V-type proton ATPase 116 kDa subunit a isoform 3 encoded by TCIRG1 gene is a subunit of a large protein complex known as a vacuolar H+-ATPase (V-ATPase). TCIRG1 is located at 11q13, consists of 20 exons, and through alternate splicing gives rise to two main isoforms: TCIRG1-isoa and TCIRG1-isob. TCIRG1-isoa is a full length isoform and encodes a3 subunit of vacuolar H+-ATPase. TCIRG1-isob is a shorter isoform, lacking the first 5 exons of the longer isoform. TCIRG1 isoa is highly expressed in osteoclasts and is essential for bone resorption.
|Basic Information of TCIRG1|
|Protein Name||V-type proton ATPase 116 kDa subunit an isoform 3|
|Aliases||a3, Stv1, Vph1, Atp6i, OC116, OPTB1, TIRC7, ATP6N1C, ATP6V0A3, OC-116kDa|
|Organism||Homo sapiens (Human)|
TCIRG1 comprises the largest subunit of the osteoclastic V-ATPase. The main function of the V-ATPase in osteoclasts is to deliver protons to the ongoing acidification of the resorption lacunae during bone resorption. Located in the membrane embedded V0 domain of the V-ATPase, the TCIRG1 contains two hemi channels allowing access of protons for transport across the plasma membrane. TCIRG1 was initially identiﬁed in mice as anosteoclast-speciﬁc gene, whose targeted deletion causes osteo-clast-rich osteopetrosis. Mutations in TCIRG1 account for about 50% of the cases of infantile malignant osteopetrosis. Isoform ‘‘b’’ is a transmembrane molecule expressed on activated T cells. It represents an inhibitory receptor that plays an essential role in the regulation of the immune response.
Fig.1 Candidate genes for susceptibility to osteoporosis. (Ralston, 2006)
Two unrelated patients with severe congenital neutropenia, identified by authors, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.
CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and there is a need to modify the current classification of osteopetrosis.
This study shows that a low level of normal TCIRG1 protein can suppress the clinical presentation of TCIRG1-dependent autosomal recessive osteopetrosis (ARO).
This article reports case of a patient with osteopetrosis who carries TCIRG1 and CLCN7 mutations. In addition, among the three mutations, TCIRG1 c.909C>A and CLCN7 c.1798-1G>T are novel mutations.
This investigation is to prove the resorptive function of IMO osteoclasts can be restored by lentiviral mediated gene transfer of the TCIRG1 cDNA.
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