Loss-of-function mutations in the human GL12 gene are associated with pituitary anomalies and holoprosencephaly-like features
Loss-of-function mutations in the human GL12 gene are associated with pituitary anomalies and holoprosencephaly-like features
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DOI：
10.1073/pnas.2235734100
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发表时间：
2003-11-11
影响因子：
11.1
通讯作者：
Muenke, M
中科院分区：
文献类型：
--
作者：
Roessler, E;Du, YZ;Muenke, M
减弱的Sonic Hedgehog（Shh）信号传导与人类中最常见的前脑缺陷，前脑无裂畸形（HPE）相关，其包括独眼畸形，这是一种在具有缺陷Shh信号传导的小鼠和其他脊椎动物中也可见的表型。分泌的蛋白Shh是腹侧前脑形成模式的关键因素，并且是将原始眼区和大脑分成两个离散部分所必需的。Gli2是脊椎动物Shh信号转导的三种转录因子之一。在这里，我们表明，在人类GLI2基因的功能缺失突变与一个独特的表型（HPE谱内），其主要特征包括有缺陷的垂体前叶形成和泛垂体功能减退，有或没有明显的前脑卵裂异常，和HPE样面中部发育不全。我们还证明了这些突变缺乏GLI2活性。我们报告了GLI2与人类疾病之间的功能关联，并强调了GLI2在人类头部发育中的作用。
Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into two discrete halves. Gli2 is one of three vertebrate transcription factors implicated as obligatory mediators of Shh signal transduction. Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like mid-facial hypoplasia. We also demonstrate that these mutations lack GLI2 activity. We report on a functional association between GLI2 and human disease and highlight the role of GLI2 in human head development.