Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis

Osteopetrosis includes a group of inherited diseases in which inadequate bo ne resorption is caused by osteoclast dysfunction. Although molecular defec ts have been described for many animal models of osteopetrosis. the gene re sponsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessi ve osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome , generally within the first decade of life. Osteoclasts are present in nor mal or elevated numbers in individuals affected by autosomal recessive oste opetrosis(1), suggesting that the defect is not in osteoclast differentiati on, but in a gene involved in the functional capacity of mature osteoclasts . Some of the mouse mutants have a decreased number of osteoclasts. which s uggests that the defect directly interferes with osteoclast differentiation (2,3). In other mutants, it is the function of the osteoclast that seems to be affected, as they show normal or elevated numbers of non-functioning os teoclasts(2,4-6). Here we show that TCIRG1, encoding the osteoclast-specifi c 116-kD subunit of the vacuolar proton pump, is mutated in five of nine pa tients with a diagnosis of infantile malignant osteopetrosis. Our data indi cate that mutations in TCIRG1 are a frequent cause of autosomal recessive o steopetrosis in humans.