Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development.
Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development.
复制标题
DOI：
10.3389/fnmol.2023.1134839
复制
发表时间：
2023
影响因子：
4.8
通讯作者：
Chen, Shiming
中科院分区：
文献类型：
--
作者：
Sun, Chi;Chen, Shiming
关键词：
脊椎动物视觉系统的光感受器发育受复杂的转录调控网络控制。OTX 2在有丝分裂的视网膜祖细胞（RPC）中表达并控制光感受器发生。由OTX 2激活的CRX在细胞周期退出后在光感受器前体中表达。NEUROD 1也存在于准备指定为视杆和视锥感光器亚型的感光器前体中。NRL是视杆细胞命运所必需的，并调节下游视杆细胞特异性基因，包括孤儿核受体NR 2 E3，其进一步激活视杆细胞特异性基因并同时抑制视锥细胞特异性基因。视锥细胞亚型的特化也受到几种转录因子如THRB和RXRG的相互作用的调节。这些关键转录因子的突变导致出生时的眼部缺陷，如小眼症和遗传性光感受器疾病，如Leber先天性黑蒙（LCA）、视网膜色素变性（RP）和相关营养不良。特别是，许多突变以常染色体显性方式遗传，包括CRX和NRL中的大多数错义突变。在这篇综述中，我们描述了与上述转录因子突变相关的光感受器缺陷的光谱，并总结了致病突变的分子机制的现有知识。最后，我们讨论了我们对基因型-表型相关性的理解中存在的突出差距，并概述了未来治疗策略研究的途径。
Photoreceptor development of the vertebrate visual system is controlled by a complex transcription regulatory network. OTX2 is expressed in the mitotic retinal progenitor cells (RPCs) and controls photoreceptor genesis. CRX that is activated by OTX2 is expressed in photoreceptor precursors after cell cycle exit. NEUROD1 is also present in photoreceptor precursors that are ready to specify into rod and cone photoreceptor subtypes. NRL is required for the rod fate and regulates downstream rod-specific genes including the orphan nuclear receptor NR2E3 which further activates rod-specific genes and simultaneously represses cone-specific genes. Cone subtype specification is also regulated by the interplay of several transcription factors such as THRB and RXRG. Mutations in these key transcription factors are responsible for ocular defects at birth such as microphthalmia and inherited photoreceptor diseases such as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and allied dystrophies. In particular, many mutations are inherited in an autosomal dominant fashion, including the majority of missense mutations in CRX and NRL. In this review, we describe the spectrum of photoreceptor defects that are associated with mutations in the above-mentioned transcription factors, and summarize the current knowledge of molecular mechanisms underlying the pathogenic mutations. At last, we deliberate the outstanding gaps in our understanding of the genotype–phenotype correlations and outline avenues for future research of the treatment strategies.
登录
查看更多内容
影响因子：
8.1
作者：
Yang P;Chiang PW;Weleber RG;Pennesi ME
通讯作者：
Pennesi ME
影响因子：
4.4
作者：
Audo, Isabelle;Michaelides, Michel;Holder, Graham E.
通讯作者：
Holder, Graham E.
影响因子：
5.3
作者：
Ashkenazi-Hoffnung, Liat;Lebenthal, Yael;Gat-Yablonski, Galia
通讯作者：
Gat-Yablonski, Galia
影响因子：
11.2
作者：
Adamson DC;Shi Q;Wortham M;Northcott PA;Di C;Duncan CG;Li J;McLendon RE;Bigner DD;Taylor MD;Yan H
通讯作者：
Yan H
影响因子：
64.5
作者：
Berger, Michael F.;Badis, Gwenael;Hughes, Timothy R.
通讯作者：
Hughes, Timothy R.