ATXN2 loss of function results in glaucoma-related features supporting a role for Ataxin-2 in primary open-angle glaucoma (POAG) pathogenesis

IF 1.5 4区心理学 Q4 NEUROSCIENCES

Vision Research Pub Date : 2024-11-02 DOI:10.1016/j.visres.2024.108508

Shi Song Rong, Anna Larson, Janey L. Wiggs, NEIGHBORHOOD consortium

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引用次数: 0

Abstract

Glaucoma is a leading cause of irreversible blindness worldwide. The most common form, primary open-angle glaucoma (POAG), is a genetically complex trait with high heritability. Genome-wide association studies have identified significant POAG and IOP association of a genomic region on chromosome 12 that includes ATXN2 as well as 7 other genes. Association of protein disrupting ATXN2 variants in the NEIGHBORHOOD case-control cohort and the UK Biobank suggests that ATXN2 is a key gene in this locus. To investigate functional effects, we utilized a zebrafish (Danio rerio) CRISPR/Cas9 edited atxn2-knockdown line to show that loss of atxn2 results in reduced eye size, diminished retinal ganglion cells (RGC), increased intraocular pressure (IOP), and impaired visual function in zebrafish. Complementation assays supported functional effects for 14 POAG-associated human ATXN2 missense variants. These results suggest a loss-of-function mechanism underlying a potential role for ATXN2 in POAG pathogenesis.

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ATXN2 功能缺失会导致青光眼相关特征，支持 Ataxin-2 在原发性开角型青光眼（POAG）发病机制中的作用。

青光眼是导致全球不可逆失明的主要原因。最常见的原发性开角型青光眼（POAG）是一种遗传性状复杂的疾病，遗传率很高。全基因组关联研究发现，POAG 和眼压与 12 号染色体上的一个基因组区域有显著关联，该区域包括 ATXN2 和其他 7 个基因。在 NEIGHBORHOOD 病例对照队列和英国生物库（UK Biobank）中，蛋白质干扰 ATXN2 变体的关联表明，ATXN2 是该基因座中的一个关键基因。为了研究其功能效应，我们利用斑马鱼（Danio rerio）CRISPR/Cas9编辑的atxn2-knockdown品系表明，atxn2缺失会导致斑马鱼眼球缩小、视网膜神经节细胞（RGC）减少、眼压（IOP）升高和视觉功能受损。补体测定证实了 14 个与 POAG 相关的人类 ATXN2 错义变体的功能效应。这些结果表明 ATXN2 在 POAG 发病机制中的潜在作用是一种功能缺失机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Vision Research 医学-神经科学

CiteScore

3.70

自引率

16.70%

发文量

111

审稿时长

66 days

期刊介绍： Vision Research is a journal devoted to the functional aspects of human, vertebrate and invertebrate vision and publishes experimental and observational studies, reviews, and theoretical and computational analyses. Vision Research also publishes clinical studies relevant to normal visual function and basic research relevant to visual dysfunction or its clinical investigation. Functional aspects of vision is interpreted broadly, ranging from molecular and cellular function to perception and behavior. Detailed descriptions are encouraged but enough introductory background should be included for non-specialists. Theoretical and computational papers should give a sense of order to the facts or point to new verifiable observations. Papers dealing with questions in the history of vision science should stress the development of ideas in the field.