TCIRG1 Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the TCIRG1 gene, its role in osteoclast function, associated diseases, and mutation spectrum.
Gene Information Card
| Symbol | TCIRG1 |
|---|---|
| Full Name | T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3 |
| Gene Type | protein-coding |
| Chromosomal Location | 11q13.2 |
| NCBI Gene ID | 10312 ncbi.nlm.nih.gov/gene/10312 |
| Ensembl ID | ENSG00000110719 |
| UniProt ID | Q13488 |
| OMIM ID | 604592 |
| HGNC ID | 11649 |
| Aliases | ATP6V0A3, OC-116, OPTB1, a3, VPP3, Stv1 |
Description
The TCIRG1 gene encodes the a3 subunit of the vacuolar H+-ATPase (V-ATPase), a multi-subunit enzyme that acidifies intracellular compartments and the extracellular microenvironment. In osteoclasts, TCIRG1 is essential for bone resorption, as it pumps protons into the resorption lacuna, dissolving hydroxyapatite and degrading bone matrix. Mutations in TCIRG1 are the most common cause of autosomal recessive osteopetrosis (ARO), a severe bone disease characterized by increased bone density due to defective osteoclast function. The gene is also expressed in other tissues, including the kidney and inner ear, where it contributes to acid-base balance and endolymph pH regulation.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Autosomal recessive osteopetrosis (ARO) | Loss-of-function mutations in TCIRG1 impair V-ATPase-mediated proton transport in osteoclasts, leading to defective bone resorption and increased bone density. | ClinVar, OMIM, multiple publications |
| Osteopetrosis, intermediate form | Some missense mutations may retain partial function, resulting in a milder phenotype. | OMIM, case reports |
| Osteopetrosis, infantile malignant type | Severe mutations (nonsense, frameshift) cause complete loss of function, leading to early-onset, life-threatening disease. | OMIM, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Bone marrow | High | Osteoclasts are derived from myeloid precursors in bone marrow. |
| Bone | High | Osteoclasts are abundant in bone tissue. |
| Kidney | Medium | Expressed in renal intercalated cells for acid secretion. |
| Inner ear | Medium | Involved in endolymph pH regulation. |
| Lung | Low | Low expression in alveolar cells. |
| Liver | Low | Minimal expression. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Osteoclasts | High | Primary site of expression and function. |
| Macrophages | Medium | Related myeloid cells express TCIRG1. |
| HEK293 | Low | Embryonic kidney cells show low endogenous expression. |
| HeLa | Low | Cervical cancer cell line with low expression. |
| K562 | Medium | Chronic myeloid leukemia cell line expresses moderate levels. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.242delC (p.Pro81LeufsTer23) | Frameshift | Common in ARO patients | Loss of function, premature truncation. |
| c.1175+1G>A | Splice site | Reported in ARO | Aberrant splicing, loss of function. |
| c.1975C>T (p.Arg659Ter) | Nonsense | Reported in ARO | Premature stop codon, loss of function. |
| c.1544G>A (p.Arg515Gln) | Missense | Reported in intermediate osteopetrosis | Partial loss of function, reduced proton transport. |
| c.2233C>T (p.Arg745Cys) | Missense | Reported in ARO | Loss of function, impaired V-ATPase assembly. |
Mutation functional classification
Loss of Function (LOF)
Most TCIRG1 mutations are loss-of-function, leading to defective osteoclast-mediated bone resorption and osteopetrosis.
Gain of Function (GOF)
No gain-of-function mutations have been reported for TCIRG1.
Dominant Negative (DN)
Not applicable; TCIRG1 mutations are inherited in an autosomal recessive pattern.
View complete mutation data：
Gene Ontology (GO)
| • ATP hydrolysis activity | • proton transmembrane transporter activity |
| • V-type proton ATPase complex | • osteoclast differentiation |
| • bone resorption | • vacuolar acidification |
| • response to pH |
Pathways
• V-ATPase-mediated acidification
• Osteoclast signaling (RANKL/RANK pathway)
• Bone remodeling
Protein Summary
The TCIRG1 protein, also known as ATP6V0A3, is a 830-amino acid subunit of the V-ATPase complex. It is a transmembrane protein with multiple hydrophobic domains that form the proton-conducting pore. The a3 isoform is specifically expressed in osteoclasts and is critical for the acidification of the resorption lacuna. The protein interacts with other V-ATPase subunits to form a functional proton pump. Mutations in TCIRG1 disrupt this pump, leading to osteopetrosis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TCIRG1 Overexpression THP-1 Stable Cell Line | EDC90140 | Human | 10312 | Details Get a Quote |
| TCIRG1 Knockout HEK293 Cell Line | EDJ-KQ7002 | Human | 10312 | Details Get a Quote |
| TCIRG1 Knockout A-549 Cell Line | EDJ-KQ30357 | Human | 10312 | Details Get a Quote |
| TCIRG1 Knockout HCT 116 Cell Line | EDJ-KQ31738 | Human | 10312 | Details Get a Quote |
| TCIRG1 Knockout HeLa Cell Line | EDJ-KQ31739 | Human | 10312 | Details Get a Quote |
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