Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis

Abstract

Although the gene defects for several mouse mutants with severe osteopetrosis are known, the genes underlying human infantile malignant recessive osteopetrosis remain elusive. Osteopetrosis is thought to be caused by a defect in osteoclast function. These cells degrade bone material in a tightly sealed extracellular compartment that is acidified by a vacuolar (V)-type H(+)-ATPase. Genes encoding components of the acidification machinery are candidate genes for osteopetrosis. In five of ten patients with infantile malignant osteopetrosis, we now demonstrate five different mutations in OC116, the gene encoding the a3 subunit of the V-ATPase from osteoclasts. Two independent patients were homozygous for mutations that predict a total loss of function by severely truncating the protein. By affecting a splice site, another homozygous mutation deletes 14 amino acids within the N-terminus, which interacts with other subunits of the proton pump. On the other hand, in four patients no mutations were found, and one patient from a consanguineous family did not show homozygosity at the OC116 locus, suggesting that mutations in at least one different gene may underlie osteopetrosis. Our work shows that mutations in the gene encoding the a3 subunit of the proton pump are a rather common cause of infantile osteopetrosis and suggests that this disease is genetically heterogeneous.

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

“…V-ATPases are proton-translocating transporters that become enriched in ruffled borders of polarized osteoclasts and mediate acidification of the resorptive space [24,25]. A lack of V-ATPases in the ruffled border results in impaired bone resorption, and in humans and mouse models, a malignant form of osteopetrosis [26][27][28][29]. Figure 5B shows confocal sections at the base of either a control-transfected (top panels) or Tm-4 overexpressing (bottom panels) cell.…”

Molecular Understanding of Osteoclast Differentiation and Physiology

“…Cross-linked bone collagen and the peptides containing cross-links used to estimate the rate of bone resorption in serum or urine are not degraded by proteinases. A mutation in the Atp6i also causes an osteopetrosis in human [17,18].…”

Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function

“…The V-ATPase molecules located in the outer fusion zone of the ruffled border pump the protons out into the resorption lacunae. If this enzyme function is compromised, mineral dissolution does not occur (Kornak et al 2000). Matrix metallopeptidase-9 (MMP-9) appears to be essential for osteoclast migration and precursor recruitment into bone (Okada et al 1995;Yu et al 2003).…”