Multiple Synostoses Syndrome Is Due to a Missense Mutation in Exon 2 of FGF9 Gene

Abstract

Fibroblast growth factors (FGFs) play diverse roles in several developmental processes. Mutations leading to deregulated FGF signaling can cause human skeletal dysplasias and cancer.(1,2) Here we report a missense mutation (Ser99Asp) in exon 2 of FGF9 in 12 patients with multiple synostoses syndrome (SYNS) in a large Chinese family. In vitro studies demonstrate that FGF9(S99N) is expressed and secreted as efficiently as wild-type FGF9 in transfected cells. However, FGF9(S99N) induces compromised chondrocyte proliferation and differentiation, which is accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells (BMSCs). Biochemical analysis reveals that S99N mutation in FGF9 leads to significantly impaired FGF signaling, as evidenced by diminished activity of Erk1/2 pathway and decreased beta-catenin and c-Myc expression when compared with wild-type FGF9. Importantly, the binding of FGF9(S99N) to its receptor is severely impaired although the dimerization ability of mutant FGF9 itself or with wild-type FGF9 is not detectably affected, providing a basis for the defective FGFR signaling. Collectively, our data demonstrate a previously uncharacterized mutation in FGF9 as one of the causes of SYNS, implicating an important role of FGF9 in normal joint development.

Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism

“…2,11 In addition to NOG mutations, mutations in growth differentiation factor-5 (GDF5) on chromosome 20q11.2 or in fibroblast growth factor 9 (FGF9) on chromosome 13q12 have been found in patients with SYNS1. 12,13 However, as the GDF5 protein interacts with the NOG protein, 14,15 the diagnostic category of NOG-SSD does appear to be promising.…”

Fibroblast growth factor signaling in skeletal development and disease

“…The elbow knee synostosis (EKS) mutation in mice and the multiple synostosis syndrome in humans reduce the affinity of FGF9 for its coreceptor, HS. Although reduced affinity for HS impairs receptor binding, the resulting increased diffusion of FGF9 through the extracellular matrix effectively increases its domain of activity in developing chondrocytes and surrounding tissue (Harada et al 2009;Kalinina et al 2009;Wu et al 2009). The joint fusion phenotype is very similar to mice that cell-autonomously overexpress an activated FGFR in developing chondrocytes (Wang et al 2001).…”

Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis

“…Until now, the only mutation identified in FGF9 was p.Ser99Asn, which was identified in several members of a fivegeneration Chinese family with multiple synostosis syndrome. However, neither the genital characteristics nor the gonadal function of the 15 affected members of that family (six 46,XX and nine 46,XY) were described [24].…”