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Human Molecular Genetics, 2001, Vol. 10, No. 12 1255-1264
© 2001 Oxford University Press

Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice

Tomoko Iwata+, Cui-Ling Li1, Chu-Xia Deng1 and Clair A. Francomano

Medical Genetics Branch, National Human Genome Research Institute and 1Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10/3D51, 10 Center Drive, Bethesda, MD, 20892, USA

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.

+ To whom correspondence should be addressed at present address: Developmental Biology Programme, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany. Tel: +49 6221 387 425; Fax: +49 6221 387 166; Email: tomoko.iwata@embl-heidelberg.de


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