ATPase H+ transporting V0 subunit a3 (TCIRG1) (TCIRG1)

TCIRG1 (T-cell immune regulator 1) encodes the a3 subunit of the vacuolar H+-ATPase (V-ATPase) complex, which is essential for the acidification of the resorptive lacuna by osteoclasts (UniProt Q13488). Mutations in this gene are the primary cause of Infantile Malignant Osteopetrosis (IMO), a rare and fatal genetic disorder characterized by abnormally dense bone, bone marrow failure, and neurological impairment due to lack of bone resorption (NIH/GARD). The therapeutic approach involves the genomic integration of a functional TCIRG1 cDNA into autologous CD34+ hematopoietic stem cells using viral vectors, typically lentiviral (PubMed: 31558489). These modified stem cells then differentiate into functional osteoclasts capable of resorbing bone, thereby restoring skeletal homeostasis. This gene therapy aims to provide a safer alternative to allogeneic hematopoietic stem cell transplantation, which carries high risks of graft-versus-host disease and rejection (ClinicalTrials.gov: NCT04408183).

Other names

T-cell immune regulator 1V-type proton ATPase 116 kDa subunit a isoform 3OC116OPTB1TIRC7a3 subunit of V-ATPaseV-type proton ATPase subunit a isoform 3

Restoration of functional V-ATPase activity in osteoclasts through ex vivo lentiviral-mediated delivery of TCIRG1 cDNA into autologous hematopoietic stem cells, enabling bone resorption and skeletal remodeling.