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Human Molecular Genetics, 2000, Vol. 9, No. 2 249-258
© 2000 Oxford University Press

Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3G380R transgenic mice

Orit Segev1,2, Irina Chumakov1,2, Zvi Nevo3, David Givol1, Liora Madar-Shapiro2, Yuri Sheinin2, Miron Weinreb4 and Avner Yayon1,+

1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel, 2ProChon Biotech Ltd, Kiryat Weizmann, Science Park, Rehovot 76114, Israel, 3Department of Clinical Biochemistry and 4Department of Oral Biology, Goldschleger School of Dental Medicine, Tel Aviv University, Ramat Aviv 69978, Israel

Achondroplasia, the most common genetic form of human dwarfism, results from a point mutation (G380R) in the gene for fibroblast growth factor receptor 3 (FGFR-3). Heterozygotes for the mutation share disproportionate, proximal shortening of the limbs, mid-face hypoplasia and relative macrocephaly due to a failure in endochondral ossification. Here we have generated transgenic mice expressing the human mutant FGFR-3 under the transcriptional control of the mouse gene. Mice that are hemizygous for the mutant human gene display disproportionate dwarfism with skeletal phenotypes remarkably similar to those of human achondroplasia. Mice that are homozygous for the transgene suffer from a profound delay in skeletal development and die at birth, similar in that respect to humans homozygous for the achondroplasia mutant gene. Microscopic analysis of long bones demonstrates growth plate morphology compatible with that of human achondroplasia cases, sharing endochondral growth inhibition with restrained chondrocyte proliferation and maturation, penetration of ossification tufts and aberrant vascularization.

+ To whom correspondence should be addressed. Tel: +972 8 9342696; Fax: +972 8 9344125; Email: liyayon@wiccmail.weizmann.ac.il


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