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Achondroplasia (ACH), the most common genetic dwarfism in human, is caused by a gain-of function mutation in fibroblast growth factor receptor 3 ( FGFR3 ). Currently, there is no effective treatment for ACH. The development of an appropriate human-relevant model is important for testing potential therapeutic interventions before human clinical trials. Here, we have generated an ACH mouse model in which the endogenous mouse  Fgfr3  gene was replaced with human  FGFR3   G380R   ( FGFR3   ACH  ) cDNA, the most common mutation in human ACH. Heterozygous ( FGFR3  ACH/+ ) and homozygous ( FGFR3  ACH/ACH ) mice expressing human  FGFR3  G380R  recapitulate the phenotypes observed in ACH patients, including growth retardation, disproportionate shortening of the limbs, round head, mid-face hypoplasia at birth, and kyphosis progression during postnatal development. We also observed premature fusion of the cranial sutures and low bone density in newborn  FGFR3  G380R  mice. The severity of the disease phenotypes corresponds to the copy number of activated  FGFR3   G380R  , and the phenotypes become more pronounced during postnatal skeletal development. This mouse model offers a tool for assessing potential therapeutic approaches for skeletal dysplasias related to over - activation of human  FGFR3 , and for further studies of the underlying molecular mechanisms.

Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia