Mutations in the gene account for approximately 5% of cases of primary open angle glaucoma (POAG). encodes for the protein myocilin, a multimeric secreted glycoprotein composed of N-terminal coiled-coil (CC) and leucine zipper (LZ) domains that are connected via a disordered linker to a 30 kDa olfactomedin (OLF) domain. More than 90% of glaucoma-causing mutations are localized to the OLF domain. While myocilin is expressed in numerous tissues, mutant myocilin is only associated with disease in the anterior segment of the eye, in the trabecular meshwork. The prevailing pathogenic mechanism involves a gain of toxic function whereby mutant myocilin aggregates intracellularly instead of being secreted, which causes cell stress and an early timeline for TM cell death, elevated intraocular pressure, and subsequent glaucoma-associated retinal degeneration. In this review, we focus on the work our lab has conducted over the past ∼15 years to enhance our molecular understanding of myocilin-associated glaucoma, which includes details of the molecular structure and the nature of the aggregates formed by mutant myocilin. We conclude by discussing open questions, such as predicting phenotype from genotype alone, the elusive native function of myocilin, and translational directions enabled by our work.

中文翻译：

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肌纤蛋白错误折叠和青光眼：20 年更新


该基因突变约占原发性开角型青光眼 (POAG) 病例的 5%。编码肌纤蛋白，这是一种多聚体分泌糖蛋白，由 N 端卷曲螺旋 (CC) 和亮氨酸拉链 (LZ) 结构域组成，这些结构域通过无序接头连接到 30 kDa 嗅觉素 (OLF) 结构域。超过 90% 的青光眼致病突变位于 OLF 结构域。虽然肌纤蛋白在许多组织中表达，但突变型肌纤蛋白仅与眼前段小梁网的疾病相关。主要的致病机制涉及毒性功能的获得，突变型肌纤蛋白在细胞内聚集而不是分泌，这会导致细胞应激和TM细胞死亡的早期时间表、眼内压升高以及随后的青光眼相关视网膜变性。在这篇综述中，我们重点关注我们的实验室在过去~15年中为增强我们对肌纤蛋白相关青光眼的分子理解而进行的工作，其中包括分子结构的细节和突变肌纤蛋白形成的聚集体的性质。最后，我们讨论了一些悬而未决的问题，例如仅根据基因型预测表型、肌纤蛋白难以捉摸的天然功能以及我们的工作实现的转化方向。