Pallister-Hall syndrome phenotype in mice mutant for Gli3
Pallister-Hall syndrome phenotype in mice mutant for Gli3
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DOI：
10.1093/hmg/11.9.1129
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发表时间：
2002-05-01
影响因子：
3.5
通讯作者：
Rüther, U
中科院分区：
文献类型：
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作者：
Böse, J;Grotewold, L;Rüther, U
GLI3 基因突变已在多种人类畸形综合征中被发现。这些常染色体显性发育障碍之一是 Pallister-Hall 综合征（PHS；MIM146510），它与中央多指畸形和其他畸形有关。有趣的是，在 PHS 患者中发现的 GLI3 转录因子基因突变仅限于锌指编码结构域的 3' 区域，使该 DNA 结合结构域保持完整。我们通过在小鼠中引入靶向突变，研究了这种突变对多器官系统发育的影响。我们发现，该突变纯合的小鼠表现出中央多指畸形，从而模拟了人类综合症的主要异常之一。此外，Gli3突变小鼠表现出多种发育异常，几乎涵盖所有常见的PHS特征，包括肛门闭锁、胃肠道、会厌和喉部缺陷、肾脏发育异常以及肾上腺缺失。因此，我们的 Gli3 突变小鼠为研究 PHIS 的发病机制和受影响器官系统发育中的 Gli3 功能提供了一个极好的模型。
Mutations in the GLI3 gene have been identified in several human malformation syndromes. One of these autosomal dominant developmental disorders is Pallister-Hall syndrome (PHS; MIM146510), which is associated with central polydactyly and other malformations. Interestingly, the mutations in the GLI3 transcription factor gene identified in patients with PHS are restricted to the region 3' of the zinc finger-encoding domain, leaving this DNA-binding domain intact. We have investigated the consequences of this mutation on the development of multiple organ systems by introducing a targeted mutation in mice. We found that mice homozygous for the mutation showed a central polydactyly, thus modeling one of the major abnormalities of the human syndrome. Moreover, Gli3-mutant mice displayed a wide range of developmental abnormalities encompassing almost all of the common PHS features, including imperforate anus, gastrointestinal, epiglottis and larynx defects, abnormal kidney development, and absence of adrenal glands. Thus, our Gli3-mutant mice provide an excellent model for studies of both the pathogenesis of PHIS and Gli3 functions in the development of the affected organ systems.