SH3BP2 – Cherubism

Cherubism is a rare autosomal dominant craniofacial disorder characterized by bilateral multilocular cystic lesions of the jaws that appear in early childhood and often regress after puberty. Heterozygous gain-of-function missense mutations in SH3BP2 disrupt a critical SH3-binding domain, leading to excessive osteoclastogenesis and fibrous tissue replacement of jawbone ([PMID:12900899], [PMID:32620450]).

Genetic evidence includes identification of SH3BP2 mutations in over 100 unrelated probands across more than 60 families, with segregation of variants such as c.1244G>A (p.Arg415Gln) in multiple affected relatives and absence in unaffected family members ([PMID:22795151], [PMID:32620450]). Penetrance is complete in males and variable in females, and recurrent mutations cluster in exon 9 (residues 415–420). No loss-of-function SH3BP2 variants have been implicated, consistent with a dominant gain-of-function mechanism.

Functional assays in patient‐derived cells demonstrate that cherubism-associated SH3BP2 variants enhance PLCγ phosphorylation, NFATc1 activation, and TRAP-positive osteoclast differentiation in response to RANKL and TNF-α ([PMID:20872577]). Transient expression of p.Asp419Asn and other exon 9 mutants similarly upregulates NFAT-driven transcription, confirming a shared pathogenic mechanism ([PMID:16786512]).

A Sh3bp2P416R knock-in mouse model recapitulates key features of human cherubism, including jawbone osteolysis, systemic bone loss, reduced osteoblast maturation, and increased bone fragility ([PMID:20117257]). Pharmacologic inhibition of calcineurin with tacrolimus in an aggressive case yielded clinical stabilization, reduced NFATc1 staining, and increased OPG expression, illustrating proof-of-principle for targeted therapy ([PMID:25491283]).

No credible conflicting evidence disputes the SH3BP2–cherubism association; alternative candidate genes (e.g., OGFRL1) have not recapitulated human phenotypes in vivo. The collective data establish SH3BP2 as the definitive genetic etiology of cherubism.

Key take-home: SH3BP2 gain-of-function mutations cause cherubism via enhanced osteoclastogenesis, enabling molecular diagnosis, family counseling, and exploration of targeted therapies.

References

• American journal of medical genetics. Part A • 2003 • Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism. PMID:12900899
• International journal of oral and maxillofacial surgery • 2021 • Cherubism: a systematic literature review of clinical and molecular aspects. PMID:32620450
• Pediatric dentistry • 2012 • Mutations of the SH3BP2 gene in 2 families of cherubism. PMID:22795151
• Journal of orthopaedic research • 2010 • SH3BP2 mutations potentiate osteoclastogenesis via PLCγ. PMID:20872577
• Bone • 2010 • Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. PMID:20117257
• Journal of bone and mineral research • 2015 • The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism. PMID:25491283

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