Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations
Mutations of the PAX6 gene detected in patients with a variety of optic-nerve malformations
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DOI：
10.1086/375555
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发表时间：
2003-06-01
影响因子：
9.8
通讯作者：
Yamada, M
中科院分区：
文献类型：
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作者：
Azuma, N;Yamaguchi, Y;Yamada, M
PAX6基因与眼形态发生有关，在发育中的中枢神经系统和众多眼组织中均有表达。Pax6基因突变在各种眼畸形中被检测到，包括无虹膜、彼得斯畸形、角膜营养不良、先天性白内障和中心凹发育不全。然而，在患有视神经畸形的患者中还没有发现这种情况。在这里，我们在8个有视神经畸形的家系中发现了新的突变，包括缺损、牵牛花盘异常、视神经发育不良/再生障碍和持续性增生性初级玻璃体。功能分析表明，每个突变都通过配对的DNA结合域降低了PAX6的转录激活潜力。Pax6和PAX2都被认为下调了另一种基因的表达。在报告实验中，四个检测到的突变影响了PAX6介导的PAX2启动子的转录抑制。由于在乳头状肾综合征中检测到PAX2基因突变，PAX6突变引起的PAX2功能改变可能会影响视神经畸形的表型表现。
The PAX6 gene is involved in ocular morphogenesis and is expressed in the developing central nervous system and numerous ocular tissues during development. PAX6 mutations have been detected in various ocular anomalies, including aniridia, Peters anomaly, corneal dystrophy, congenital cataracts, and foveal hypoplasia. However, it has not been identified in patients with optic-nerve malformations. Here, we identified novel mutations in eight pedigrees with optic-nerve malformations, including coloboma, morning glory disc anomaly, optic-nerve hypoplasia/aplasia, and persistent hyperplastic primary vitreous. A functional assay demonstrated that each mutation decreased the transcriptional activation potential of PAX6 through the paired DNA-binding domain. PAX6 and PAX2 are each thought to downregulate the expression of the other. Four of the detected mutations affected PAX6-mediated transcriptional repression of the PAX2 promoter in a reporter assay. Because PAX2 gene mutations were detected in papillorenal syndrome, alternation of PAX2 function by PAX6 mutations may affect phenotypic manifestations of optic-nerve malformations.