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

TLDR

Sclerosteosis is an autosomal recessive bone dysplasia marked by generalized hyperostosis and sclerosis of the skull, mandible, ribs, clavicles, and long bones, causing cranial nerve compression and resembling van Buchem disease but with hand malformations and tall stature. Linkage analysis and positional cloning localized both sclerosteosis and van Buchem disease to a ~1 Mb region on chromosome 17q12–q21, where the SOST gene was identified as the disease‑causing gene. The SOST gene encodes a secreted cysteine‑knot protein, and loss‑of‑function mutations in sclerosteosis patients abolish its bone‑suppressive activity, resulting in excessive bone growth and suggesting SOST as a therapeutic target for osteoporosis.

Abstract

Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12–q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to ~1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.