Gene Symbol: Tcirg1
Description: T cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 protein A3
Alias: ATP6N1C, ATP6a3, Atp6i, OC-116, OPTB1, Stv1, TIRC7, Vph1, V-type proton ATPase 116 kDa subunit a, ATPase, H+ transporting, lysosomal I, V-ATPase a3, osteosclerotic
Species: mouse
Products:     Tcirg1

Top Publications

  1. Blin Wakkach C, Breuil V, Quincey D, Bagnis C, Carle G. Establishment and characterization of new osteoclast progenitor cell lines derived from osteopetrotic and wild type mice. Bone. 2006;39:53-60 pubmed
    ..In the majority of patients as in Tcirg1oc/oc mouse, the gene involved is the Tcirg1 gene, encoding the a3 subunit of the vacuolar proton pump...
  2. Johansson M, Jansson L, Ehinger M, Fasth A, Karlsson S, Richter J. Neonatal hematopoietic stem cell transplantation cures oc/oc mice from osteopetrosis. Exp Hematol. 2006;34:242-9 pubmed
    ..Fifty percent of the patients have a mutation in the TCIRG1 gene coding for one subunit of an osteoclast proton pump...
  3. Li Y, Chen W, Liang Y, Li E, Stashenko P. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet. 1999;23:447-51 pubmed
    ..We previously cloned a gene (Atp6i, for V-proton pump, H+ transporting (vacuolar proton pump) member I) encoding a putative osteoclast-specific ..
  4. Scimeca J, Franchi A, Trojani C, Parrinello H, Grosgeorge J, Robert C, et al. The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone. 2000;26:207-13 pubmed
  5. Toyomura T, Oka T, Yamaguchi C, Wada Y, Futai M. Three subunit a isoforms of mouse vacuolar H(+)-ATPase. Preferential expression of the a3 isoform during osteoclast differentiation. J Biol Chem. 2000;275:8760-5 pubmed
    ..These findings suggest that the a3 isoform is a component of the plasma membrane V-ATPase essential for bone resorption. ..
  6. Schinke T, Schilling A, Baranowsky A, Seitz S, Marshall R, Linn T, et al. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med. 2009;15:674-81 pubmed publisher
    ..Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, ..
  7. Tabata H, Kawamura N, Sun Wada G, Wada Y. Vacuolar-type H(+)-ATPase with the a3 isoform is the proton pump on premature melanosomes. Cell Tissue Res. 2008;332:447-60 pubmed publisher
    ..These observations suggest that the V-ATPase keeps the lumen of premature melanosomes acidic, whereas melanosomal acidification is less significant in mature melanosomes. ..
  8. Sun Wada G, Tabata H, Kawamura N, Futai M, Wada Y. Differential expression of a subunit isoforms of the vacuolar-type proton pump ATPase in mouse endocrine tissues. Cell Tissue Res. 2007;329:239-48 pubmed
    ..We have found that the a3 isoform is strongly expressed in all these endocrine tissues. Our results suggest that functions of the a3 isoform are commonly involved in the process of exocytosis in regulated secretion. ..
  9. Wakkach A, Mansour A, Dacquin R, Coste E, Jurdic P, Carle G, et al. Bone marrow microenvironment controls the in vivo differentiation of murine dendritic cells into osteoclasts. Blood. 2008;112:5074-83 pubmed publisher
    ..Our results open new insights in the differentiation of OCLs and DCs and offer new basis for analyzing the relations between bone and immune systems. ..

More Information


  1. Askmyr M, Holmberg J, Flores C, Ehinger M, Hjalt T, Richter J. Low-dose busulphan conditioning and neonatal stem cell transplantation preserves vision and restores hematopoiesis in severe murine osteopetrosis. Exp Hematol. 2009;37:302-8 pubmed publisher
    Infantile malignant osteopetrosis is a fatal disease caused by lack of functional osteoclasts. In most of patients, TCIRG1, encoding a subunit of a proton pump essential for bone resorption, is mutated...
  2. Kasper D, Planells Cases R, Fuhrmann J, Scheel O, Zeitz O, Ruether K, et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 2005;24:1079-91 pubmed
    ..There are important medical implications as defects in the H(+)-ATPase and ClC-7 can underlie human osteopetrosis...
  3. Toyomura T, Murata Y, Yamamoto A, Oka T, Sun Wada G, Wada Y, et al. From lysosomes to the plasma membrane: localization of vacuolar-type H+ -ATPase with the a3 isoform during osteoclast differentiation. J Biol Chem. 2003;278:22023-30 pubmed
    ..These findings indicate that V-ATPases with the a3 isoform localized in late endosomes/lysosomes are transported to the cell periphery during differentiation and finally assembled into the plasma membrane of mature osteoclasts. ..
  4. Sun Wada G, Tabata H, Kawamura N, Aoyama M, Wada Y. Direct recruitment of H+-ATPase from lysosomes for phagosomal acidification. J Cell Sci. 2009;122:2504-13 pubmed publisher
    ..We modified the mouse Tcirg1 locus encoding subunit a3, to express an a3-GFP fusion protein...
  5. Li Y, Chen W, Stashenko P. Molecular cloning and characterization of a putative novel human osteoclast-specific 116-kDa vacuolar proton pump subunit. Biochem Biophys Res Commun. 1996;218:813-21 pubmed
    ..OC-116KDa mRNA was localized to multinucleated giant cells within the osteoclastoma tumor by in situ hybridization. ..
  6. Oka T, Murata Y, Namba M, Yoshimizu T, Toyomura T, Yamamoto A, et al. a4, a unique kidney-specific isoform of mouse vacuolar H+-ATPase subunit a. J Biol Chem. 2001;276:40050-4 pubmed
    ..These results suggest that the V-ATPase, with the a4 isoform, is important for renal acid/base homeostasis. ..
  7. Blin Wakkach C, Wakkach A, Sexton P, Rochet N, Carle G. Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis. Leukemia. 2004;18:1505-11 pubmed
    ..oc/oc mouse displays a bone phenotype similar to the one observed in IMO patients, and the same gene, Tcirg1, is mutated in this model and in the majority of these patients...
  8. Utku N, Boerner A, Tomschegg A, Bennai Sanfourche F, Bulwin G, Heinemann T, et al. TIRC7 deficiency causes in vitro and in vivo augmentation of T and B cell activation and cytokine response. J Immunol. 2004;173:2342-52 pubmed
    The membrane protein T cell immune response cDNA 7 (TIRC7) was recently identified and was shown to play an important role in T cell activation...
  9. Tondelli B, Blair H, Guerrini M, Patrene K, Cassani B, Vezzoni P, et al. Fetal liver cells transplanted in utero rescue the osteopetrotic phenotype in the oc/oc mouse. Am J Pathol. 2009;174:727-35 pubmed publisher
    ..In half of human cases, ARO is the result of mutations in the TCIRG1 gene, which codes for a subunit of the vacuolar proton pump that plays a fundamental role in the acidification of ..
  10. Blin Wakkach C, Wakkach A, Quincey D, Carle G. Interleukin-7 partially rescues B-lymphopoiesis in osteopetrotic oc/oc mice through the engagement of B220+ CD11b+ progenitors. Exp Hematol. 2006;34:851-9 pubmed
    ..Among the possible factors, interleukin (IL)-7 is involved in the control of B lymphopoiesis and osteoclastogenesis. Therefore, we hypothesized that IL-7 could regulate the accumulation of the B220+ CD11b+ population in oc/oc mice...
  11. Sun Wada G, Toyomura T, Murata Y, Yamamoto A, Futai M, Wada Y. The a3 isoform of V-ATPase regulates insulin secretion from pancreatic beta-cells. J Cell Sci. 2006;119:4531-40 pubmed
    ..The secretion of insulin from isolated islets in response to glucose or depolarizing stimulation was impaired. These results suggest that the a3 isoform of V-ATPase has a regulatory function in the exocytosis of insulin secretion. ..
  12. Seifert M, Marks S. Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse. Am J Anat. 1985;172:141-53 pubmed
    ..of osteoclasts, and the morphology of mineralized bone surfaces in a lethal osteopetrotic mutation, the osteosclerotic (oc) mouse...
  13. Schulz N, Dave M, Stehberger P, Chau T, Wagner C. Differential localization of vacuolar H+-ATPases containing a1, a2, a3, or a4 (ATP6V0A1-4) subunit isoforms along the nephron. Cell Physiol Biochem. 2007;20:109-20 pubmed
  14. Cappariello A, Berardi A, Peruzzi B, Del Fattore A, Ugazio A, Bottazzo G, et al. Committed osteoclast precursors colonize the bone and improve the phenotype of a mouse model of autosomal recessive osteopetrosis. J Bone Miner Res. 2010;25:106-13 pubmed publisher
    ..These results provide first-hand information on the feasibility of a support osteoclast precursor therapy in osteopetrosis. ..
  15. Alzamora R, Thali R, Gong F, Smolak C, Li H, Baty C, et al. PKA regulates vacuolar H+-ATPase localization and activity via direct phosphorylation of the a subunit in kidney cells. J Biol Chem. 2010;285:24676-85 pubmed publisher
    ..In summary, these results indicate a novel mechanism for the regulation of V-ATPase localization and activity in kidney cells via direct PKA-dependent phosphorylation of the A subunit at Ser-175. ..
  16. Voronov I, Ochotny N, Jaumouillé V, Owen C, Manolson M, Aubin J. The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis. J Bone Miner Res. 2013;28:108-18 pubmed publisher
    ..Our data indicate that increased lysosomal pH in osteoclasts leads to decreased NFATc1 signaling and nuclear translocation, resulting in a cell autonomous impairment of osteoclastogenesis in vitro. ..
  17. Crasto G, Kartner N, Yao Y, Li K, Bullock L, Datti A, et al. Luteolin inhibition of V-ATPase a3-d2 interaction decreases osteoclast resorptive activity. J Cell Biochem. 2013;114:929-41 pubmed publisher
    ..We conclude that the V-ATPase a3-d2 interaction is a viable target for novel anti-resorptive therapeutics that potentially preserve osteoclast-osteoblast signaling important for bone remodeling. ..
  18. Ma J, Chen W, Zhang L, Tucker B, Zhu G, Sasaki H, et al. RNA interference-mediated silencing of Atp6i prevents both periapical bone erosion and inflammation in the mouse model of endodontic disease. Infect Immun. 2013;81:1021-30 pubmed
    ..this study, we applied a novel gene-therapeutic approach using recombinant adeno-associated virus (AAV)-mediated Atp6i RNA interference (RNAi) knockdown of Atp6i/TIRC7 gene expression to simultaneously target periapical bone ..
  19. Wakkach A, Augier S, Breittmayer J, Blin Wakkach C, Carle G. Characterization of IL-10-secreting T cells derived from regulatory CD4+CD25+ cells by the TIRC7 surface marker. J Immunol. 2008;180:6054-63 pubmed
    ..Our experiments indicate that TIRC7, T cell immune response cDNA 7, a novel membrane molecule involved in the regulation of T lymphocyte activation, ..
  20. Ye L, Morse L, Zhang L, Sasaki H, Mills J, Odgren P, et al. Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption. PLoS Genet. 2015;11:e1005057 pubmed publisher
    ..These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake. ..
  21. Hosokawa H, Dip P, Merkulova M, Bakulina A, Zhuang Z, Khatri A, et al. The N termini of a-subunit isoforms are involved in signaling between vacuolar H+-ATPase (V-ATPase) and cytohesin-2. J Biol Chem. 2013;288:5896-913 pubmed publisher
    ..Thus, here we have uncovered an evolutionarily conserved function of the V-ATPase as a novel cytohesin-signaling receptor. ..
  22. Schreiber M, Poirier C, Franchi A, Kurzbauer R, Guenet J, Carle G, et al. Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis). Oncogene. 1997;15:1171-8 pubmed
    ..The segregation of fra-1 in two different crosses of mice carrying oc and an allelism test between oc and a targeted disruption of fra-1 demonstrate that fra-1 and oc are two distinct genes rather than oc being a mutant allele of fra-1...
  23. Bronckers A, Lyaruu D, Bervoets T, Medina J, DenBesten P, Richter J, et al. Murine ameloblasts are immunonegative for Tcirg1, the v-H-ATPase subunit essential for the osteoclast plasma proton pump. Bone. 2012;50:901-8 pubmed publisher
    ..ameloblasts is a proton pump, we determined whether these cells express the lysosomal, T-cell, immune regulator 1 (Tcirg1, v-H-Atp6v(0)a(3)), which is an essential part of the plasma membrane proton pump that is present in osteoclasts...
  24. Kawamura N, Tabata H, Sun Wada G, Wada Y. Optic nerve compression and retinal degeneration in Tcirg1 mutant mice lacking the vacuolar-type H-ATPase a3 subunit. PLoS ONE. 2010;5:e12086 pubmed publisher
    ..Mutations in the Tcirg1 (also known as Atp6V0a3) locus, which encodes the a3 subunit of V-ATPase, cause severe autosomal recessive ..
  25. Deng W, Stashenko P, Chen W, Liang Y, Shimizu K, Li Y. Characterization of mouse Atp6i gene, the gene promoter, and the gene expression. J Bone Miner Res. 2001;16:1136-46 pubmed
    ..cloned a gene encoding a putative osteoclast-specific proton pump subunit, termed OC-116 kDa, approved mouse Atp6i (ATPase, H+ transporting, [vacuolar proton pump] member I)...
  26. Belaid A, Cerezo M, Chargui A, Corcelle Termeau E, Pedeutour F, Giuliano S, et al. Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis, and genomic stability. Cancer Res. 2013;73:4311-22 pubmed publisher
    ..Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy...
  27. Ferron M, Wei J, Yoshizawa T, Del Fattore A, Depinho R, Teti A, et al. Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell. 2010;142:296-308 pubmed publisher
    ..Hence, in a feed-forward loop, insulin signals in osteoblasts activate a hormone, osteocalcin, that promotes glucose metabolism. ..
  28. Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, et al. The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet. 2001;10:1767-73 pubmed
    ..Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/..
  29. Mouline C, Beranger G, Schmid Antomarchi H, Quincey D, Momier D, Boukhechba F, et al. Monocytes differentiation upon treatment with a peptide corresponding to the C-terminus of activated T cell-expressed Tirc7 protein. J Cell Physiol. 2012;227:3088-98 pubmed publisher
    Atp6v0a3 gene encodes for two alternative products, Tirc7 and a3 proteins, which are differentially expressed in activated T cells and resorbing osteoclasts, respectively...
  30. Mansour A, Abou Ezzi G, Sitnicka E, Jacobsen S, Wakkach A, Blin Wakkach C. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J Exp Med. 2012;209:537-49 pubmed publisher
    ..These findings broaden our knowledge of the HSC niche formation, which is critical for understanding normal and pathological hematopoiesis. ..
  31. Serrano E, Ricofort R, Zuo J, Ochotny N, Manolson M, Holliday L. Regulation of vacuolar H(+)-ATPase in microglia by RANKL. Biochem Biophys Res Commun. 2009;389:193-7 pubmed publisher
    ..In summary, microglia express the a3-subunit of V-ATPase. The expression of a3 and the interaction between V-ATPases and microfilaments was modulated by RANKL. These data suggest a novel molecular pathway for regulating microglia. ..
  32. Jiang H, Chen W, Zhu G, Zhang L, Tucker B, Hao L, et al. RNAi-mediated silencing of Atp6i and Atp6i haploinsufficiency prevents both bone loss and inflammation in a mouse model of periodontal disease. PLoS ONE. 2013;8:e58599 pubmed publisher
    ..For this purpose, we used AAV-mediated RNAi knockdown of Atp6i/TIRC7 gene expression to target bone resorption and gingival inflammation simultaneously...
  33. Nakamura I, Takahashi N, Udagawa N, Moriyama Y, Kurokawa T, Jimi E, et al. Lack of vacuolar proton ATPase association with the cytoskeleton in osteoclasts of osteosclerotic (oc/oc) mice. FEBS Lett. 1997;401:207-12 pubmed
    We examined the pathogenetic mechanism underlying the lack of bone resorption in osteosclerotic oc/oc mice...
  34. Utku N, Heinemann T, Winter M, Bulwin C, Schlawinsky M, Fraser P, et al. Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice. Clin Exp Immunol. 2006;144:142-51 pubmed
    b>TIRC7 is a cell surface molecule which is expressed in T and B lymphocytes and negatively regulates their function. Anti-TIRC7 specific monoclonal antibody (mAb) inhibited T cell memory response to recall antigens...
  35. Ochotny N, Flenniken A, Owen C, Voronov I, Zirngibl R, Osborne L, et al. The V-ATPase a3 subunit mutation R740S is dominant negative and results in osteopetrosis in mice. J Bone Miner Res. 2011;26:1484-93 pubmed publisher
    ..It was found to carry a dominant missense mutation in the Tcirg1 gene that encodes the a3 subunit of the vacuolar type H(+)-ATPase (V-ATPase), resulting in replacement of a highly ..
  36. Marks S, Seifert M, Lane P. Osteosclerosis, a recessive skeletal mutation on chromosome 19 in the mouse. J Hered. 1985;76:171-6 pubmed
    ..Extensive extramedullary hemopoiesis occurs in the liver and spleen of mutants. This unique constellation of features suggests that the oc mutation is a valuable model in which to investigate the pathogenesis of osteopetrosis. ..
  37. Koehne T, Marshall R, Jeschke A, Kahl Nieke B, Schinke T, Amling M. Osteopetrosis, osteopetrorickets and hypophosphatemic rickets differentially affect dentin and enamel mineralization. Bone. 2013;53:25-33 pubmed publisher
    ..Moreover, since defects of dental mineralization may trigger premature tooth decay and thereby osteomyelitis of the jaw, they further underscore the importance of discriminating between OP and OPR in the respective individuals...
  38. Beranger G, Momier D, Guigonis J, Samson M, Carle G, Scimeca J. Differential binding of poly(ADP-Ribose) polymerase-1 and JunD/Fra2 accounts for RANKL-induced Tcirg1 gene expression during osteoclastogenesis. J Bone Miner Res. 2007;22:975-83 pubmed
    We studied Tcirg1 gene expression on RANKL-induced osteoclastic differentiation of the mouse model RAW264.7 cells...
  39. Brady K, Dushkin H, Förnzler D, Koike T, Magner F, Her H, et al. A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics. 1999;56:254-61 pubmed
    ..In situ studies show that Roct is expressed in developing bone. We propose that the absence of Roct expression results in an osteopetrosis phenotype in mice. ..
  40. Udagawa N, Sasaki T, Akatsu T, Takahashi N, Tanaka S, Tamura T, et al. Lack of bone resorption in osteosclerotic (oc/oc) mice is due to a defect in osteoclast progenitors rather than the local microenvironment provided by osteoblastic cells. Biochem Biophys Res Commun. 1992;184:67-72 pubmed
    ..Using this co-culture system, we examined the pathogenetic mechanism underlying the lack of bone resorption in osteosclerotic oc/oc mice...
  41. Henriksen K, Flores C, Thomsen J, Brüel A, Thudium C, Neutzsky Wulff A, et al. Dissociation of bone resorption and bone formation in adult mice with a non-functional V-ATPase in osteoclasts leads to increased bone strength. PLoS ONE. 2011;6:e27482 pubmed publisher
    ..In conclusion, these data show that attenuation of acid secretion in adult mice leads to uncoupling and improves bone strength. ..
  42. Beranger G, Momier D, Rochet N, Quincey D, Guigonis J, Samson M, et al. RANKL treatment releases the negative regulation of the poly(ADP-ribose) polymerase-1 on Tcirg1 gene expression during osteoclastogenesis. J Bone Miner Res. 2006;21:1757-69 pubmed
    The Tcirg1 gene encodes the osteoclast-specific a3 isoform of the V-ATPase a subunit. Using the mouse osteoclastic model RAW264...
  43. Nishi T, Forgac M. Molecular cloning and expression of three isoforms of the 100-kDa a subunit of the mouse vacuolar proton-translocating ATPase. J Biol Chem. 2000;275:6824-30 pubmed
    ..The results obtained suggest that isoforms of the 100-kDa a subunit may contribute to tissue-specific functions of the V-ATPase. ..
  44. Ochotny N, Voronov I, Owen C, Aubin J, Manolson M. The R740S mutation in the V-ATPase a3 subunit results in osteoclast apoptosis and defective early-stage autophagy. J Cell Biochem. 2013;114:2823-33 pubmed publisher