The role of SH3BP2 in the pathophysiology of cherubism.
Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.
Department of Reconstructive Sciences, Center for Regenerative Medicine and Skeletal Development, University of Connecticut Health Center, Farmington, CT, USA. reichenberger@uchc.edu
Ernst J
EJ
Reichenberger
Michael A
MA
Levine
Bjorn R
BR
Olsen
Maria E
ME
Papadaki
Steven A
SA
Lietman
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D001862:Bone Resorption / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D019703:Calcineurin / Q000378:metabolism; D002636:Cherubism / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018095:Germ-Line Mutation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C109073:SH3BP2 protein, human; D019703:Calcineurin