Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 21 P5

1University of Oxford, Oxford, UK; 2MRC Harwell, Harwell, UK; 3University of Sheffield, Sheffield, UK; 4University of Queensland, Woolloongabba, Queensland, Australia.

Investigations of skeletal dysplasias which are often inherited have yielded important insights in the molecular mechanisms of bone development, osteoporosis and osteoarthritis. However, these studies have been hampered by the lack of available patients and affected families. To overcome this limitation, we have investigated mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for hereditary musculoskeletal disorders. Mice were kept in accordance with national welfare guidelines and project license restrictions. At 12 weeks of age, all mice underwent phenotypic assessments that included dysmorphology, radiography and serum biochemistry. These processes identified a mutant mouse with a waddling gait designated Slip. Slip mice had bilateral deformation of the calcaneum, extended tuberosities, and abnormal metaphyses in the knee joints, metatarsals and metacarpals. Micro-computed tomography scanning of Slip mice revealed a shortening of bone lengths, decreased total bone volume, cortical bone volume, trabecular bone volume and trabecular number. The tibiae of the Slip mice also had an increased structure model index suggesting a more rod-like scaffold indicative of low bone density. These features had similarities to those for Jansen’s metaphyseal chondrodysplasia which is due to activating mutations of the parathyroid hormone receptor (PTH1R). However, only male mice were affected with the Slip phenotype and inheritance testing demonstrated an X-linked inheritance. Furthermore, genetic mapping studies using DNA from 14 affected mice localized the Slip locus to a 151 Mb region on the X chromosome indicating that the phenotype could not be due to a mutation in the Pth1r which is located on mouse chromosome 9. Thus, our studies have established a mouse model for an X-linked metaphyseal chondrodysplasia that may potentially identify a component in the Pth1r signalling pathway encoded by a gene on the X chromosome.

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