A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes
A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes
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DOI：
10.1073/pnas.071586898
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发表时间：
2001-03-27
影响因子：
11.1
通讯作者：
Dickson, C
中科院分区：
文献类型：
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作者：
Hajihosseini, MK;Wilson, S;Dickson, C
成纤维细胞生长因子的细胞间信号传导在胚胎发生过程中起着至关重要的作用。缺乏成纤维细胞生长因子受体（FgfR）的小鼠表现出早期原肠胚形成和着床异常、上皮间质相互作用破坏以及膜骨和软骨内骨形成的严重缺陷。激活 FGFR 突变是人类多种颅缝早闭和侏儒症综合征的根本原因。在这里，我们证明小鼠中 FgfR2-外显子 g (IIIc) 的杂合性废除会导致剪接开关，从而导致功能获得性突变。其后果是新生儿生长迟缓和死亡、冠状缝早闭、眼球突出、胸骨融合过早以及经历分支形态发生的多个器官的次级分支异常。这种表型与一些阿佩尔综合征和普法伊弗综合征患者有很强的相似性。
Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon g (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.