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

Sci Rep. 2017 Feb 23:7:43220. doi: 10.1038/srep43220.


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 FGFR3G380R (FGFR3ACH) cDNA, the most common mutation in human ACH. Heterozygous (FGFR3ACH/+) and homozygous (FGFR3ACH/ACH) mice expressing human FGFR3G380R 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 FGFR3G380R mice. The severity of the disease phenotypes corresponds to the copy number of activated FGFR3G380R, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Achondroplasia / genetics
  • Achondroplasia / pathology*
  • Animals
  • Disease Models, Animal*
  • Gene Dosage
  • Gene Knock-In Techniques*
  • Heterozygote
  • Homozygote
  • Humans
  • Mice
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation, Missense
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism*


  • Mutant Proteins
  • FGFR3 protein, human
  • Receptor, Fibroblast Growth Factor, Type 3