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Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent.
Calcif Tissue Int 2013; 92(5):451-66CT

Abstract

Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in fibroblast growth factor receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate the biologic mechanisms by which the Crouzon syndrome-associated FGFR2(C342Y) mutation leads to abnormal craniofacial skeletal development, we created congenic BALB/c FGFR2(C342Y/+) mice. Here, we show that BALB/c FGFR2(C342Y/+) mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis, and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2(C342Y/+) mice on the BALB/c genetic background differ significantly in form and shape from their wild-type littermates and that in this genetic background the FGFR2(C342Y) mutation preferentially affects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2(C342Y) mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2(C342Y/+) frontal, but not parietal, bones exhibit significantly diminished bone volume and density compared to wild-type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients.

Authors+Show Affiliations

Department of Orthodontics and Pediatric Dentistry, University of Michigan, 1011 N University Avenue, Ann Arbor, MI 48109-1078, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23358860

Citation

Liu, Jin, et al. "Further Analysis of the Crouzon Mouse: Effects of the FGFR2(C342Y) Mutation Are Cranial Bone-dependent." Calcified Tissue International, vol. 92, no. 5, 2013, pp. 451-66.
Liu J, Nam HK, Wang E, et al. Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent. Calcif Tissue Int. 2013;92(5):451-66.
Liu, J., Nam, H. K., Wang, E., & Hatch, N. E. (2013). Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent. Calcified Tissue International, 92(5), pp. 451-66. doi:10.1007/s00223-013-9701-2.
Liu J, et al. Further Analysis of the Crouzon Mouse: Effects of the FGFR2(C342Y) Mutation Are Cranial Bone-dependent. Calcif Tissue Int. 2013;92(5):451-66. PubMed PMID: 23358860.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Further analysis of the Crouzon mouse: effects of the FGFR2(C342Y) mutation are cranial bone-dependent. AU - Liu,Jin, AU - Nam,Hwa Kyung, AU - Wang,Estee, AU - Hatch,Nan E, Y1 - 2013/01/29/ PY - 2012/07/02/received PY - 2013/01/04/accepted PY - 2013/1/30/entrez PY - 2013/1/30/pubmed PY - 2013/12/18/medline SP - 451 EP - 66 JF - Calcified tissue international JO - Calcif. Tissue Int. VL - 92 IS - 5 N2 - Crouzon syndrome is a debilitating congenital disorder involving abnormal craniofacial skeletal development caused by mutations in fibroblast growth factor receptor-2 (FGFR2). Phenotypic expression in humans exhibits an autosomal dominant pattern that commonly involves premature fusion of the coronal suture (craniosynostosis) and severe midface hypoplasia. To further investigate the biologic mechanisms by which the Crouzon syndrome-associated FGFR2(C342Y) mutation leads to abnormal craniofacial skeletal development, we created congenic BALB/c FGFR2(C342Y/+) mice. Here, we show that BALB/c FGFR2(C342Y/+) mice have a consistent craniofacial phenotype including partial fusion of the coronal and lambdoid sutures, intersphenoidal synchondrosis, and multiple facial bones, with minimal fusion of other craniofacial sutures. This phenotype is similar to the classic and less severe form of Crouzon syndrome that involves significant midface hypoplasia with limited craniosynostosis. Linear and morphometric analyses demonstrate that FGFR2(C342Y/+) mice on the BALB/c genetic background differ significantly in form and shape from their wild-type littermates and that in this genetic background the FGFR2(C342Y) mutation preferentially affects some craniofacial bones and sutures over others. Analysis of cranial bone cells indicates that the FGFR2(C342Y) mutation promotes aberrant osteoblast differentiation and increased apoptosis that is more severe in frontal than parietal bone cells. Additionally, FGFR2(C342Y/+) frontal, but not parietal, bones exhibit significantly diminished bone volume and density compared to wild-type mice. These results confirm that FGFR2-associated craniosynostosis occurs in association with diminished cranial bone tissue and may provide a potential biologic explanation for the clinical finding of phenotype consistency that exists between many Crouzon syndrome patients. SN - 1432-0827 UR - https://www.unboundmedicine.com/medline/citation/23358860/Further_analysis_of_the_Crouzon_mouse:_effects_of_the_FGFR2_C342Y__mutation_are_cranial_bone_dependent_ L2 - https://dx.doi.org/10.1007/s00223-013-9701-2 DB - PRIME DP - Unbound Medicine ER -