Kallam Anji Reddy Molecular Genetics Laboratory, Prof. Brien Holden Eye Research Center, L.V. Prasad Eye Institute, Hyderabad 500034, Telangana, India.
Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
Int J Mol Sci. 2024 Sep 18;25(18):10028. doi: 10.3390/ijms251810028.
Primary congenital glaucoma (PCG) occurs in children due to developmental abnormalities in the trabecular meshwork and anterior chamber angle. Previous studies have implicated rare variants in , , and and their interactions with , , and in the genetic complexity and clinical heterogeneity of PCG. Given that some of the gene-encoded proteins are localized in the centrosomes () and perform ciliary functions (), we explored the involvement of a core centrosomal protein, , which is responsible for ocular development and regulation of intraocular pressure. Deep sequencing of in a PCG cohort devoid of homozygous mutations in candidate genes (n = 298) and controls (n = 1757) revealed rare pathogenic variants in 16 cases (5.36%). Co-occurrences of heterozygous alleles of with other genes were seen in four cases (1.34%), and a physical interaction was noted for CEP164 and CYP1B1 in HEK293 cells. Cases of co-harboring alleles of the and other genes had a poor prognosis compared with those with a single copy of the allele. We also screened , which synergistically interacts with , and observed a lower frequency of pathogenic variants (0.67%). Our data suggest the potential involvements of and and the yet unexplored cilia-centrosomal functions in PCG pathogenesis.
原发性先天性青光眼 (PCG) 是由于小梁网和前房角的发育异常而发生在儿童身上的。先前的研究表明，在 PCG 的遗传复杂性和临床异质性中，稀有变异与 、 、 及其与 、 、 的相互作用有关。鉴于一些基因编码的蛋白质定位于中心体（centrioles）中并发挥纤毛功能（cilia），我们探索了核心中心体蛋白 的参与，该蛋白负责眼部发育和调节眼内压。在一个没有候选基因（n=298）和对照（n=1757）纯合突变的 PCG 队列中对 进行深度测序，在 16 例（5.36%）中发现了罕见的致病性变异。在 4 例（1.34%）中观察到 杂合等位基因与其他基因的共等位基因，并且在 HEK293 细胞中注意到 CEP164 和 CYP1B1 的物理相互作用。与单个 等位基因相比，同时携带 和其他基因等位基因的病例预后较差。我们还筛选了 ，它与 协同相互作用，并观察到致病性变异的频率较低（0.67%）。我们的数据表明 和 以及尚未探索的纤毛 - 中心体功能可能参与了 PCG 的发病机制。
