HGNC Approved Gene Symbol: SH3BP2
SNOMEDCT: 76098004; ICD10CM: M27.8;
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:2,793,085-2,841,096 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | Cherubism | 118400 | Autosomal dominant | 3 |
Bell et al. (1997) isolated a 2.4-kb cDNA clone corresponding to the mouse Sh3bp2 gene from a human fetal brain cDNA library. The deduced 561-residue protein contains an Src homology 2 (SH2) domain, an Src homology 3 (SH3)-binding domain, and a pleckstrin (173570) homology domain, suggesting a possible role in signal transduction.
The SH3BP2 gene contains 13 exons and spans approximately 16 kb (Bell et al., 1997).
Bell et al. (1997) determined that the SH3BP2 gene maps to chromosome 4p16.3.
Bell et al. (1997) noted that SH3BP2 is a gene of interest in cancer because of potential negative regulation of the ABL (189980) oncogene. However, mutational analysis and expression studies in bladder cancer samples found no evidence that this gene is a tumor suppressor gene involved in bladder cancer.
In affected members of 12 families with cherubism (118400), an autosomal dominant disorder characterized by excessive bone degradation of the upper and lower jaws, Ueki et al. (2001) identified mutations in the SH3BP2 gene (see, e.g., 602104.0001-602104.0007). All mutations were located in exon 9 and affected 3 amino acids within a 6-amino acid sequence (RSPPDG) located 31 to 36 amino acids upstream of the SH2 domain and 205 to 210 amino acids downstream of the SH3-binding domain. Mutations in pro418 were the most common and occurred in 8 families. The results and the clustering of mutations in SH3BP2 supported the hypothesis that the mutations in SH3BP2 lead to a gain of function or act in a dominant-negative manner.
Ueki et al. (2007) found that mice with a P416R mutation in the Sh3bp2 gene, which is equivalent to P418R in humans (602104.0002), showed trabecular bone loss, osteoporosis, increased numbers of osteoclasts, TNF-alpha (191160)-dependent systemic macrophage inflammation, and cortical bone erosion. The phenotype was more evident in homozygous mice. Cellular studies showed that mutant myeloid cells showed increased responses to M-CSF (120420) and RANKL (602642) stimulation and formed macrophages that expressed high levels of TNF-alpha. There was also increased phosphorylation of SYK kinase (600085). Ueki et al. (2007) concluded that cherubism is primarily a consequence of abnormal gain of myeloid cell function and that SH3BP2 is a critical regulator of myeloid cell responses.
Ueki et al. (2001) found a pro418-to-leu (P418L) mutation of the SH3BP2 gene in patients with cherubism (118400).
Ueki et al. (2001) found a pro418-to-arg (P418R) mutation of the SH3BP2 gene in patients with cherubism (118400).
Ueki et al. (2001) found a pro418-to-his (P418H) mutation of the SH3BP2 gene in patients with cherubism (118400).
Ueki et al. (2001) found an arg415-to-pro (A415P) mutation of the SH3BP2 gene in patients with cherubism (118400).
Ueki et al. (2001) found an arg415-to-gln (A415Q) mutation of the SH3BP2 gene in patients with cherubism (118400).
In 5 individuals with cherubism (118400) from 2 generations of a family, Lo et al. (2003) identified a G-to-A transition in exon 9 of the SH3BP2 gene, resulting in a gly420-to-arg (G420R) substitution. In this family, G420R was caused by the change of GGG (gly) to AGG (arg); a family in which G420R was caused by a change from GGG to CGG (arg) had previously been reported (Ueki et al., 2001). The manifestations were on the whole milder than those of many published cases (see, e.g., Figure 1 in Ueki et al. (2001)). One transmitting female was judged to be unaffected. In the proband, the diagnosis had been made at the age of 8 years and surgical excision of fibrodysplastic lesions performed at the age of 11 years; at 41 years of age, he was well and had no health concerns. See also G420E (602104.0007).
In a family with cherubism (118400), Ueki et al. (2001) identified a GGG-to-GAG transition in exon 9 of the SH3BP2 gene, which changed codon 420 from gly to glu (G420E).
Bell, S. M., Shaw, M., Jou, Y.-S., Myers, R. M., Knowles, M. A. 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, 1997. [PubMed: 9299232] [Full Text: https://doi.org/10.1006/geno.1997.4849]
Lo, B., Faiyaz-Ul-Haque, M., Kennedy, S., Aviv, R., Tsui, L.-C., Teebi, A. S. Novel mutation in the gene encoding c-Abl-binding protein SH3BP2 causes cherubism. Am. J. Med. Genet. 121A: 37-40, 2003. [PubMed: 12900899] [Full Text: https://doi.org/10.1002/ajmg.a.20226]
Ueki, Y., Lin, C.-Y., Senoo, M., Ebihara, T., Agata, N., Onji, M., Saheki, Y., Kawai, T., Mukherjee, P. M., Reichenberger, E., Olsen, B. R. Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 'cherubism' mice. Cell 128: 71-83, 2007. [PubMed: 17218256] [Full Text: https://doi.org/10.1016/j.cell.2006.10.047]
Ueki, Y., Tiziani, V., Santanna, C., Fukai, N., Maulik, C., Garfinkle, J., Ninomiya, C., doAmaral, C., Peters, H., Habal, M., Rhee-Morris, L., Doss, J. B., Kreiborg, S., Olsen, B. R., Reichenberger, E. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nature Genet. 28: 125-126, 2001. [PubMed: 11381256] [Full Text: https://doi.org/10.1038/88832]