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
| Autor: | L. Van Wesenbeeck, Bram Perdu, Paul R. Odgren, W. Van Hul, Karen Jennes, C. C. MacKay |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Vacuolar Proton-Translocating ATPases Candidate gene Sodium-Hydrogen Exchangers Veterinary medicine Endocrinology Diabetes and Metabolism Mutant Osteoclasts Ion Pumps medicine.disease_cause Article Bone and Bones Rats Mutant Strains TCIRG1 Endocrinology Chloride Channels medicine Animals Genetic Predisposition to Disease Orthopedics and Sports Medicine Biology Gene Genetics Mutation biology Pharmacology. Therapy Chromosome Mapping Osteopetrosis Exons ATP6V0C medicine.disease Molecular biology Introns Rats Cytoskeletal Proteins Disease Models Animal Proton-Translocating ATPases Rats Inbred Lew biology.protein CLCN7 |
| Zdroj: | Calcified tissue international |
| ISSN: | 1432-0827 0171-967X |
| DOI: | 10.1007/s00223-009-9229-7 |
| Popis: | 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 non-functioning osteoclasts and severe osteopetrosis [1]. Dobbins et al. (2002) localised the disease causing gene to a 1.5 cM genetic interval on rat chromosome 10, which we confirm in the present report [2]. We also refined the genomic localisation 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, both in 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 in either the coding regions nor 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. |
| Databáze: | OpenAIRE |
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