A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes

Intercellular signaling by fibroblast growth factors plays vital roles duri ng embryogenesis. Mice deficient for fibroblast growth factor receptors (Fg fRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in mem branous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in hum ans. Here we show that a heterozygotic abrogation of FgfR2-exon g (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. T he consequences are neonatal growth retardation and death, coronal synostos is, ocular proptosis, precocious sternal fusion, and abnormalities in secon dary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome pat ients.