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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 <jats:italic>Fgfr3<\/jats:italic> gene was replaced with human <jats:italic>FGFR3<\/jats:italic><jats:sup><jats:italic>G380R<\/jats:italic><\/jats:sup> (<jats:italic>FGFR3<\/jats:italic><jats:sup><jats:italic>ACH<\/jats:italic><\/jats:sup>) cDNA, the most common mutation in human ACH. Heterozygous (<jats:italic>FGFR3<\/jats:italic><jats:sup>ACH\/+<\/jats:sup>) and homozygous (<jats:italic>FGFR3<\/jats:italic><jats:sup>ACH\/ACH<\/jats:sup>) mice expressing human <jats:italic>FGFR3<\/jats:italic><jats:sup>G380R<\/jats:sup> 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 <jats:italic>FGFR3<\/jats:italic><jats:sup>G380R<\/jats:sup> mice. The severity of the disease phenotypes corresponds to the copy number of activated <jats:italic>FGFR3<\/jats:italic><jats:sup><jats:italic>G380R<\/jats:italic><\/jats:sup>, 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 <jats:italic>FGFR3<\/jats:italic>, and for further studies of the underlying molecular mechanisms.<\/jats:p>","DOI":"10.1038\/srep43220","type":"journal-article","created":{"date-parts":[[2017,2,23]],"date-time":"2017-02-23T10:37:05Z","timestamp":1487846225000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia"],"prefix":"10.1038","volume":"7","author":[{"given":"Yi-Ching","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Wen","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ju","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-De","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Tsong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,23]]},"reference":[{"key":"BFsrep43220_CR1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/S0140-6736(07)61090-3","volume":"370","author":"WA Horton","year":"2007","unstructured":"Horton, W. 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