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

Endocrine Abstracts (2011) 25 P14

A gene causing autosomal dominant kyphoscoliosis in an N-ethyl-N-nitrosourea (ENU) mutagenised mouse model is located on a 5 Mb interval on mouse chromosome 4 band A3

Christopher Esapa1,2, Rosie Head1,2, Holly Evans3, Gethin Thomas4, Matthew Brown4, Peter Croucher3, Roger Cox2, Steve Brown2 & Rajesh Thakker1

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

Kyphosis and scoliosis are common spinal disorders that lead to significant morbidity in childhood, adolescence and adulthood. Familial and twin studies have implicated a genetic involvement, although the causative genes remain to be identified. To facilitate these studies, 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 and dual-energy X-ray absorptiometry (DEXA). These studies identified a mouse with fused lumbar vertebrae in association with kyphoscoliosis, designated Hvf. Inheritance testing revealed the phenotype to be transmitted as an autosomal dominant trait. Hvf mice, when compared to wild-type (WT) littermates, had: a 27% lower body weight (P<0.001); a 42% decrease in fat mass (P<0.001); a 22% reduction in lean mass (P<0.001); and a 33% increase in weight-adjusted whole body areal bone mineral density (BMD) (P<0.001). Histological analysis using haematoxylin and eosin stained sections revealed the Hvf mutant mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centres. Micro-computed tomography analysis of lumbar vertebrae from female Hvf mutant mice, when compared to WT littermates, revealed significant increases in trabecular thickness (Hvf versus WT=0.036 mm×10−2 vs 0.028 mm×10−2, P<0.01), trabecular bone volume as a proportion of tissue volume (15 vs 11%, P<0.05), and bone density (Hvf versus WT=1.27 vs 1.11 g/cm3, P<0.01). Genetic mapping localised the Hvf locus to a 5 Mb region on chromosome 4, which contains 50 genes. Thus, our studies which have established a mouse model for a monogenic form of kyphoscoliosis associated with fusion of lumbar vertebrae will help to identify a gene that has a role in the cellular and molecular mechanisms of kyphoscoliosis.