The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants

Bone. 2000 Mar;26(3):207-13. doi: 10.1016/s8756-3282(99)00278-1.

Abstract

Osteosclerosis (oc) is an autosomal recessive lethal mutation that impairs bone resorption by osteoclasts, and induces a general increase of bone density in affected mice. Genetic mapping of the oc mutation was used as a backbone in a positional cloning approach in the pericentromeric region of mouse chromosome 19. Perfect cosegregation of the osteopetrotic phenotype with polymorphic markers enabled the construction of a sequence-ready bacterial artificial chromosome (BAC) contig of this region. Genomic sequencing of a 200-kb area revealed the presence of the mouse homologue to the human gene encoding the osteoclast-specific 116-kDa subunit of the vacuolar proton pump. This gene was located recently on human 11q13, a genomic region conserved with proximal mouse chromosome 19. Sequencing of the 5' end of the gene in oc/oc mice showed a 1.6-kb deletion, including the translation start site, which impairs genuine transcription of this subunit. The inactivation of this osteoclast-specific vacuolar proton ATPase subunit could be responsible for the lack of this enzyme in the apical membranes of osteoclast cells in oc/oc mice, thereby preventing the resorption function of these cells, which leads to the osteopetrotic phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Chromosomes, Artificial, Yeast
  • DNA Primers
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation*
  • Osteoclasts / enzymology*
  • Osteosclerosis / genetics*
  • Proton-Translocating ATPases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Deletion*
  • Sequence Homology, Amino Acid
  • Vacuolar Proton-Translocating ATPases*

Substances

  • DNA Primers
  • Vacuolar Proton-Translocating ATPases
  • Proton-Translocating ATPases