Disease relevance of TCIRG1

• The TCIRG1 gene was shown to underly autosomal recessive osteopetrosis (ARO), and, recently, mutations in the LRP5 gene were found both in the osteoporosis-pseudoglioma syndrome and the high bone mass trait [1].
• Since various products with nearly ubiquitous tissue distribution are generated from TCIRG1, this gene may be involved in other processes besides immune response and bone resorption [2].
• Mutations in human a3 and a4 result in osteopetrosis and distal renal tubular acidosis, respectively [3].
• TIRC7 and OC116, a recently described putative subunit of the vacuolar proton pump that was demonstrated to be expressed in an osteoclastoma tumor as well as in a human pancreatic adenocarcinoma cell line, are demonstrated to be alternative transcripts of the same gene [4].
• Similarly, in humans with liver cirrhosis, mitochondrial cytochrome a + a3 content is elevated and has been used to assess the risk for hepatectomy [5].

High impact information on TCIRG1

• Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans [6].
• Modulation of TIRC7-mediated signals with specific anti-TIRC7 antibodies in vitro efficiently prevents human T cell proliferation and IL-2 secretion [7].
• A novel 75 kDa membrane protein, TIRC7, is described that exhibits a central role in T cell activation in vitro and in vivo [7].
• Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein [7].
• 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/osteoclast interface, are responsible for a subset of this condition [8].

Biological context of TCIRG1

• In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women [9].
• Two transcript variants (TV) of the T cell immune regulator gene 1 (TCIRG1) have already been characterized [2].
• Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women [9].
• In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects [10].
• Two subjects were compound heterozygotes for TCIRG1 defects; both had CD14 cells that attached to bone but did not acidify attachments; cell fusion and attachment occurred, however, in RANKL and CSF-1 [10].

Anatomical context of TCIRG1

• As shown in this patient, the autosomal recessive form caused by a TCIRG1 gene mutation may be amenable to bone marrow transplantation [11].
• Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae [12].
• We found that V-ATPase with the a3 isoform is highly expressed in pancreatic islets, and is localized to membranes of insulin-containing secretory granules in beta-cells. oc/oc mice, which have a null mutation at the a3 locus, exhibited a reduced level of insulin in the blood, even with high glucose administration [13].
• Moreover, the identification of TIRC7 in graft infiltrating lymphocytes might serve as a diagnostic marker to detect allograft rejection [14].

Associations of TCIRG1 with chemical compounds

• Mutations in a3 resulted in wild type vacuolar acidification and growth on media containing 4 mM ZnCl2, 200 mM CaCl2, or buffered to pH 7.5 with V-ATPase hydrolytic and pumping activity decreased by 30-35% [3].
• We assign the 1670-cm-1 band to the heme a formyl substituent and propose that the intensity of the 1670 cm-1 is high for reduced cytochrome a3 because the C==O lies in the porphyrin plane and is very weak for oxidized and reduced cytochrome a, oxidized cytochrome a3, and oxidized and reduced heme a-imidazole because the C==O lies out of the plane [15].
• Semi-quantitative RT-PCR analysis showed that the gene transcripts of putative Bafilomycin A1 binding subunit, V-ATPase-subunit a3, were expressed in the preosteoclastic RAW cell line, and up-regulated during RANKL-induced osteoclastogenesis [16].

Other interactions of TCIRG1

• Because both genes map within the candidate region for ADOI, it can not be excluded that ADOI is caused by mutations in either the TCIRG1 or the LRP5 gene [1].
• Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters [17].
• Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II [17].
• Malignant osteopetrosis, a severe disease causing early infantile death in humans, is caused by mutations in the TCIRG1, CLCN7, or OSTM1 genes [18].
• The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase [19].
• The inhibition of cell proliferation mediated by TIRC7 is dependent on CTLA-4 expression because the TIRC7-mediated inhibitory effects on cell proliferation and cytokine expression are abolished by Ab blockade of CTLA-4 [20].

Analytical, diagnostic and therapeutic context of TCIRG1

• Based on the search in dbEST, we validated by RT-PCR six new alternative splice events in TCIRG1 in most of the 28 human tissues studied [2].
• An anti-TIRC7 antibody that cross-reacts with the 75 kDa rat homolog exhibits inhibition of rat alloimmune response in vitro and significantly prolongs kidney allograft survival in vivo [7].
• Sequence analysis of the TCIRG1 gene encoding the a3 subunit revealed two novel mutations: a deletion/insertion mutation in exon 9 and a T-to-C transition at the splice donor site of intron 19 [21].
• Cytochromes a, b and c show a simple oxidative response to electrical stimulation; the kinetics of this oxidative response are similar to those of the oxidative transient of the cyt a3 response [22].
• In this report, transcript variant 3 of T cell immune regulator gene 1 was used as a model to demonstrate a new method to ensure PCR specificity [23].

References