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

TLDR

Fibroblast growth factor signaling is essential for embryonic development, and activating FGFR mutations underlie craniosynostosis and dwarfism syndromes. A heterozygous deletion of FgfR2 exon 9 in mice triggers a splicing switch that produces a gain‑of‑function allele, causing neonatal growth retardation, death, cranial synostosis, ocular proptosis, sternal fusion, and branching defects reminiscent of Apert and Pfeiffer syndromes.

Abstract

Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.