title: FGFR3 mutation causes abnormal membranous ossification in achondroplasia.
abstract: FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) 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(Y367C/+) 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(Y367C/+) 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.
authors.affiliation: INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hopital Necker-Enfants malades, Paris, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Di Rocco
authors.forename: Martin
authors.initials: M
authors.lastname: Biosse Duplan
authors.forename: Yann
authors.initials: Y
authors.lastname: Heuzé
authors.forename: Nabil
authors.initials: N
authors.lastname: Kaci
authors.forename: Davide
authors.initials: D
authors.lastname: Komla-Ebri
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Emilie
authors.initials: E
authors.lastname: Mugniery
authors.forename: Catherine
authors.initials: C
authors.lastname: Benoist-Lasselin
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D000130:Achondroplasia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D019902:Chondrocytes / Q000166:cytology / Q000201:enzymology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009999:Ossification, Heterotopic; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D012886:Skull / Q000033:anatomy & histology / Q000196:embryology / Q000201:enzymology / Q000473:pathology
chemical_list: D051498:Receptor, Fibroblast Growth Factor, Type 3