Odgren Lab Publications


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

UMMS Affiliation

Department of Cell Biology

Publication Date


Document Type



Animals; Bone and Bones; Chloride Channels; Chromosome Mapping; Cytoskeletal Proteins; Disease Models, Animal; Exons; Genetic Predisposition to Disease; Introns; Ion Pumps; Male; Mutation; Osteoclasts; Osteopetrosis; Proton-Translocating ATPases; Rats; Rats, Inbred Lew; Rats, Mutant Strains; Vacuolar Proton-Translocating ATPases


Cell Biology


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.

DOI of Published Version



Calcif Tissue Int. 2009 May;84(5):355-60. Epub 2009 Mar 4. Link to article on publisher's site

Journal/Book/Conference Title

Calcified tissue international

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PubMed ID