The Cellular Degradation of Crouzon Syndrome Mutant FGFR2 Protein

Abstract

Humans and mice with Crouzon Syndrome craniosynostosis have distinct craniofacial features including dome-shaped skulls, wide-set bulging eyes, premature fusion of coronal and facial sutures, and a severely retrusive midface. Surgical intervention is the only available treatment. Crouzon Syndrome is caused by mutations in the FGFR2 gene, which have also shown correlation to severe neurodevelopmental disorders including Autism Spectrum Disorder. It remains unknown how the Crouzon mutations cause the distinct craniofacial phenotype. The goal of this study is to gain insight into the mechanism of Crouzon Syndrome by investigating the preferred method of mutant FGFR2C342Y degradation. We have previously shown that FGFR2C342Y exhibits dimerization and increased degradation. Based on these findings, we hypothesize that FGFR2C342Y is recognized as aggregated by the cell and thus degraded via autophagy. In order to influence autophagy in a laboratory setting, we treated cells with rapamycin, a known inducer of autophagy. To test the hypothesis, we studied protein amounts in cells following rapamycin treatment and transient transfection of wild type FGFR2 or FGFR2C342Y plasmids. If autophagy is a preferred degradation mechanism in Crouzon Syndrome, we anticipate less FGFR2C342Y protein inside the cells following treatment. This work will further our understanding of how FGFR2C342Y is intracellularly processed, potentially providing clarity on how the distinct Crouzon Syndrome phenotype arises. Without early intervention, the neurological and psychosocial consequences of the disease can be devastating to affected individuals. Information gained from this project can ultimately contribute to new treatments and quality of life improvements.