The Muenke Syndrome Mutation (FgfR3P244R) Causes Cranial Base Shortening Associated with Growth Plate Dysfunction and Premature Perichondrial Ossification in Murine Basicranial Synchondroses
The Muenke Syndrome Mutation (FgfR3P244R) Causes Cranial Base Shortening Associated with Growth Plate Dysfunction and Premature Perichondrial Ossification in Murine Basicranial Synchondroses
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DOI：
10.1002/dvdy.22752
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发表时间：
2011-11-01
影响因子：
2.5
通讯作者：
Nah, Hyun-Duck
中科院分区：
文献类型：
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作者：
Laurita, Jason;Koyama, Eiki;Nah, Hyun-Duck
由 FGFR3(P250R) 突变引起的 Muenke 综合征是一种常染色体显性遗传疾病，主要表现为冠状缝骨性连接，但也表现为其他颅面部表型，包括轻度至中度中面部发育不全。 Muenke 综合征突变被认为会调节颅缝处的膜内骨化，但不会干扰颅骨中软骨内骨的形成。我们在这项研究中表明，携带导致 Muenke 综合征 (FgfR3(P244R)) 的突变的敲入小鼠表现出出生后颅底缩短以及软骨联合生长板功能障碍，其特征是休息、增殖和肥大软骨细胞区丧失以及 Ihh 表达减少。此外，沿软骨膜的静息软骨细胞过早转化为肥大前软骨细胞导致软骨膜骨桥形成，有效终止颅底的出生后生长。因此，我们得出结论，Muenke 综合征突变扰乱了颅底软骨内和软骨周骨化，解释了患者中面发育不全的原因。发展动态 240：2584-2596，2011。(C) 2011 Wiley 期刊公司。
Muenke syndrome caused by the FGFR3(P250R) mutation is an autosomal dominant disorder mostly identified with coronal suture synostosis, but it also presents with other craniofacial phenotypes that include mild to moderate midface hypoplasia. The Muenke syndrome mutation is thought to dysregulate intramembranous ossification at the cranial suture without disturbing endochondral bone formation in the skull. We show in this study that knock-in mice harboring the mutation responsible for the Muenke syndrome (FgfR3(P244R)) display postnatal shortening of the cranial base along with synchondrosis growth plate dysfunction characterized by loss of resting, proliferating and hypertrophic chondrocyte zones and decreased Ihh expression. Furthermore, premature conversion of resting chondrocytes along the perichondrium into prehypertrophic chondrocytes leads to perichondrial bony bridge formation, effectively terminating the postnatal growth of the cranial base. Thus, we conclude that the Muenke syndrome mutation disturbs endochondral and perichondrial ossification in the cranial base, explaining the midface hypoplasia in patients. Developmental Dynamics 240: 2584-2596, 2011. (C) 2011 Wiley Periodicals, Inc.