A Mouse Model of Beare Stevenson Cutis Gyrata Syndrome

Beare Stevenson cutis gyrata syndrome is a rare human autosomal dominant condition characterized by craniosynostosis, high arched or cleft palate, hypertelorism, furrowed skin, acanthosis nigricans, digital anomalies, umbilical and anogenital abnormalities and early death. A Tyr375Cys mutation in the transmembrane domain of FGFR2 is the most common mutation associated with this condition. Objectives: The objective of the current study was to determine the suitability of a transgenic mouse with the FGFR2 Tyr375Cys mutation as a model to elucidate the role of the mutation in mammalian developmental dermatologic and skeletal abnormalities. Methods: Chimeric mice were created with a FGFR2 construct containing the Tyr375Cys mutation upstream of an intron containing a floxed neo cassette. Chimeric mice were crossbred into the C57BL6 mouse strain. Breeding the transgenic mice with E2A-Cre transgenic mice induced Cre-mediated excision of the neo gene in resulting pups, and thus generated mice expressing the FGFR2 Tyr375Cys mutation. Results: Visual and histopathologic examination of FGFR2 Tyr375Cys pups revealed maxillary hypoplasia, abnormal coronal suture development, furrowed skin with hyperkeratosis that is very similar to affected human skin in Beare Stevenson cutis gyrata syndrome. Postnatal mutant pups showed severely retarded growth (2.1 ± 0.5 gm. mean wt., n=5, vs. 5.2 ± 0.4 gm. mean wt., n=6, for wild type littermates at 7 days postnatal). Mutant pups also suffered early death with 93% of the pups dead by 14 days postnatal. Ki67 immunohistochemical staining of embryonic and newborn mutant pup tissue sections demonstrated that abnormal epithelial cell proliferation contributed to the abnormal skin phenotype of the mutant pups. Conclusion: The results suggest that the FGFR2 Tyr375Cys mouse is a useful model to study the role of this mutation in developmental anomalies associated with Beare Stevenson cutis gyrata syndrome. Supported in part by NIH/NIDCR grant DE07309-08.