Grants Funded

Abstract
"An activating mutation of Fibroblast Growth Factor Receptor 2 (FGFR2) has been identified as the underlying cause of Crouzon syndrome. This mutation is caused by a replacement of cysteine by tyrosine at position 342 on exon 9 that prevents formation of the IIIc isoform (Reardon, 1994). In collaboration with the laboratory of Professor Peter Lonai, Weizmann Institute, a mouse model for Crouzon syndrome has recently been developed (Eswarakumar, 2(03). This transgenic mouse model provides an excellent way to study the role of Fgfr2IlIc in craniofacial development from an embryonic stage through adult maturation. The aim of the proposed study is to gain further insight into the relationship between Fgfr21IIc, and craniofacial skeletal growth. Our goal is to link genetic mutations causing abnormalities in the developmental process with the phenotypic findings seen in affected individuals. To do this, we must take approaches on both the molecular and morphologic level. Molecular biology techniques such as in-situ hybridization, Northern analysis and Western analysis will be performed to study gene expression different embryonic stages. To study phenotype morphology, we must evaluate skulls both for shape (geometric properties of an object invariant to size, location, or orientation) as well as form (shape + size). This will be done using Euclidian Distance Matrix Analysis (EDMA), a computational technique that enables the statistical determination of regions of morphological divergence and conservatism within groups of biological shapes. This technique is well described for analyzing the craniofacial skeleton. It is for this portion of the project that we are applying for funding. This particular project will test the following hypothesis: 1. The phenotypic abnormalities seen in the mouse mutant parallel those seen in affected humans, thus validating the transgenic mice as a model for experimental study of Crouzon syndrome. 2. Comparison of wild-type mice to heterozygotes and homozygotes will show that extent of midface hypoplasia, craniosynostosis, hypertelorism, and skull base shortening, as well as skeletal growth, correlates to extent of abnormal activation of Fgfr2IlIc. This study is clinically relevant as it will allow for statistical analysis of how the face and skull grow from infancy through adult maturation in the presence of an Fgfr2 mutation. Understanding the natural history of such growth is critical to performing and evaluating craniofacial surgical procedures designed to restore normalcy to the abnormal components of the region. "