A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa
A Mutation in ZNF513, a Putative Regulator of Photoreceptor Development, Causes Autosomal-Recessive Retinitis Pigmentosa
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DOI：
10.1016/j.ajhg.2010.08.003
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发表时间：
2010-09-10
影响因子：
9.8
通讯作者：
Hejtmancik, J. Fielding
中科院分区：
文献类型：
--
作者：
Li, Lin;Nakaya, Naoki;Hejtmancik, J. Fielding
色素性视网膜炎（RP）是一种表型和遗传异质性的遗传性视网膜变性，临床表现为夜盲症、视野进行性收缩和视力丧失，病理表现为杆状和锥状光感受器的进行性丧失。常染色体隐性RP （arRP）在巴基斯坦的一个近亲家庭中，以前与染色体2p22.3-p24.1相关，结果显示是由纯合错义突变引起的(C . 1015t >C [p。C33912])在ZNF513中，编码一种推定的转录因子。Znf513在视网膜中表达，尤其是在外核层、内核层和光感受器中。znf513基因在斑马鱼体内的表达下调会减少眼睛的大小、视网膜的厚度、视杆蛋白和视锥蛋白的表达，并导致光感受器的特异性丧失。这些效应可以通过与野生型（WT）共注射而不是p.C339R-znf5/3 mRNA来恢复。正常和p.C339R突变体在COS-7细胞中表达的ZNF513蛋白都定位于细胞核。ChIP分析显示，只有野生型而非突变型ZNF513与Pax6、Sp4、Arr3、Irbp和光感受器视蛋白启动子结合。这些结果表明，ZNF513 p.C339R突变负责该家族的RP，并且ZNF513在视网膜发育和光感受器维持的光受体特异性基因调控中起关键作用。
Retinitis pigmentosa (RP) is a phenotypically and genetically heterogeneous group of inherited retinal degenerations characterized clinically by night blindness, progressive constriction of the visual fields, and loss of vision, and pathologically by progressive loss of rod and then cone photoreceptors. Autosomal-recessive RP (arRP) in a consanguineous Pakistani family previously linked to chromosome 2p22.3-p24.1 is shown to result from a homozygous missense mutation (c.1015T>C [p.C33912]) in ZNF513, encoding a presumptive transcription factor. znf513 is expressed in the retina, especially in the outer nuclear layer, inner nuclear layer, and photoreceptors. Knockdown of znf513 in zebrafish reduces eye size, retinal thickness, and expression of rod and cone opsins and causes specific loss of photoreceptors. These effects are rescued by coinjection with wild-type (WT) but not p.C339R-znf5/3 mRNA. Both normal and p.C339R mutant ZNF513 proteins expressed in COS-7 cells localize to the nucleus. ChIP analysis shows that only the wild-type but not the mutant ZNF513 binds to the Pax6, Sp4, Arr3, Irbp, and photoreceptor opsin promoters. These results suggest that the ZNF513 p.C339R mutation is responsible for RP in this family and that ZNF513 plays a key role in the regulation of photoreceptor-specific genes in retinal development and photoreceptor maintenance.