A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis.

Abstract

Apert syndrome is one of the most severe craniosynostosis that is mainly caused by either a Ser252Trp(S252W) or Pro253Arg(P253R) mutation in fibroblast growth factor receptor 2 (FGFR2). As an autosomal dominant disorder, Apert syndrome is mainly characterized by skull malformation resulting from premature fusion of craniofacial sutures, as well as syndactyly, etc. A P253R mutation of FGFR2 results in nearly one-thirds of the cases of Apert syndrome. The pathogenesis of Apert syndrome resulting from P253R mutation of FGFR2 is still not fully understood. Here we reported a knock-in mouse model carrying P253R mutation in Fgfr2. The mutant mice exhibit smaller body size and brachycephaly. Analysis of the mutant skulls and long bones revealed premature fusion of coronal suture, shortened cranial base and growth plates of long bones. In vitro organ culture studies further revealed that, compared with wild-type littermates, the mutant mice have prematurely fused coronal sutures and retarded long bone growth. Treatment of the cultured calvaria and femur with PD98059, an Erk1/2 inhibitor, resulted in partially alleviated coronal suture fusion and growth retardation of femur respectively. Our data indicated that the P253R mutation in Fgfr2 directly affect intramembranous and endochondral ossification, which resulted in the premature closure of coronal sutures and growth retardation of long bones and cranial base. And the Erk1/2 signaling pathway partially mediated the effects of P253R mutation of Fgfr2 on cranial sutures and long bones.

• Authors: Liangjun Yin, Xiaolan Du, Cuiling Li, Xiaoling Xu, Zhi Chen, Nan Su, Ling Zhao, Huabing Qi, Fubing Li, Jing Xue, Jing Yang, Min Jin, Chuxia Deng, Lin Chen
• Journal: Bone (Bone) Vol. 42 Issue 4 Pg. 631-43 (Apr 2008) ISSN: 8756-3282 [Print] United States
• PMID: 18242159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arginine
• Proline
• Receptor, Fibroblast Growth Factor, Type 2
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Acrocephalosyndactylia (genetics, metabolism, pathology)
• Animals
• Arginine (genetics, metabolism)
• Biomimetics
• Cells, Cultured
• Chondrogenesis (genetics)
• Disease Models, Animal
• Humans
• MAP Kinase Signaling System
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mutation (genetics)
• Ossification, Heterotopic (genetics, metabolism, pathology)
• Osteogenesis (genetics)
• Proline (genetics, metabolism)
• Receptor, Fibroblast Growth Factor, Type 2 (genetics, metabolism)
• Skeleton