Human Molecular Genetics

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Human Molecular Genetics, 2001, Vol. 10, No. 5 537-543
© 2001 Oxford University Press

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

Wendy Balemans¹, Martin Ebeling², Neela Patel³, Els Van Hul¹, Pam Olson³, Marianna Dioszegi³, Charlemagne Lacza³, Wim Wuyts¹, Jenneke Van Den Ende¹, Patrick Willems⁴, Auristela F. Paes-Alves⁵, Suvimol Hill⁶, Manuel Bueno⁷, Feliciano J. Ramos⁷, Paolo Tacconi⁸, Frederik G. Dikkers⁹, Constantine Stratakis¹⁰, Klaus Lindpaintner¹¹, Brian Vickery³, Dorothee Foernzler¹¹ and Wim Van Hul^1,+

¹Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium, ²Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland, ³Musculoskeletal Research, Inflammatory Disease Unit, Roche Bioscience, Palo Alto, CA, USA, ⁴Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands, ⁵Departamento de Ginecología, Obstetrícia e Reprodução Humana, Universidade Federal de Bahia, Salvador, Brazil, ⁶Department of Radiology,Clinical Center, National Institutes of Health, Bethesda, MD, USA, ⁷Departamento de Pediatria Radiologia Y Medicina Fisica, Universidad de Zaragoza, Zaragoza, Spain, ⁸Istituto di Neurologia Universita di Cagliari, Cagliari, Italy, ⁹Department of Otorhinolaryngology, University Hospital Groningen, Groningen, The Netherlands, ¹⁰Unit on Genetics of Endocrinology,National Institute of Child Health and Human Development, Bethesda, MD, USA and ¹¹Roche Genetics, F. Hoffmann-La Roche Ltd, Basel, Switzerland

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.

⁺ To whom correspondence should be addressed. Tel: +32 3 820 2585; Fax: +32 3 820 2566; Email: vhul@uia.ac.be

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