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A c.1244G>A (p.Arg415Gln) mutation in SH3BP2 gene causes cherubism in a Turkish family: report of a family with review of the literature.

ABSTRACT: OBJECTIVES:The present study was aimed at advancing the understanding of the pathogenesis of cherubism by presenting a case study based on history, physical examination, typical radiological features, molecular and histopathological laboratory tests and a review of the literature. STUDY DESIGN:This study began with a 7-year-old boy who was referred due to mandibular overgrowth. A panoramic radiograph revealed multilocular radiolucent lesions of the upper/lower jaws suggestive of cherubism. Overall, a total of four family members were tested for SH3BP2 mutations, namely two siblings and their parents. Both siblings had been clinically diagnosed with cherubism; however, the parents were clinically normal. Peripheral blood was collected from all participants and genomic DNA sequencing was carried out. RESULTS:A missense mutation was found in the two affected siblings and their asymptomatic mother. The mutation was a 1244 G>A transversion which resulted in an amino acid substitution from arginine to glutamine (p.Arg415Gln) in exon 9. CONCLUSIONS:The present study emphasized the importance of further clinical and molecular investigation even when only a single case of cherubism is identified within a family. Genotype-phenotype association studies in individuals with cherubism are necessary to provide important insights into the molecular mechanisms associated with this disease.

SUBMITTER: Sekerci AE

PROVIDER: S-EPMC4119308 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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A c.1244G>A (p.Arg415Gln) mutation in SH3BP2 gene causes cherubism in a Turkish family: report of a family with review of the literature.

Sekerci Ahmet-Ercan AE Balta Burhan B Dundar Munis M Hu Ying Y Reichenberger Ernst-J EJ Etoz Osman-A OA Nazlim Sinan S Bayrakdar Ibrahim-Sevki IS

Medicina oral, patologia oral y cirugia bucal 20140701 4

<h4>Objectives</h4>The present study was aimed at advancing the understanding of the pathogenesis of cherubism by presenting a case study based on history, physical examination, typical radiological features, molecular and histopathological laboratory tests and a review of the literature.<h4>Study design</h4>This study began with a 7-year-old boy who was referred due to mandibular overgrowth. A panoramic radiograph revealed multilocular radiolucent lesions of the upper/lower jaws suggestive of c ...[more]

PMID: 24608212

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Project description:Cherubism (OMIM# 118400) is a genetic disorder with excessive jawbone resorption caused by mutations in SH3 domain binding protein 2 (SH3BP2), a signaling adaptor protein. Studies on the mouse model for cherubism carrying a P416R knock-in (KI) mutation have revealed that mutant SH3BP2 enhances tumor necrosis factor (TNF)-? production and receptor activator of nuclear factor-?B ligand (RANKL)-induced osteoclast differentiation in myeloid cells. TNF-? is expressed in human cherubism lesions, which contain a large number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, and TNF-? plays a critical role in inflammatory bone destruction in homozygous cherubism mice (Sh3bp2(KI/KI) ). The data suggest a pathophysiological relationship between mutant SH3BP2 and TNF-?-mediated bone loss by osteoclasts. Therefore, we investigated whether P416R mutant SH3BP2 is involved in TNF-?-mediated osteoclast formation and bone loss. Here, we show that bone marrow-derived M-CSF-dependent macrophages (BMMs) from the heterozygous cherubism mutant (Sh3bp2(KI/+) ) mice are highly responsive to TNF-? and can differentiate into osteoclasts independently of RANKL in vitro by a mechanism that involves spleen tyrosine kinase (SYK) and phospholipase C?2 (PLC?2) phosphorylation, leading to increased nuclear translocation of NFATc1. The heterozygous cherubism mutation exacerbates bone loss with increased osteoclast formation in a mouse calvarial TNF-? injection model as well as in a human TNF-? transgenic mouse model (hTNFtg). SH3BP2 knockdown in RAW264.7 cells results in decreased TRAP-positive multinucleated cell formation. These findings suggest that the SH3BP2 cherubism mutation can cause jawbone destruction by promoting osteoclast formation in response to TNF-? expressed in cherubism lesions and that SH3BP2 is a key regulator for TNF-?-induced osteoclastogenesis. Inhibition of SH3BP2 expression in osteoclast progenitors could be a potential strategy for the treatment of bone loss in cherubism as well as in other inflammatory bone disorders.

Dataset Information

A c.1244G>A (p.Arg415Gln) mutation in SH3BP2 gene causes cherubism in a Turkish family: report of a family with review of the literature.

Publications

A c.1244G>A (p.Arg415Gln) mutation in SH3BP2 gene causes cherubism in a Turkish family: report of a family with review of the literature.

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