![]() In this report, we developed a human-relevant ACH mouse model by replacing mouse Fgfr3 with human FGFR3 cDNA containing the FGFR3 G380R ACH mutation. ![]() It is important to develop a human-relevant in vivo model to provide a robust system for testing potential therapeutic interventions before human clinical trials. ![]() The C-type natriuretic peptide analogue has reached clinical trials 17. The effects of statins have been examined using the in vitro human-relevant model of chondrocytes differentiated from induced pluripotent stem cells from either TD I or ACH patients. An FGFR3-binding peptide 12, a C-type natriuretic peptide analogue 13, a soluble form of human FGFR3 14, parathyroid hormone 15, and statins 16 have been shown to improve bone growth in genetically manipulated ACH or TD I mouse models in vivo or ex vivo. Several potential therapeutic strategies targeting either the over-activated FGFR3 or its downstream effects are currently under development. However, some phenotypes have not been fully described or examined in these models.Ĭurrently, there is no effective treatment for skeletal dysplasias caused by activating mutations of FGFR3. These mouse models share some ACH phenotypes. Three ACH mouse models express murine ACH mutation ( Fgfr3 ACH), introduced using knock-in 8, 9 or transgenic 10 approaches, and one ACH mouse model transgenically expresses human FGFR3 ACH 11. Several ACH mouse models have been established to study the roles of FGFR3 in skeletal development and disease. Morphometric examination revealed the shortening of growth plates in ACH patients 7. The majority of ACH cases (over 80%) occur spontaneously through mutations in sperm related to advanced paternal age 4.įGFR3 is expressed mainly in proliferating chondrocytes in the developing long bones 5 and has been proven to be a negative regulator of endochondral bone growth 6. The clinical features of heterozygous ACH are consistent among patients, and homozygous ACH causes severe skeletal deformities that lead to early death. Over 99% of individuals affected with ACH have the same point mutation, G380R, in the transmembrane domain of FGFR3 protein ( FGFR3 G380R) 2, 3. ACH is characterised by short stature with disproportionately short limbs, macrocephaly, characteristic faces with frontal bossing, midface hypoplasia, and exaggerated thoracolumbar kyphosis 1. Achondroplasia (ACH) (OMIM 100800) is the most common form of genetic short-limbed dwarfism in human. These skeletal dysplasias are characterised by varying degrees of skeletal deformities ranging from least to most severe as follows: hypochondroplasia (HCH), achondroplasia (ACH), severe achondroplasia with developmental delay and acanthosis nigricans, and thanatophoric dysplasia (TD) types 1 and 2. Gain-of-function point mutations in fibroblast growth factor receptor 3 ( FGFR3) cause a variety of congenital skeletal dysplasias inherited as an autosomal dominant trait. 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. ![]() 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. We also observed premature fusion of the cranial sutures and low bone density in newborn FGFR3 G380R mice. 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. 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. The development of an appropriate human-relevant model is important for testing potential therapeutic interventions before human clinical trials. Currently, there is no effective treatment for ACH. Achondroplasia (ACH), the most common genetic dwarfism in human, is caused by a gain-of function mutation in fibroblast growth factor receptor 3 ( FGFR3). ![]()
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