FGFR3 mutation causes abnormal membranous ossification in achondroplasia

Rocco, Federico Di; Duplan, Martin Biosse; Heuzé, Yann; Kaci, Nabil; Komla-Ebri, Davide; Münnich, Arnold; Mugniery, Emilie; Benoist-Lasselin, Catherine; Legeai-Mallet, Laurence

doi:10.1093/hmg/ddu004

Cited by 69 publications

(74 citation statements)

References 49 publications

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“…Besides FGFR1 and FGFR2 mutations, activating FGFR3 mutations in achondroplasia may also cause partial premature fusion of the coronal sutures, suggesting a role for FGFR3 activation in membranous ossification (Twigg et al 2009;Di Rocco et al 2014). Indeed, chondrocyte-specific activation of Fgfr3 in mice was found to induce premature suture closure and indirectly enhance osteoblast differentiation through MAPK activation and BMP signaling (Matsushita et al 2009b).…”

Section: Craniosynostosis Syndromesmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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Section: Craniosynostosis Syndromesmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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“…ACH is caused by an activating mutation of Fibroblast Growth Factor Receptor 3 ( FGFR3 ) that affects both endochondral and membranous ossification (3–5). FGFR3 over-activation disturbs the proliferation and differentiation of chondrocytes in the growth plate of long bones (6–8) and synchondroses of the cranial base (3,9). Other cartilaginous structures are affected in ACH, such as the inner ear (10), vertebral bodies and intervertebral disc (11) and joints (7).…”

Section: Introductionmentioning

confidence: 99%

Meckel’s and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible

et al. 2016

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Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3Y367C/+ mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel’s) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel’s and condylar cartilages defects ex vivo. Moreover, we show that low dose of NVP-BGJ398 improves in vivo condyle growth and corrects dysmorphologies in Fgfr3Y367C/+ mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders.

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“…During their early years, children with achondroplasia (like many synostosis-related syndromes also due to a mutation in the FGFR "cascade"-FGFR3 16 ) can run elevated ICP (including plateau waves) due to a combination of venous hypertension and upper airway obstruction. 39,59,71 It is not, however, a condition associated with impaired cognitive development.…”

Section: Achondroplasiamentioning

confidence: 99%