FGFR3 mutation causes abnormal membranous ossification in achondroplasia

FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to a FGFR3 activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3 mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3 mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non ossified gaps in frontal bones were also present in Fgfr3 mice and ACH patients. Our data provide strong support that, not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches. at Penylvania State U niersity on Jauary 5, 2014 ht://hm g.oxfournals.org/ D ow nladed from