Craniosynostosis and related limb anomalies.
Craniosynostosis and related limb anomalies.
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颅缝早闭及相关肢体异常。
DOI：
10.1002/0470846658.ch9
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发表时间：
2001
影响因子：
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通讯作者：
Robert E. Maxson
中科院分区：
文献类型：
--
作者：
Andrew ONI Wilkie;M. Oldridge;Zequn Tang;Robert E. Maxson
许多遗传决定的颅缝早闭综合征的特点是肢体畸形，这意味着颅缝和肢体形态发生的途径有一些相同的组成部分。颅缝早闭症中FGFR 1、FGFR 2、FGFR 3、TWIST和MSX 2杂合突变的鉴定特别关注这些基因。在这里，我们探讨两个主题：使用临床/分子分析为病理生理学和功能丧失和获得突变的对比效应提供新的线索。Apert综合征是一种严重的颅缝早闭/并指（趾）畸形，通常由FGFR 2中的特异性取代（Ser 252 Trp或Pro253 Arg）引起。这两种突变的颅骨和四肢畸形的相对严重程度呈相反方向变化，表明这些表型由不同的机制引起。临床和生化证据支持FGFR 2的选择性剪接形式介导这些不同作用的模型。与Pro253 Arg/FGFR 2突变相当的Pro-->Arg取代发生在FGFR 1和FGFR 3中，并且也与颅缝早闭相关。这表明了一种常见的病理机制，即对有限的组织特异性配体库的亲和力增强过度抑制颅缝中的信号传导。在颅缝早闭症中的第一个MSX 2突变在1993年被描述，但这仍然是唯一的例子。我们最近发现了三个MSX 2突变与不同的颅表型，顶骨孔。DNA结合研究表明，颅缝早闭症和顶骨孔分别由功能的获得和丧失引起。
Many genetically determined craniosynostosis syndromes feature limb anomalies, implying that pathways of cranial suture and limb morphogenesis share some identical components. Identification of heterozygous mutations in FGFR1, FGFR2, FGFR3, TWIST and MSX2 in craniosynostosis has focused particular attention on these genes. Here we explore two themes: use of clinical/molecular analysis to provide new clues to pathophysiology and the contrasting effects of loss- and gain-of-function mutations. Apert syndrome is a severe craniosynostosis/syndactyly disorder usually caused by specific substitutions (Ser252Trp or Pro253Arg) in FGFR2. The relative severity of cranial and limb malformations varies in opposite directions for the two mutations, suggesting that these phenotypes arise by different mechanisms. Clinical and biochemical evidence supports a model in which alternative splice forms of FGFR2 mediate these distinct effects. Pro-->Arg substitutions equivalent the Pro253Arg/FGFR2 mutation occur in both FGFR1 and FGFR3, and are also associated with craniosynostosis. This suggests a common pathological mechanism, whereby enhanced affinity for a limited repertoire of tissue-specific ligand(s) excessively prolongs signalling in the cranial suture. The first MSX2 mutation in craniosynostosis was described in 1993 but this remains the only example. We have recently identified three MSX2 mutations associated with a different cranial phenotype, parietal foramina. DNA binding studies show that the craniosynostosis and parietal foramina arise from gain and loss of function, respectively.