The most common autosomal dominant, craniosynostotic syndromes are Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. Crouzon syndrome with a birth prevalence of 1/25,000 is characterized by shallow orbits, ocular proptosis, and maxillary hypoplasia. Jackson-Weiss syndrome, unlike Crouzon, is associated with highly variable phenotypic expression and foot (rarely hand) anomalies. Pfeiffer and Apert syndromes involve not only cranial and foot, but also hand abnormalities; the latter condition is the most severe with respect to digital and multi-organ system manifestations. Dr. Jab's laboratory determined that Crouzon and Jackson-Weiss syndrome loci map to the same chromosomal region 10q23-26. Mutational analysis of candidate genes in this region revealed mutations in the Fibroblast Growth Factor Receptor 2 gene (FGFR2) in all four of these conditions. Mutations were detected in the conserved region of the immunoglobulin III domain which is involved in ligand binding. Normal ligand binding is required for FGFR2 to effect its role in development. Upon ligand binding, FGFR2 oligomerizes and triggers its intrinsic tyrosine kinase activity and signaling pathways. Further studies are proposed to focus on FGFR2 mutational and in vivo and in vitro functional analyses to correlate the molecular and biochemical alterations with their phenotypic effects.
The specific aims of the project are to determine: 1) the spectrum of FGFR2 mutations in Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndrome patients; 2) whether mutations in FGFR2 and/or keratinocyte growth factor receptor (KGFR) are present in Crouzon syndrome patients with acanthosis nigricans, isolated craniosynostosis, isolated foot and hand anomalies, unidentified craniosynostotic or limb syndromes. This analysis will determine the range of clinical features associated with FGFR2/KGFR mutations; 3) phenotype/genotype correlations and defining the extent of intra- and interfamilial phenotypic variation of recurrent FGFR2 mutations; 4) modifying factors [chromosomal background, genes (multiple loci or mutations, allelic variants)] that account for the variable phenotypic expression, especially in the large Amish, Jackson-Weiss syndrome family; 5) altered ligand (e.g., FGF1 and FGF2) binding properties of mutant FGFR2s; 6) altered ligand-activated tyrosine kinase activity of mutant FGFR2s, 7) altered properties of mutant FGFR2 expressing cells (cell growth kinetics, oncogenicity); 8) developmental consequences of mutant FGFR2 in transgenic mice. Identification of FGFR2/KGFR mutations and their biologic effects will be important for accurate diagnosis and elucidation of the pathogenesis of these craniosynostotic conditions.
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