Osteoclast rich osteopetrosis due to defects in TCIRG1 gene.

The discovery that mutations in TCIRG1 (also known as Atp6i) gene are responsible for the majority of autosomal recessive osteopetrosis (ARO) forms in humans heralded a new era for comprehension of this heterogeneous rare bone disease. TCIRG1 gene encodes the a3 subunit, an essential isoform of the vacuolar ATPase proton pump involved in the acidification of the resorption lacuna and in secretory lysosome trafficking. The gene defects lead to inefficient bone resorption by unfunctional osteoclasts which are seen in abundance on bone marrow biopsy, delineating this form of ARO as 'osteoclast-rich'. Patients usually present in early childhood with features of extramedullary haematopoiesis (hepatosplenomegaly, anaemia, thrombocytopenia) due to bone marrow fibrosis, and cranial nerve encroachment (blindness in particular). Impaired gastric calcium uptake due to high pH causes the co-occurrence of rickets, described as "osteopetrorickets". Osteoclast dysfunction leads to early death if untreated and allogeneic haematopoietic stem cell transplantation is the treatment of choice. Combined studies in patients and mouse models carrying spontaneous (the oc/oc mouse) or targeted disruption of Atp6i (TCIRG1) gene have been instrumental for the insight into disease pathogenesis and for the development of novel cellular therapies exploiting gene correction.