Shi Song Rong, Anna Larson, Janey L. Wiggs, NEIGHBORHOOD consortium
{"title":"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。","authors":"Shi Song Rong, Anna Larson, Janey L. Wiggs, NEIGHBORHOOD consortium","doi":"10.1016/j.visres.2024.108508","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>ATXN2</em> as well as 7 other genes. Association of protein disrupting <em>ATXN2</em> variants in the NEIGHBORHOOD case-control cohort and the UK Biobank suggests that <em>ATXN2</em> is a key gene in this locus. To investigate functional effects, we utilized a zebrafish (Danio rerio) CRISPR/Cas9 edited <em>atxn2</em>-knockdown line to show that loss of <em>atxn2</em> 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 <em>ATXN2</em> missense variants. These results suggest a loss-of-function mechanism underlying a potential role for <em>ATXN2</em> in POAG pathogenesis.</div></div>","PeriodicalId":23670,"journal":{"name":"Vision Research","volume":"226 ","pages":"Article 108508"},"PeriodicalIF":1.5000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ATXN2 loss of function results in glaucoma-related features supporting a role for Ataxin-2 in primary open-angle glaucoma (POAG) pathogenesis\",\"authors\":\"Shi Song Rong, Anna Larson, Janey L. Wiggs, NEIGHBORHOOD consortium\",\"doi\":\"10.1016/j.visres.2024.108508\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>ATXN2</em> as well as 7 other genes. Association of protein disrupting <em>ATXN2</em> variants in the NEIGHBORHOOD case-control cohort and the UK Biobank suggests that <em>ATXN2</em> is a key gene in this locus. To investigate functional effects, we utilized a zebrafish (Danio rerio) CRISPR/Cas9 edited <em>atxn2</em>-knockdown line to show that loss of <em>atxn2</em> 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 <em>ATXN2</em> missense variants. These results suggest a loss-of-function mechanism underlying a potential role for <em>ATXN2</em> in POAG pathogenesis.</div></div>\",\"PeriodicalId\":23670,\"journal\":{\"name\":\"Vision Research\",\"volume\":\"226 \",\"pages\":\"Article 108508\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2024-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Vision Research\",\"FirstCategoryId\":\"102\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0042698924001524\",\"RegionNum\":4,\"RegionCategory\":\"心理学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Vision Research","FirstCategoryId":"102","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0042698924001524","RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
ATXN2 loss of function results in glaucoma-related features supporting a role for Ataxin-2 in primary open-angle glaucoma (POAG) pathogenesis
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.
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.