EYA4, Deleted in a Case with Middle Interhemispheric Variant of Holoprosencephaly, Interacts with SIX3 both Physically and Functionally
EYA4, Deleted in a Case with Middle Interhemispheric Variant of Holoprosencephaly, Interacts with SIX3 both Physically and Functionally
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DOI：
10.1002/humu.21094
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发表时间：
2009-10-01
期刊：
影响因子：
3.9
通讯作者：
Miyashita, Toshiyuki
中科院分区：
文献类型：
--
作者：
Abe, Yuichi;Oka, Akira;Miyashita, Toshiyuki
前脑无裂畸形（HPE）是人类前脑发育中最常见的先天性畸形，表现为大脑两半球不同程度的分离障碍。虽然已经在多达9个基因中发现了病理性突变，但许多其他基因以及环境因素可能与HPE有关。在这里，我们描述了一个病例与中间interhemispheric变异，一个温和的变种HPE，携带一个类似于10.4 Mb的缺失在6q22.31-q23.2，其中包括EYA 4基因。EYA 4是黑腹果蝇基因的四种脊椎动物直系同源基因之一，没有眼睛。EYA 4与SIX 3共免疫沉淀，SIX 3是已知HPE基因之一的产物。此外，在共聚焦显微镜下观察到EYA 4蛋白被核蛋白SIX 3募集到核中。EYA 4是一种转录辅激活因子，通过报告基因分析显示其与转录因子SIX 3协同作用。这些结果证明了EYA 4和SIX 3之间的物理和功能关联，表明EYA 4是HPE的新候选基因，其单倍不足通过SIX 3的功能受损导致HPE。(C)2009 Wiley-Liss，Inc.
Holoprosencephaly (HPE) is the most common congenital malformation of the developing human forebrain, in which the two cerebral hemispheres fail to separate to various degrees. Although pathological mutations have been identified in up to nine genes, a number of other genes as well as environmental factors are likely to be involved in HPE. Here, we describe a case with the middle interhemispheric variant, a milder variant of HPE, carrying a deletion of similar to 10.4 Mb at 6q22.31-q23.2, which includes the EYA4 gene. EYA4 is one of four vertebrate orthologs of the Drosophila melanogaster gene, eyes absent. EYA4 was co-immunoprecipitated with SIX3, the product of one of the known HPE genes. Moreover, the EYA4 protein was observed to be recruited to the nucleus by the nuclear protein SIX3 under a confocal microscope. EYA4 is a transcriptional coactivator, and was shown to cooperate with transcription factor SIX3 by reporter gene assays. These results demonstrate physical and functional association between EYA4 and SIX3, suggesting that EYA4 is a novel candidate gene of HPE, whose haploinsufficiency leads to HPE through the compromised function of SIX3. (C) 2009 Wiley-Liss, Inc.