immunology High 17082597
2008 HLA-DR alpha 2 domain directly binds TIRC7 on lymphocytes, delivering negative signals that inhibit proliferation and induce apoptosis in CD4+ and CD8+ T cells via the intrinsic apoptotic pathway; this interaction recruits SHP-1 to TIRC7, decreases phosphorylation of STAT4, TCR-zeta chain and ZAP70, and inhibits IFN-γ and FasL expression; HLA-DRα2 and TIRC7 co-localize at the APC–T cell interaction site. Pulldown/co-localization; SHP-1 recruitment assay; phosphorylation assays; apoptosis assay; in vivo LPS model PloS one High 18270567
2010 In Tcirg1-/- mice, the a3 subunit accumulates in choriocapillary meshwork of uveal tissues; loss of a3 leads to narrowed skull foramina causing optic nerve compression and increased retinal apoptosis; compensatory upregulation of the a4 V-ATPase subunit isoform occurs in mutant choriocapillary meshwork, revealing isoform compensation among V-ATPase a-subunits. X-ray microtomography; immunohistochemistry for V-ATPase subunit isoforms; apoptosis assay in retina; Tcirg1-/- mouse model PloS one Medium 20711468
2012 Tcirg1 (a3 subunit) is not detectably expressed in mouse maturation-stage ameloblasts despite their use of V-ATPase; Tcirg1-null mice have normal enamel formation and mineral content, demonstrating that the osteoclast-type plasma membrane proton pump using the a3 subunit is not required for ameloblast enamel acidification. Immunohistochemistry; mineral content analysis; Tcirg1 null mouse model analysis Bone Medium 22245629
2013 Lentiviral gene transfer of TCIRG1 cDNA into peripheral blood CD34+ cells from infantile malignant osteopetrosis patients restores osteoclast bone resorption to ~70-80% of normal, as measured by Ca2+ release, CTX-I bone degradation product, and resorption pit formation, demonstrating that re-expression of TCIRG1 is sufficient to restore V-ATPase-dependent osteoclast function. Lentiviral transduction; qPCR; Western blot; Ca2+ release assay; CTX-I ELISA; bone resorption pit assay; NSG mouse engraftment Bone High 23907031
2013 AAV-mediated RNAi knockdown of Atp6i/TCIRG1 in periodontal tissues impairs osteoclast extracellular acidification and bone resorption, and also reduces T-cell infiltration and inflammatory cytokine expression; Atp6i+/- haploinsufficient mice are similarly protected from P. gingivalis-induced bone loss and gingival inflammation, establishing a dual role for Atp6i in bone resorption and tissue inflammation. AAV-shRNA delivery in vivo; bone resorption quantification; T-cell number measurement; cytokine gene expression; Atp6i+/- haploinsufficiency model PloS one Medium 23577057
2014 TCIRG1 mutations (but not CLCN7 or TNFRSF11A mutations) are specifically associated with severe osteoid accumulation and decreased calcium content in bone matrix (osteomalacia), demonstrating that loss of V-ATPase a3 specifically impairs bone matrix mineralization in addition to bone resorption. Undecalcified iliac crest biopsy histology; calcium content analysis; genotype-phenotype comparison across osteopetrosis subtypes Journal of bone and mineral research High 24108692
2016 TCIRG1 protein expression from a bicistronic lentiviral vector is post-transcriptionally regulated: protein accumulates only in mature osteoclasts, not in precursors or macrophages, preventing ectopic overexpression; codon optimization increased mRNA but paradoxically lowered protein and functional rescue, revealing post-transcriptional control of TCIRG1 expression. Lentiviral vector expression analysis; flow cytometry; Western blot at different differentiation stages; codon optimization comparison; bone resorption assay Calcified tissue international Medium 27541021
2019 Transgenic TCIRG1 expression in iPSC-derived osteoclasts from an infantile malignant osteopetrosis patient restores cathepsin K (CTSK) and TRAP expression and rescues pit formation, establishing that TCIRG1 function is required for downstream expression of bone remodeling enzymes in addition to proton pumping. iPSC generation from patient fibroblasts; osteoclast differentiation; transgenic TCIRG1 rescue; qPCR for CTSK/TRAP; pit formation assay The Journal of bone and joint surgery. American volume Medium 31567691
2020 Knockdown of Tcirg1 in mouse bone marrow-derived monocytes inhibits formation of large osteoclasts (>100 μm) by decreasing NFATc1 and IP3R2 expression; reduced IP3R2 lowers intracellular calcium levels, which limits nuclear translocation of NFATc1 during RANKL-induced osteoclastogenesis. Lentiviral shRNA knockdown; osteoclast size quantification; NFATc1 and IP3R2 expression assay; intracellular calcium measurement; nuclear translocation assay PloS one Medium 32790690
2012 A peptide corresponding to the C-terminus of Tirc7 (the T-cell isoform of Atp6v0a3/TCIRG1) induces differentiation of RAW264.7 cells and bone marrow CD11b+ cells into TRAP-positive multinucleated osteoclast-like cells and stimulates an autocrine/paracrine regulatory loop, revealing that the extracellular C-terminus of Tirc7 directly signals to osteoclast precursor cells. Molecular cloning of Tirc7 C-terminal peptide; treatment of RAW264.7, CD11b+ cells, and primary monocytes; TRAP staining; multinucleation assay; F4/80 immunostaining Journal of cellular physiology Medium 22015593
2023 In Atp6i-/- mice, osteoclast dysfunction prevents TGF-β1 release from alveolar bone matrix, impairing TGF-β1/Smad2/3 signaling in radicular odontoblasts and arresting tooth root formation; ectopic TGF-β1 partially rescues root development in Atp6i-/- tooth germ transplants, placing Atp6i-dependent bone resorption upstream of TGF-β1 release required for odontoblast differentiation. Atp6i-/- mouse model; RNA-seq; qPCR for odontoblast markers; Smad2/3 phosphorylation assay; anti-TGF-β1 neutralization; conditioned medium experiments; kidney capsule transplantation rescue International journal of oral science Medium 37599332
2025 TCIRG1 deficiency in knockout mice delays osteoarthritis progression; in vitro, Tcirg1 knockdown in osteoclasts inhibits cell fusion and bone resorption by impairing lysosome acidification and peripheral lysosome accumulation, establishing a role for the a3 subunit in lysosomal trafficking to the cell periphery during osteoclast activation. Tcirg1-knockout OA mouse model (DMM surgery); histology; micro-CT; in vitro osteoclast differentiation with shRNA knockdown; lysosome acidification and distribution assays Frontiers in cell and developmental biology Medium 40995561
2025 iPSCs from congenital neutropenia patients bearing heterozygous TCIRG1 mutations (R736C, R736S, R736P, E722D) show defects in myeloid differentiation and increased cell death; CRISPR/Cas9 correction of R736C restores normal neutrophil differentiation; mutant TCIRG1 protein shows reduced expression and a more diffuse cytosolic distribution instead of normal vesicular/V-ATPase localization. iPSC generation; in vitro hematopoietic differentiation; CRISPR/Cas9 correction; immunofluorescence for TCIRG1 localization; neutrophil differentiation assay Journal of cellular immunology Medium 40964614
2024 VMA21 stabilizes TCIRG1 protein by binding to it and inhibiting its ubiquitination-dependent degradation in triple-negative breast cancer cells, establishing VMA21 as a regulator of TCIRG1 protein stability through the ubiquitin-proteasome pathway. Immunoprecipitation; ubiquitination assay; VMA21 knockdown with TCIRG1 protein level measurement American journal of cancer research Low 39267677
2004 Splicing mutations in TCIRG1 flanking splice sites (c.117+4A>T, c.1673+5G>A, c.504-8G>A) cause aberrant mRNA processing demonstrated in hybrid minigene assays; complementary U1 snRNA corrects the c.117+4A>T 5' splice site defect but not the c.1673+5G>A mutation, revealing mechanistic differences between mutations near invariant GT donor sites and those further from splice junctions. Hybrid minigene splicing assay; U1 snRNA cotransfection rescue experiments Human mutation Medium 15300850
2019 The TCIRG1 c.G630A mutation causes exons 5-6 skipping (ΔE56); the ΔE56 truncated protein lacking part of the cytoplasmic N-terminal domain fails to support V-ATPase-mediated vacuolar acidification in yeast (Vph1p ortholog growth assay on Zn2+-containing plates), demonstrating that exons 5-6 encode a functionally essential domain for V-ATPase activity. RT-PCR splicing analysis; yeast complementation assay (Vph1p); osteoclast differentiation and bone resorption assay; TCIRG1 Western blot Journal of cellular biochemistry Medium 31111556

Source papers

Stage 0 corpus · 73 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 521 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 84 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 60 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 36 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 35 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 32 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
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
2018 Sclerosing bone dysplasias with hallmarks of dysosteosclerosis in four patients carrying mutations in SLC29A3 and TCIRG1. Bone 21 30537558
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
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 19 15023142
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 18 37649034
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
2022 Osteoclast rich osteopetrosis due to defects in the TCIRG1 gene. Bone 17 35981697
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
2017 Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families. Acta pharmacologica Sinica 16 28816234
2013 Lentiviral gene transfer of TCIRG1 into peripheral blood CD34(+) cells restores osteoclast function in infantile malignant osteopetrosis. Bone 16 23907031
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
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
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 13 27541021
2005 Identification of new alternative splice events in the TCIRG1 gene in different human tissues. Biochemical and biophysical research communications 13 15809087
2020 Knockdown of Tcirg1 inhibits large-osteoclast generation by down-regulating NFATc1 and IP3R2 expression. PloS one 12 32790690
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
2020 Generation of an immunodeficient mouse model of tcirg1-deficient autosomal recessive osteopetrosis. Bone reports 11 31938717
2013 A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation. Journal of pediatric endocrinology & metabolism : JPEM 11 23412864
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
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 9 31567691
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
2003 Osteoclast morphology in autosomal recessive malignant osteopetrosis due to a TCIRG1 gene mutation. Pediatric pathology & molecular medicine 7 12687885
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
2014 A founder mutation in the TCIRG1 gene causes osteopetrosis in the Ashkenazi Jewish population. Clinical genetics 6 24989235
2005 TIRC7 pathway as a target for preventing allograft rejection. Drug news & perspectives 6 15883619
2024 Autosomal Dominant Osteopetrosis (ADO) Caused by a Missense Variant in the TCIRG1 Gene. The Journal of clinical endocrinology and metabolism 5 38261998
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
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 Tcirg1 deficiency delays osteoarthritis progression by impairing lysosome acidification and peripheral accumulation in osteoclasts. Frontiers in cell and developmental biology 1 40995561
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
2025 Modeling TCIRG1 Neutropenia by Utilizing Patient Derived Induced Pluripotent Stem Cells. Journal of cellular immunology 0 40964614
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