title: The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants.
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.
authors.affiliation: Instabilité et Altérations des Génomes, UMR6549 CNRS/UNSA, Faculté de Médecine de l'Université de Nice-Sophia Antipolis, Nice, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Scimeca
authors.forename: A
authors.initials: A
authors.lastname: Franchi
authors.forename: C
authors.initials: C
authors.lastname: Trojani
authors.forename: H
authors.initials: H
authors.lastname: Parrinello
authors.forename: J
authors.initials: J
authors.lastname: Grosgeorge
authors.forename: C
authors.initials: C
authors.lastname: Robert
authors.forename: O
authors.initials: O
authors.lastname: Jaillon
authors.forename: C
authors.initials: C
authors.lastname: Poirier
authors.forename: P
authors.initials: P
authors.lastname: Gaudray
authors.forename: G F
authors.initials: GF
authors.lastname: Carle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018244:Chromosomes, Artificial, Yeast; D017931:DNA Primers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D010010:Osteoclasts / Q000201:enzymology*; D010026:Osteosclerosis / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D017931:DNA Primers; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases