Genetics of bone diseases: Paget's disease, fibrous dysplasia, osteopetrosis, and osteogenesis imperfecta

Over the last few years, research into the genetics of bone diseases has produced new insights into the pathophysiology of bone remodeling. The identification of SQSTM1 mutations in Paget's disease of bone established that osteoclast activation involved both binding to ubiquitin and the proteasome pathway. However, murine models fail to replicate the full phenotype, and somatic SQSTM1 mutations have been identified, suggesting a role for complex mechanisms. In patients with fibrous dysplasia of bone, postzygotic somatic mutations in the GNAS gene are now well documented. Technological advances have improved the detection of somatic mutations in peripheral blood cells. Osteopetrosis is characterized by increased bone density due to deficient osteoclastic bone resorption. Most of the genes involved in the various clinical patterns of osteopetrosis have been identified. The identification of LRP5 gain-of-function mutations in autosomal dominant osteopetrosis type I prompted a revision of the classification scheme, and this form is now being included among the high-bone-mass diseases. Osteogenesis imperfecta is characterized by an inherited abnormality in bone formation that manifests as osteopenia with increased bone fragility. Mutations in the COL1A1 and COL1A2 genes are found in over 90% of patients. The recent identification of mutations in the CRTAP, LEPRE1, and PPIB genes in recessive forms has radically changed the classification of osteogenesis imperfecta and generated new pathophysiological hypotheses.