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

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.