ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 OC4.1

A mouse with an ENU-induced mutation (Tyr209Asn) in the natriuretic peptide receptor 3 (Npr3) develops autosomal recessive kyphosis

Christopher Esapa1,2, Rosie Head1,2, Gethin Thomas3, Matthew Brown3, Peter Croucher4, Roger Cox2, Steve Brown2 & Rajesh Thakker1

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

Kyphosis is a common spinal disorder affecting up to 8.3% of the population, and associated with significant morbidity. Familial and twin studies have implicated a genetic involvement. However, the causative genes have not been identified. Studies investigating the underlying molecular mechanisms are hampered by genetic heterogeneity, small families and variable modes of inheritance displayed by different kindreds. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments that included dysmorphology, radiography, dual-energy X-ray absorptiometry (DEXA). These studies identified a mouse with kyphosis, designated Kylb. Inheritance testing revealed the phenotype to be transmitted as an autosomal recessive trait. Kylb mice, when compared to unaffected littermates, had: a 12% lower body weight (P<0.05); a 7% greater length (P<0.001); a 44% decrease in fat mass (P<0.05); a 14% increase in bone area (P<0.01); and a 6% reduction in areal bone mineral density (P<0.05). The characteristic hunch back deformity was present in mice by 10 days of age. Radiology and whole-skeletal staining using alcian blue and alizarin red revealed Kylb mice to have lumbo-thoracic kyphosis, longer vertebrae and long bones. Genetic mapping localised the Kylb locus to a 5.5 Mb region on chromosome 15 which contains 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a T to A transversion at codon 209, which altered a highly conserved tyrosine (Tyr) residue to an asparagine (Asn) residue. Thus, our studies which have established a mouse model for kyphosis due to excessive vertebral growth will help to identify the role of Npr3 in regulating the cellular and molecular mechanisms of vertebral bone growth.

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