title: Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice.
abstract: Several gain-of-function mutations in a receptor tyrosine kinase, fibroblast growth factor receptor 3 (FGFR3), cause dwarfism in humans. Two particularly severe dwarfisms, thanatophoric dysplasia type II (TDII) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), are associated with glutamic acid (E) and methionine (M) substitutions at the K650 residue in the kinase domain. TDII is lethal at birth, whereas most of the SADDAN patients survive the perinatal period. However, FGFR3 with the SADDAN mutation is more activated than FGFR3 with the TDII mutation in vitro. To find out whether the K650M mutation also causes the SADDAN phenotype, we introduced the corresponding point mutation (K644M) into the mouse Fgfr3 gene. Heterozygous mutant mice show a phenotype similar to human SADDAN, e.g. the majority of the SADDAN mice survive the perinatal period. This suggests that the survival of SADDAN patients is indeed attributed to the K650M mutation in FGFR3. The long bone abnormalities in SADDAN mice are milder than the TDII model. In addition, overgrowth of the cartilaginous tissues is observed in the rib cartilage, trachea and nasal septum. The FGF ligand at the low concentration differentially activates Map kinase in primary chondrocyte cultures from wild-type and SADDAN mice. Comparisons of the molecular bases of the phenotypic differences in SADDAN and TDII mice may increase our understanding of the factors that influence the severity in these two related skeletal dysplasias.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10/3D51, 10 Center Drive, Bethesda, MD, 20892, USA. tomoko.iwata@embl-heidelberg.de
authors.forename: T
authors.initials: T
authors.lastname: Iwata
authors.forename: C L
authors.initials: CL
authors.lastname: Li
authors.forename: C X
authors.initials: CX
authors.lastname: Deng
authors.forename: C A
authors.initials: CA
authors.lastname: Francomano
mesh_terms: D000052:Acanthosis Nigricans / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D000130:Achondroplasia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D019943:Amino Acid Substitution; D000818:Animals; D002356:Cartilage / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D019902:Chondrocytes / Q000473:pathology; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D013796:Thanatophoric Dysplasia / Q000235:genetics* / Q000503:physiopathology
chemical_list: D017468:Receptors, Fibroblast Growth Factor; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3