title: Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation.
abstract: We describe a novel missense mutation (Aspartic acid to Asparagine, p.D419N (g.1371G>A, c.1255G>A) within exon 9 of SH3BP2 in a patient with cherubism, an autosomal dominant syndrome characterized by excessive osteoclastic bone resorption of the jaw. Two siblings and the father were carriers but lacked phenotypic features. Transient expression of p.D419N (c.1255G>A), as well as three previously described exon 9 mutations from cherubism patients (p.R415Q (c.1244G>A), p.D420E (c.1259G>A), and p.P418R (c.1253C>G)) increased activity of NFAT (nuclear factor of activated T-cells), an osteoclastogenic mediator, indicating that cherubism results from gain of function mutations in SH3BP2.
authors.affiliation: The Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio 44195, USA. lietmas@ccf.org
authors.forename: Steven A
authors.initials: SA
authors.lastname: Lietman
authors.forename: Natasha
authors.initials: N
authors.lastname: Kalinchinko
authors.forename: Xichao
authors.initials: X
authors.lastname: Deng
authors.forename: Ronald
authors.initials: R
authors.lastname: Kohanski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D002636:Cherubism / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010375:Pedigree; D011859:Radiography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050778:NFATC Transcription Factors; C109073:SH3BP2 protein, human