The Muenke syndrome mutation (FgfR3P244R) causes cranial base shortening associated with growth plate dysfunction and premature perichondrial ossification in murine basicranial synchondroses.
Muenke syndrome caused by the FGFR3(P250R) 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 (FgfR3(P244R)) 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.
Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Jason
J
Laurita
Eiki
E
Koyama
Bianca
B
Chin
Jesse A
JA
Taylor
Gregory E
GE
Lakin
Kurt D
KD
Hankenson
Scott P
SP
Bartlett
Hyun-Duck
HD
Nah
D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001120:Arginine / Q000235:genetics; D003393:Cranial Sutures / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D003398:Craniosynostoses / Q000235:genetics*; D006132:Growth Plate / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D020125:Mutation, Missense / Q000502:physiology; D009999:Ossification, Heterotopic / Q000235:genetics*; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D011392:Proline / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000502:physiology; D019291:Skull Base / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000378:metabolism; D055114:X-Ray Microtomography
D001120:Arginine; D011392:Proline; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3