title: Refined genomic localization of the genetic lesion in the osteopetrosis (op) rat and exclusion of three positional and functional candidate genes, Clcn7, Atp6v0c, and Slc9a3r2.
abstract: Osteopetrosis is a disease characterised by a generalized skeletal sclerosis resulting from a reduced osteoclast-mediated bone resorption. Several spontaneous mutations lead to osteopetrotic phenotypes in animals. Moutier et al. (1974) discovered the osteopetrosis (op) rat as a spontaneous, lethal, autosomal recessive mutant. op rats have large nonfunctioning osteoclasts and severe osteopetrosis. Dobbins et al. (2002) localized the disease-causing gene to a 1.5-cM genetic interval on rat chromosome 10, which we confirm in the present report. We also refined the genomic localization of the disease gene and provide statistical evidence for a disease-causing gene in a small region of rat chromosome 10. Three strong functional candidate genes are within the delineated region. Clcn7 was previously shown to underlie different forms of osteopetrosis, in both human and mice. ATP6v0c encodes a subunit of the vacuolar H(+)-ATPase or proton pump. Mutations in TCIRG1, another subunit of the proton pump, are known to cause a severe form of osteopetrosis. Given the critical role of proton pumping in bone resorption, the Slc9a3r2 gene, a sodium/hydrogen exchanger, was also considered as a candidate for the op mutation. RT-PCR showed that all 3 genes are expressed in osteoclasts, but sequencing found no mutations either in the coding regions or in intron splice junctions. Our ongoing mutation analysis of other genes in the candidate region will lead to the discovery of a novel osteopetrosis gene and further insights into osteoclast functioning.
authors.affiliation: Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Perdu
authors.forename: P R
authors.initials: PR
authors.lastname: Odgren
authors.forename: L
authors.initials: L
authors.lastname: Van Wesenbeeck
authors.forename: K
authors.initials: K
authors.lastname: Jennes
authors.forename: C C
authors.initials: CC
authors.lastname: Mackay
authors.forename: W
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018118:Chloride Channels / Q000235:genetics; D002874:Chromosome Mapping; D003598:Cytoskeletal Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007438:Introns / Q000235:genetics; D016623:Ion Pumps / Q000737:chemistry / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D010010:Osteoclasts / Q000378:metabolism; D010022:Osteopetrosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006180:Proton-Translocating ATPases / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D011922:Rats, Mutant Strains; D017923:Sodium-Hydrogen Exchangers; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics
chemical_list: C484226:Atp6ap1 protein, mouse; C437713:Atp6v0c protein, mouse; D018118:Chloride Channels; C490802:Clcn7 protein, rat; D003598:Cytoskeletal Proteins; D016623:Ion Pumps; C498832:Slc9a3r2 protein, rat; D017923:Sodium-Hydrogen Exchangers; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases