ClinVar

In 12 affected members of a 5-generation Chinese family with autosomal dominant multiple synostoses syndrome (SYNS3; 612961), Wu et al. (2009) identified heterozygosity for a 296G-A transition in exon 2 of the FGF9 gene, resulting in a ser99-to-asn (S99N) substitution predicted to alter binding to FGFR3 (134934). The mutation was not found in unaffected family members or in 250 unrelated ethnically matched controls. In vitro studies demonstrated that mutant FGF9 was expressed and secreted as efficiently as wildtype in transfected cells; however, it induced compromised chondrocyte proliferation and differentiation, accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells. Biochemical analysis revealed that the S99N mutation caused significantly impaired FGF signaling, as evidenced by diminished activity of the ERK1/2 pathway (see 176948) and decreased beta-catenin (116806) and c-MYC (190080) expression when compared with wildtype FGF9. Binding of mutant protein to the receptor FGFR3 was severely impaired, although homodimerization of mutant FGF9 to itself or wildtype was not detectably affected, providing a basis for the observed defective FGF9 signaling.