Génétique des maladies osseuses

Abstract

During the past years, genetics of bone disease led to a better understanding of bone remodelling pathophysiology. Thus, the discovery of SQSTM1 mutations in Paget's disease of bone has highlighted the role of ubiquitin-binding and proteasomal pathway in osteoclast activation. However, the absence of reproduction of the whole phenotype in mice models and the recent identification of somatic mutations of SQSTM1 suggest more complex mechanisms. In fibrous dysplasia of bone, the presence of post-zygotic somatic mutations of GNAS gene is now well known. Technological progresses have been accomplished to increase the detection of somatic mutations in peripheral blood. Osteopetrosis is characterized by an increased bone density due to a defect in osteoclastic resorption. Most of the genes involved in the different clinical forms are now known. The discovery of “gain of function” in the LRP5 gene in type 1 autosomal dominant osteopetrosis led to a revision of the classification, this form now belonging to the high bone mass family. Osteogenesis imperfecta is characterized by a hereditary disorder of bone formation with osteopenia and bone fragility. COL1A1 and COL1A2 genes are mutated in 90 % of cases. The recent identification of mutations in CRTAP, LEPRE1 and PPIB genes in autosomal recessive forms drastically alters the classification of this entity and opens new pathophysiological horizons.