Singh Ajeet, Ratnapriya Rinki
Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin St, NC205, Houston, TX 77030 United States.
Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 6565 Fannin St, NC205, Houston, TX 77030 United States.
Hum Mol Genet. 2025 Feb 17;34(5):454-465. doi: 10.1093/hmg/ddaf001.
Human diseases with similar phenotypes can be interconnected through shared biological pathways, genes, or molecular mechanisms. Inherited retinal diseases (IRDs) cause photoreceptor dysfunction due to mutations in approximately 300 genes, affecting visual transduction, photoreceptor morphogenesis, and transcription factors, suggesting common pathobiological mechanisms. This study examined the functional relationship between known IRDs genes by integrating binding sites and gene expression data from the key photoreceptor transcription factors (TFs), Crx and Nrl. We show that the targets of these TFs were enriched in IRDs causal genes. Co-expression network analysis revealed that IRD-centric networks were disrupted when Crx and Nrl were knocked out. Finally, we identified a highly connected core module comprising 14 IRD and 39 target genes, of which 29 were dysregulated in the rod photoreceptors of the four IRD mouse models. These findings offer a network-based interpretation of IRDs, aiding in the identification of common mechanisms, prioritizing genes for novel disease gene identification, and informing the development of gene-agnostic therapies for IRDs.
具有相似表型的人类疾病可通过共享的生物途径、基因或分子机制相互关联。遗传性视网膜疾病（IRD）由于约300个基因的突变导致光感受器功能障碍，影响视觉转导、光感受器形态发生和转录因子，提示存在共同的病理生物学机制。本研究通过整合关键光感受器转录因子（TF）Crx和Nrl的结合位点及基因表达数据，研究了已知IRD基因之间的功能关系。我们发现这些TF的靶标在IRD致病基因中富集。共表达网络分析显示，当Crx和Nrl被敲除时，以IRD为中心的网络被破坏。最后，我们确定了一个由14个IRD基因和39个靶基因组成的高度连接的核心模块，其中29个在四种IRD小鼠模型的视杆光感受器中表达失调。这些发现为IRD提供了基于网络的解释，有助于识别共同机制、为新疾病基因鉴定确定基因优先级，并为IRD的非基因特异性疗法的开发提供信息。
