Potential Involvements of Anterior Segment Dysgenesis-Associated Genes in Primary Congenital Glaucoma

The anterior segment of the eye plays a crucial role in maintaining the normal intraocular pressure and vision. Developmental defects in the anterior segment structures lead to anterior segment dysgenesis (ASD) and primary congenital glaucoma (PCG), which share overlapping clinical features. Several genes have been mapped and characterized in ASD, some of which are also involved in other glaucoma phenotypes. PCG exhibits genetic heterogeneity like ASD, but the known genes do not account for the entire genetic basis of the disease. Considering the significant phenotypic and genotypic overlap between ASD and PCG, this article explores the possible involvements of ASD-associated genes in PCG pathogenesis. A nonsystematic search in PubMed was performed using various combinations of keywords related to ASD, glaucoma, genetics, and molecular mechanisms, and articles published up until March 2024 were considered. Specifically, information pertaining to ASD-associated genes (<i>FBN1, FOXE3, HMX1, LMX1B, MAF, OTX2, PAX6, PITX2, PITX3, PRDM5, PRSS56, RAX, SLC4A11, SOX2, TRIM44, VAX1</i>, and <i>WT1</i>) was extracted, and their expressions were determined from the GTEx and EMBL-EBI Expression Atlas. Interactions of these genes were determined through the Ingenuity Pathway Analysis software. Most of the ASD-associated genes were found to be highly expressed in the early embryonic stages. Interactome analysis revealed that <i>TRIM44, PAX6, WT1, SOX2, OTX2, PRDM5</i>, and <i>FBN1</i> interacted through the NFκB and Akt/PI3K pathways, either directly, or through interactions with other partners. <i>FOXC1, PITX2</i>, and <i>HMX1</i> interacted through Wnt and Hedgehog signaling pathways. Both ASD and PCG present similar clinical features and harbor mutations in genes that are implicated in both these conditions. Collectively, we constructed a hypothetical model and proposed two parallel mechanisms comprising the defects in the anterior chamber angle and cell death in PCG pathogenesis. Our findings suggest that complex interplay of these ASD-associated genes and their interactions could potentially result in defects in the anterior chamber angle and trabecular meshwork and induce cell death, resulting in PCG pathogenesis.

眼前段在维持正常眼压及视觉功能中发挥关键作用。眼前段结构的发育缺陷可导致眼前段发育异常（anterior segment dysgenesis, ASD）与原发性先天性青光眼（primary congenital glaucoma, PCG），二者具有重叠的临床特征。ASD中已定位并鉴定出多个基因，其中部分基因也参与其他青光眼表型的发生。PCG与ASD类似，具有遗传异质性，但已知基因无法解释该病的全部遗传基础。鉴于ASD与PCG在表型及基因型上存在显著重叠，本文探讨了ASD相关基因在PCG发病机制中的潜在作用。我们在PubMed数据库中进行了非系统性检索，使用ASD、青光眼、遗传学及分子机制相关的多种关键词组合，纳入截至2024年3月发表的文章。具体而言，我们提取了与ASD相关基因（<i>FBN1、FOXE3、HMX1、LMX1B、MAF、OTX2、PAX6、PITX2、PITX3、PRDM5、PRSS56、RAX、SLC4A11、SOX2、TRIM44、VAX1</i>及<i>WT1</i>）相关的信息，并通过GTEx与EMBL-EBI Expression Atlas数据库分析了这些基因的表达情况。通过Ingenuity通路分析软件解析了这些基因间的相互作用。研究发现，大部分ASD相关基因在胚胎早期阶段高表达。互作组分析（interactome analysis）显示，<i>TRIM44、PAX6、WT1、SOX2、OTX2、PRDM5</i>及<i>FBN1</i>通过NFκB与Akt/PI3K通路发生直接或间接（通过其他伙伴分子）的相互作用。<i>FOXC1、PITX2</i>及<i>HMX1</i>则通过Wnt与Hedgehog信号通路相互作用。ASD与PCG均具有相似的临床特征，且二者均存在涉及上述两种疾病的基因突变。综上，我们构建了一个假设模型，并提出PCG发病机制中涉及前房角缺陷与细胞死亡的两条平行通路。研究结果表明，这些ASD相关基因的复杂相互作用可能导致前房角与小梁网（trabecular meshwork）缺陷，并诱导细胞死亡，最终参与PCG的发病过程。