Molecular Genetics of Cherubism

Abstract

Cherubism is a rare fibro‐osseous genetic disorder caused and maintained by autoinflammatory processes that are caused by mutations in the SH3BP2 gene. Cherubism is a form of fibrodysplasia of the jaws that affects children at 2–6 years of age. The typical symmetrical bone resorption lacunae are self‐limiting to the jaws. Bone is replaced with fibrous tissue that can expand significantly and lead to the characteristic facial swelling. Disease progression normally stops at puberty and regresses thereafter. Mutations in SH3BP2 affect a six‐amino acid recognition sequence for tankyrase, a poly(ADP‐ribose)polymerase that marks proteins for ubiquitination and degradation. SH3BP2 has multiple functions in cell types of hematopoietic origin. Elevated SH3BP2 protein levels in macrophage/osteoclast precursors cause increased osteoclastogenesis with reduced thresholds for stimulants. Increased TNF‐α levels generate an inflammatory environment in a cherubism mouse model and conceivably also in the oral cavity of cherubism patients. More research to explain the spatiotemporal progression of cherubism is needed.

Key Concepts

  • Cherubism is a temporospatially restricted bone lysis disorder with bone being substituted by expansile fibrous tissue.
  • Patients with cherubism develop symmetrical bone lesions only in the maxilla and mandible.
  • Signs of cherubism develop in children as early as 2 years of age and bone lysis typically resolves after puberty. First diagnosed often on dental radiographs.
  • Known mutations are in the adaptor protein SH3BP2, which is involved in regulating the adaptive and innate immune system.
  • Mutations in SH3BP2 are within a six‐amino acid interval and cause inhibition of tankyrase binding, which is needed for efficient degradation.
  • High levels of intracellular SH3BP2 protein cause increased osteoclastogenesis and bone resorption in jaws.
  • Bone lysis is regulated via TLR2/TLR4 and TNF‐α‐dependent autoinflammatory response.
  • Jaw‐specific bone resorption in cherubism patients likely involves response to oral bacteria (pathogen‐associated molecular patterns; PAMPS) and bone remodelling during tooth eruption (damage‐associated molecular patterns; DAMPS).
  • Diagnosis for some patients is consistent with cherubism but no mutations are found in exons of SH3BP2.

Keywords: cherubism; fibrous dysplasia of the jaws; SH3BP2 ; autoinflammation; osteoclast; fibrosis; bone; genetic

Figure 1. Patient with severe form of cherubism. CT scan shows expansion of fibrous tissue replacing the resorbed bone of the jaws and invading the orbital floor. Reproduced with permission from Ueki et al., 2001 © Nature Publishing Group.
Figure 2. Gene structure of human SH3BP2 (Bell et al., ) and mutations for cherubism in the 13‐exon SH3BP2 gene that are found in the coding region for a six‐amino acid interval (amino acids 415‐420). Mutations in unusual cherubism cases and in one case of central giant cell granuloma have been reported outside this region (asterisks). Modified from Ueki et al., 2001 © Nature Publishing Group.
Figure 3. Proposed mechanism for inflammation and bone loss in cherubism. Reproduced from Ueki et al. (2007) © Cell Press/Elsevier.
close

References

Ainsua‐Enrich E , Alvarez‐Errico D , Gilfillan AM , et al. (2012) The adaptor 3BP2 is required for early and late events in FcepsilonRI signaling in human mast cells. Journal of Immunology 189: 2727–2734.

Ainsua‐Enrich E , Serrano‐Candelas E , Alvarez‐Errico D , et al. (2015) The adaptor 3BP2 is required for KIT receptor expression and human mast cell survival. Journal of Immunology 194: 4309–4318.

Aliprantis AO , Ueki Y , Sulyanto R , et al. (2008) NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. Journal of Clinical Investigation 118: 3775–3789.

Anderson DE and McClendon JL (1962) Cherubism – hereditary fibrous dysplasia of the jaws. I. Genetic considerations. Oral Surgery, Oral Medicine and Oral Pathology 15: 5–16.

Bell SM , Shaw M , Jou YS , et al. (1997) Identification and characterization of the human homologue of SH3BP2, an SH3 binding domain protein within a common region of deletion at 4p16.3 involved in bladder cancer. Genomics 44: 163–170.

Carvalho VM , Perdigao PF , Pimenta FJ , et al. (2008) A novel mutation of the SH3BP2 gene in an aggressive case of cherubism. Oral Oncology 44: 153–155.

Carvalho VM , Perdigao PF , Amaral FR , et al. (2009) Novel mutations in the SH3BP2 gene associated with sporadic central giant cell lesions and cherubism. Oral Diseases 15: 106–110.

Deckert M , Tartare‐Deckert S , Hernandez J , et al. (1998) Adaptor function for the Syk kinases‐interacting protein 3BP2 in IL‐2 gene activation. Immunity 9: 595–605.

Deckert M and Rottapel R (2006) The adapter 3BP2: how it plugs into leukocyte signaling. Advances in Experimental Medicine and Biology 584: 107–114.

Eversole R , Su L and ElMofty S (2008) Benign fibro‐osseous lesions of the craniofacial complex. A review. Head and Neck Pathology 2: 177–202.

Fan C , Gaivin RJ , Marth TA , et al. (2012) Cloning and characterization of the human SH3BP2 promoter. Biochemical and Biophysical Research Communications 425: 25–32.

Flanagan AM , Delaney D and O'Donnell P (2010) Benefits of molecular pathology in the diagnosis of musculoskeletal disease: part II of a two‐part review: bone tumors and metabolic disorders. Skeletal Radiology 39: 213–224.

Foucault I , Liu YC , Bernard A , et al. (2003) The chaperone protein 14‐3‐3 interacts with 3BP2/SH3BP2 and regulates its adapter function. Journal of Biological Chemistry 278: 7146–7153.

Foucault I , Le Bras S , Charvet C , et al. (2005) The adaptor protein 3BP2 associates with VAV guanine nucleotide exchange factors to regulate NFAT activation by the B‐cell antigen receptor. Blood 105: 1106–1113.

Guettler S , LaRose J , Petsalaki E , et al. (2011) Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease. Cell 147: 1340–1354.

GuezGuez A , Prod'homme V , Mouska X , et al. (2010) 3BP2 adapter protein is required for receptor activator of NFkappaB ligand (RANKL)‐induced osteoclast differentiation of RAW264.7 cells. Journal of Biological Chemistry 285: 20952–20963.

Hirschhorn K , Cooper HL and Firschein IL (1965) Deletion of short arms of chromosome 4‐5 in a child with defects of midline fusion. Humangenetik 1: 479–482.

Jones WA (1933) Familial multilocular cystic disease of the jaws. American Journal of Cancer 17: 946–950.

Jones WA , Gerrie J and Pritchard J (1950) Cherubism – familial fibrous dysplasia of the jaws. Journal of Bone and Joint Surgery (British) 32‐B: 334–347.

de Lange J , van Maarle MC , van den Akker HP , et al. (2007) A new mutation in the SH3BP2 gene showing reduced penetrance in a family affected with cherubism. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 103: 378–381.

Le Bras S , Foucault I , Foussat A , et al. (2004) Recruitment of the actin‐binding protein HIP‐55 to the immunological synapse regulates T cell receptor signaling and endocytosis. Journal of Biological Chemistry 279: 15550–15560.

Levaot N , Voytyuk O , Dimitriou I , et al. (2011) Loss of Tankyrase‐mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell 147: 1324–1339.

Li CY and Yu SF (2006) A novel mutation in the SH3BP2 gene causes cherubism: case report. BMC Medical Genetics 7: 84.

Lietman SA , Kalinchinko N , Deng X , et al. (2006) Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation. Human Mutation 27: 717–718.

Lo B , Faiyaz‐Ul‐Haque M , Kennedy S , et al. (2003) Novel mutation in the gene encoding c‐Abl‐binding protein SH3BP2 causes cherubism. American Journal of Medical Genetics Part A 121A: 37–40.

Maeno K , Sada K , Kyo S , et al. (2003) Adaptor protein 3BP2 is a potential ligand of Src homology 2 and 3 domains of Lyn protein‐tyrosine kinase. Journal of Biological Chemistry 278: 24912–24920.

Mangion J , Rahman N , Edkins S , et al. (1999) The gene for cherubism maps to chromosome 4p16.3. American Journal of Human Genetics 65: 151–157.

Mukai T , Ishida S , Ishikawa R , et al. (2014) SH3BP2 cherubism mutation potentiates TNF‐alpha‐induced osteoclastogenesis via NFATc1 and TNF‐alpha‐mediated inflammatory bone loss. Journal of Bone and Mineral Research 29: 2618–2635.

Papadaki ME , Lietman SA , Levine MA , et al. (2012) Cherubism: best clinical practice. Orphanet Journal of Rare Diseases 7 (Suppl 1): S6.

Prescott T , Redfors M , Rustad CF , et al. (2013) Characterization of a Norwegian cherubism cohort; molecular genetic findings, oral manifestations and quality of life. European Journal of Medical Genetics 56: 131–137.

Proulx‐Bonneau S , Guezguez A and Annabi B (2011) A concerted HIF‐1alpha/MT1‐MMP signalling axis regulates the expression of the 3BP2 adaptor protein in hypoxic mesenchymal stromal cells. PLoS ONE 6: e21511.

Reichenberger EJ , Levine MA , Olsen BR , et al. (2012) The role of SH3BP2 in the pathophysiology of cherubism. Orphanet Journal of Rare Diseases 7 (Suppl 1): S5.

Reichenberger EJ and Flanagan AM (2013) Cherubism. In: Fletcher DM , Bridge JA , Hogendoorn PC and Mertens F (eds) World Health Organization Classification of Tumours of Soft Tissue and Bone. Lyon: World Health Organization, 374–375.

Ren R , Mayer BJ , Cicchetti P , et al. (1993) Identification of a ten‐amino acid proline‐rich SH3 binding site. Science 259: 1157–1161.

Sangu N , Shimosato T , Inoda H , et al. (2013) Novel nucleotide mutation leading to a recurrent amino acid alteration in SH3BP2 in a patient with cherubism. Congenital Anomalies 53: 166–169.

Silva EC , de Souza PE , Barreto DC , et al. (2002) An extreme case of cherubism. British Journal of Oral and Maxillofacial Surgery 40: 45–48.

Tiziani V , Reichenberger E , Buzzo CL , et al. (1999) The gene for cherubism maps to chromosome 4p16. American Journal of Human Genetics 65: 158–166.

Ueki Y , Tiziani V , Santanna C , et al. (2001) Mutations in the gene encoding c‐Abl‐binding protein SH3BP2 cause cherubism. Nature Genetics 28: 125–126.

Ueki Y , Lin CY , Senoo M , et al. (2007) Increased myeloid cell responses to M‐CSF and RANKL cause bone loss and inflammation in SH3BP2 “cherubism” mice. Cell 128: 71–83.

Von Wowern N (2000) Cherubism: a 36‐year long‐term follow‐up of 2 generations in different families and review of the literature. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 90: 765–772.

Wang C , Song Y , Peng B , et al. (2006) Expression of c‐Src and comparison of cytologic features in cherubism, central giant cell granuloma and giant cell tumors. Oncology Reports 15: 589–594.

Wang CJ , Chen IP , Koczon‐Jaremko B , et al. (2010) Pro416Arg cherubism mutation in Sh3bp2 knock‐in mice affects osteoblasts and alters bone mineral and matrix properties. Bone 46: 1306–1315.

Yoshitaka T , Mukai T , Kittaka M , et al. (2014) Enhanced TLR‐MYD88 signaling stimulates autoinflammation in SH3BP2 cherubism mice and defines the etiology of cherubism. Cell Reports 8: 1752–1766.

Zollino M , Di Stefano C , Zampino G , et al. (2000) Genotype‐phenotype correlations and clinical diagnostic criteria in wolf‐hirschhorn syndrome. American Journal of Medical Genetics 94: 254–261.

Further Reading

Hero M , Suomalainen A , Hagstrom J , et al. (2013) Anti‐tumor necrosis factor treatment in cherubism – clinical, radiological and histological findings in two children. Bone 52: 347–353.

Kadlub N , Vazquez MP , Galmiche L , et al. (2015) The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism. Journal of Bone and Mineral Research 30: 878–885.

Levaot N , Simoncic PD , Dimitriou ID , et al. (2011) 3BP2‐deficient mice are osteoporotic with impaired osteoblast and osteoclast functions. Journal of Clinical Investigation 121: 3244–3257.

Pagnini I , Simonini G , Mortilla M , et al. (2011) Ineffectiveness of tumor necrosis factor‐alpha inhibition in association with bisphosphonates for the treatment of cherubism. Clinical and Experimental Rheumatology 29: 147.

Prescott T , Redfors M , Rustad CF , et al. (2013) Characterization of a Norwegian cherubism cohort; molecular genetic findings, oral manifestations and quality of life. European Journal of Medical Genetics 56: 131–137.

Prod'Homme V , Boyer L , Dubois N , et al. (2015) Cherubism allele heterozygosity amplifies microbe‐induced inflammatory responses in murine macrophages. Journal of Clinical Investigation 125: 1396–1400.

Yoshitaka T , Ishida S , Mukai T , et al. (2014) Etanercept administration to neonatal SH3BP2 knock‐in cherubism mice prevents TNF‐alpha‐induced inflammation and bone loss. Journal of Bone and Mineral Research 29: 1170–1182.

Yoshitaka T , Kittaka M , Ishida S , et al. (2015) Bone marrow transplantation improves autoinflammation and inflammatory bone loss in SH3BP2 knock‐in cherubism mice. Bone 71: 201–209.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Reichenberger, Ernst J, and Ueki, Yasuyoshi(Mar 2016) Molecular Genetics of Cherubism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024309]