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

  title={Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis},
  author={Annalisa Frattini and Paul J. Orchard and Cristina Sobacchi and Silvia Clara Giliani and Mario Abinun and Jan P. Mattsson and D. Jeanette Keeling and Annika K. Andersson and Pia Wallbrandt and Luigi Zecca and Luigi Daniele Notarangelo and Paolo Vezzoni and Anna Villa},
  journal={Nature Genetics},
Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis, the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life… 
The mutational spectrum of human malignant autosomal recessive osteopetrosis.
This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.
Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis
It is concluded that ClCN7 mutations not only account for some dominant and malignant forms but also for intermediate forms of osteopetrosis.
Novel c.G630A TCIRG1 mutation causes aberrant splicing resulting in an unusually mild form of autosomal recessive osteopetrosis
The results show that the ΔE56 truncated protein is not functional, suggesting that the mild ARO phenotype observed in the patient is likely due to the residual full‐length protein expression.
Identification of a novel mutation in the coding region of the grey‐lethal gene OSTM1 in human malignant infantile osteopetrosis
The identification of a novel mutation in the coding sequence of the human grey‐lethal gene is described, which is the second OSTM1 mutation found in human ARO, confirming the involvement of this gene in the pathogenesis of this severe bone disease.
Osteopetrosis: genetics, treatment and new insights into osteoclast function
The genetics of ARO are described, the diagnostic role of next-generation sequencing methods are discussed and novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are discussed.
Intrafamilial phenotypic variability of osteopetrosis due to chloride channel 7 (CLCN7) mutations
CLCN7 mutations in a three generation family are reported and emphasize the intrafamilial clinical variability ranging from anemia in the neonatal period to asymptomatic increased bone density in the eldest generation.
Generation of an immunodeficient mouse model of tcirg1-deficient autosomal recessive osteopetrosis


Human autosomal recessive osteopetrosis maps to 11q13, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation.
Microsatellite markers in the region of 11q12-13 were found to be linked to osteopetrosis in two consanguineous Bedouin kindreds, and this phenotype is similar to that of the murine mutation osteosclerosis (oc), which is localized to proximal mouse chromosome 19.
Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification
It is demonstrated that targeted disruption of Atp6i in mice results in severe osteopetrosis and is unique and necessary for osteoclast-mediated extracellular acidification.
Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice.
Assaying the resorptive activity of cathepsin-K-deficient osteoclasts in vitro revealed this function to be severely impaired, which supports the contention that cathepsypsin K is of major importance in bone remodeling.
Osteosclerosis, a recessive skeletal mutation on chromosome 19 in the mouse.
A unique constellation of features suggests that the oc mutation, an osteopetrotic mutation in the mouse inherited as an autosomal recessive on chromosome 19, is a valuable model in which to investigate the pathogenesis of osteopETrosis.
Partial V(D)J Recombination Activity Leads to Omenn Syndrome
OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis
OPGL is a new regulator of lymph-node organogenesis and lymphocyte development and is an essential osteoclast differentiation factor in vivo.
Osteopetrosis and osteoporosis: two sides of the same coin.
A new trend towards understanding bone disease as a complete entity rather than as a series of unrelated disorders is illustrated, highlighting the importance of genes such as cathepsin K in understanding bone remodelling.