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NESPS 27th Annual Meeting Abstracts

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Muenke mutation (FgfR3P244R) causes premature ossification of basicranial synchondrosis cartilage and shortening of the cranial base in a knock-in mouse model
Jason T. Laurita, MB1, Gregory E. Lakin, MD1, Bianca C. Chin, MD2, Hyun-Duck Nah, PhD1.
1Children's Hospital of Philadelphia, Philadelphia, PA, USA, 2University of Pennsylvania, Philadelphia, PA, USA.

BACKGROUND:
Muenke Syndrome, which is caused by the constitutively activating P250R mutation in Fibroblast Growth Factor Receptor 3 (FGFR3), is primarily characterized by uni-/bi-coronal synostosis. Approximately 60% of cases also present with midface hypoplasia. However, little is known about the mutation’s effect on the cranial base. Given that FGFR3 plays a critical role in the regulation of endochondral ossification, we hypothesized that the FGFR3 P250R mutation might induce premature ossification of basicranial synchondrosis cartilage, leading to a shortened cranial base and associated mid-face hypoplasia.
METHODS:
The FgfR3 P244R knock-in (KI) mouse model of Muenke Syndrome was kindly provided by Dr. Twigg (Oxford, UK); the P244R substitution mutation in murine FgfR3 is analogous to P250R mutation in human FGFR3. Homozygous (HO) and heterozygous (HET) FGFR3P244R mice and wild type (WT) littermates were sacrificed at postnatal days (P) 7, 21, 35, and 6-12 months, and the skulls were analyzed by µ-CT and 3-D craniomorphometry to determine the timing and extent of presphenoidal synchondrosis (PSS) and spheno-occipital synchondrosis (SOS) closure. Skulls were also processed for histology to study any cellular changes in the synchondroses. A total of 123 mice were analyzed.
RESULTS:
In WT mice, the PSS and SOS remain patent into early adulthood (~16 weeks). In contrast, ~80% of HO FgfR3 P244R mice showed PSS closure by P21, and ~70% showed SOS closure at P35. HET mice showed a less severe phenotype, with ~50% showing PSS closure at P35, and no observed deviation from WT in SOS closure chronology. Premature closure of PSS usually copresented with Class III molar malocclusion. Craniomorphometry revealed a significantly reduced overall skull length in HO mice at P7 (p=0.031). At P21, significant hypoplasia was detected anterior to the PSS (p=0.024), and at P35, in the length of the basisphenoid (p=0.007). H&E staining of cranial base cartilage revealed that the population of resting chondrocytes was significantly reduced and the typical columnar arrangement of differentiating chondrocytes was disturbed in homozygous KI mouse synchondroses.
CONCLUSIONS:
Using a knock-in mouse model for Muenke syndrome, we show for the first time that the Munke mutation accelerates chondrocyte maturation and endochondral ossification, contributing to premature closure of the basicranial synchondroses and midface hypoplasia.


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