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 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.
Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom. kmhj@pugh.bip.bham.ac.uk
M K
MK
Hajihosseini
S
S
Wilson
L
L
De Moerlooze
C
C
Dickson
D000168:Acrocephalosyndactylia / Q000235:genetics*; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics; D001921:Brain / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D003393:Cranial Sutures / Q000378:metabolism; D005091:Exons; D005260:Female; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009999:Ossification, Heterotopic; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000172:deficiency / Q000235:genetics*; D014781:Viscera / Q000002:abnormalities
D017468:Receptors, Fibroblast Growth Factor; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2