Genetic study of osteopetrosis in the Norway rat

Moutier, R; Toyama, Kyoko; Charrier, Marimikel

doi:10.1093/oxfordjournals.jhered.a108554

Cited by 12 publications

(3 citation statements)

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“…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].…”

supporting

confidence: 88%

“…A third osteopetrotic rat model is microphthalmia blanc ( mib ) [17], which has a mild and transient form of osteopetrosis due to a large deletion that truncates the encoded microphthalmia transcription factor [18]. The fourth and only remaining unknown, osteopetrotic mutation in the rat is osteopetrosis ( op ), first discovered by Moutier et al (1974) as a spontaneous, lethal mutation [1]. The affected mutants exhibit a persistent, generalized sclerosis and show no signs of remission with age.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2009

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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.

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supporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…The osteopetrotic op op rat is a mulant of ihe Fatty/Orl-op strain and was obtained from the Centre Selection de I'Elcvagc l"Animaux de Laboratoire. CNRS, Orleans, France, by the generosity of Dr Rene Mouticr [13]. The strain is black and white in colour (hooded) and the heterozygote f+/op) and the homozygote { + /+) appear indistinguishable.…”

Section: Methodsmentioning

confidence: 99%

Bone Absorption and the Immune System

Nisbet

1981

Scand J Immunol

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The absorption of bone in Grüneberg microphthalmic mice and the op op osteopetrotic rat can be stimulated by an injection of compatible bone marrow, and complete resorption can occur. It is probable that the bone-absorbing osteoclast responsible is derived from a haematopoietic stem cell resident in the bone marrow (BM). Maintenance of the resorption depends on the survival of donor cells which has an important implication for clinical therapy in man. No evidence was found that the thymus played a leading role in the mechanism of bone absorption in the Grüneberg microphthalmic mouse, or in the op op rat.

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Cloning the full-length cDNA for rat connective tissue growth factor: Implications for skeletal development

Smock

Safadi

et al. 2000

J. Cell. Biochem.

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The mammalian osteopetroses represent a pathogenetically diverse group of skeletal disorders characterized by excess bone mass resulting from reduced osteoclastic bone resorption. Abnormalities involving osteoblast function and skeletal development have also been reported in many forms of the disease. In this study, we used the rat mutation, osteopetrosis (op), to examine differences in skeletal gene expression between op mutants and their normal littermates. RNA isolated from calvaria and long bones was used as a template for mRNA-differential display. Sequence information for one of the many cDNA that were selectively expressed in either normal or mutant bone suggested that it is the rat homologue of connective tissue growth factor (CTGF) previously cloned in the human, mouse, and other species. A consensus sequence was assembled from overlapping 5'-RACE clones and used to confirm the rat CTGF cDNA protein coding region. Northern blot analysis confirmed that this message was highly (8- to 10-fold) over-expressed in op versus normal bone; it was also upregulated in op kidney but none of the other tissues (brain, liver, spleen, thymus) examined. In primary rat osteoblast cultures, the CTGF message exhibits a temporal pattern of expression dependent on their state of differentiation. Furthermore, CTGF expression is regulated by prostaglandin E(2), a factor known to modulate osteoblast differentiation. Since members of the CTGF family regulate the expression of specific genes, such as collagen and fibronectin, we propose that CTGF may play a previously unreported role in normal skeletal modeling/remodeling. Its dramatic over-expression in the op mutant skeleton may be secondary to the uncoupling of bone resorption and bone formation resulting in dysregulation of osteoblast gene expression and function.

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Genetic study of osteopetrosis in the Norway rat

Cited by 12 publications

References 0 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

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

Bone Absorption and the Immune System

Cloning the full-length cDNA for rat connective tissue growth factor: Implications for skeletal development

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