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

Autor:	Biosse Duplan M; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.; Service d'Odontologie, Hôpital Bretonneau, HUPNVS, AP-HP, Paris, France., Komla-Ebri D; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France., Heuzé Y; UMR5199 PACEA, Université de Bordeaux, Bordeaux Archaeological Sciences Cluster Of Excellence, Université de Bordeaux, Bordeaux, France., Estibals V; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France., Gaudas E; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France., Kaci N; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France., Benoist-Lasselin C; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France., Zerah M; Neurochirurgie Pédiatrique, Unité de Chirurgie Craniofaciale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Kramer I; Novartis Institutes for BioMedical Research, Basel, Switzerland., Kneissel M; Novartis Institutes for BioMedical Research, Basel, Switzerland., Porta DG; Novartis Institutes for BioMedical Research, Basel, Switzerland., Di Rocco F; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France.; Neurochirurgie Pédiatrique, Unité de Chirurgie Craniofaciale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France., Legeai-Mallet L; INSERM U1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Paris, France laurence.legeai-mallet@inserm.fr.; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2016 Jul 15; Vol. 25 (14), pp. 2997-3010. Date of Electronic Publication: 2016 Jun 03.
DOI:	10.1093/hmg/ddw153
Abstrakt:	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 Fgfr3 Y367C/+ 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 Fgfr3 Y367C/+ 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. (© The Author 2016. Published by Oxford University Press.)
Databáze:	MEDLINE
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