The Muenke syndrome mutation (FgfR3P244R) causes cranial base shortening associated with growth plate dysfunction and premature perichondrial ossification in murine basicranial synchondroses

• Published in: Developmental dynamics Vol. 240; no. 11; pp. 2584 - 2596
• Main Authors: Laurita, Jason, Koyama, Eiki, Chin, Bianca, Taylor, Jesse A., Lakin, Gregory E., Hankenson, Kurt D., Bartlett, Scott P., Nah, Hyun‐Duck
• Format: Journal Article
• Language: English
• Published: New York Wiley‐Liss, Inc 01.11.2011
• Subjects: Amino Acid Substitution - physiology; Animals; Arginine - genetics; basicranial synchondrosis; Cranial Sutures - abnormalities; Cranial Sutures - diagnostic imaging; Cranial Sutures - metabolism; Cranial Sutures - pathology; Craniosynostoses - genetics; endochondral ossification; FGFR3; growth plate; Growth Plate - diagnostic imaging; Growth Plate - metabolism; Indian hedgehog; Mice; Mice, Transgenic; Models, Biological; Muenke syndrome; Mutation, Missense - physiology; Ossification, Heterotopic - genetics; Osteogenesis - genetics; perichondrial ossification; Phenotype; Proline - genetics; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Receptor, Fibroblast Growth Factor, Type 3 - physiology; Skull Base - abnormalities; Skull Base - diagnostic imaging; Skull Base - metabolism; X-Ray Microtomography
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.22752

Muenke syndrome caused by the FGFR3P250R mutation is an autosomal dominant disorder mostly identified with coronal suture synostosis, but it also presents with other craniofacial phenotypes that include mild to moderate midface hypoplasia. The Muenke syndrome mutation is thought to dysregulate intramembranous ossification at the cranial suture without disturbing endochondral bone formation in the skull. We show in this study that knock‐in mice harboring the mutation responsible for the Muenke syndrome (FgfR3P244R) display postnatal shortening of the cranial base along with synchondrosis growth plate dysfunction characterized by loss of resting, proliferating and hypertrophic chondrocyte zones and decreased Ihh expression. Furthermore, premature conversion of resting chondrocytes along the perichondrium into prehypertrophic chondrocytes leads to perichondrial bony bridge formation, effectively terminating the postnatal growth of the cranial base. Thus, we conclude that the Muenke syndrome mutation disturbs endochondral and perichondrial ossification in the cranial base, explaining the midface hypoplasia in patients. Developmental Dynamics 240:2584–2596, 2011. © 2011 Wiley Periodicals, Inc.