title: Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.
abstract: 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. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts, which suggests that the defect directly interferes with osteoclast differentiation. 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 osteoclasts. Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.
authors.affiliation: Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, Segrate, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Frattini
authors.forename: P J
authors.initials: PJ
authors.lastname: Orchard
authors.forename: C
authors.initials: C
authors.lastname: Sobacchi
authors.forename: S
authors.initials: S
authors.lastname: Giliani
authors.forename: M
authors.initials: M
authors.lastname: Abinun
authors.forename: J P
authors.initials: JP
authors.lastname: Mattsson
authors.forename: D J
authors.initials: DJ
authors.lastname: Keeling
authors.forename: A K
authors.initials: AK
authors.lastname: Andersson
authors.forename: P
authors.initials: P
authors.lastname: Wallbrandt
authors.forename: L
authors.initials: L
authors.lastname: Zecca
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
authors.forename: A
authors.initials: A
authors.lastname: Villa
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D018076:DNA, Complementary; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006801:Humans; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D010022:Osteopetrosis / Q000235:genetics* / Q000473:pathology; D017494:Proton Pumps / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics*; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D018076:DNA, Complementary; D017494:Proton Pumps; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases