Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST)

Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance, Radiologically, it is characterized by a gen eralized hyperostosis and sclerosis leading to a markedly thickened and scl erotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial ne rve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerost eosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated oy nana malformations and a large stature in sclerost eosis patients. By linkage analysis in one extended van Buchem family and t wo consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis t hat both conditions are caused by mutations in the same gene. After reducin g the disease critical region to similar to1 Mb, we used the positional clo ning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secreti on and a cysteine-knot motif. Two nonsense mutations and one splice site mu tation were identified in sclerosteosis patients, but no mutations were fou nd in a fourth sclerosteosis patient nor in the patients from the van Buche m family. As the three disease-causing mutations lead to loss of function o f the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the sup pression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.