{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:16:54Z","timestamp":1762899414264,"version":"3.37.3"},"reference-count":56,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2017,4,27]],"date-time":"2017-04-27T00:00:00Z","timestamp":1493251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001927","name":"Advanced Medical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001927","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["BFU2010\u201016031","BFU2013\u201043213\u2010P"],"award-info":[{"award-number":["BFU2010\u201016031","BFU2013\u201043213\u2010P"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen & Gen Med"],"published-print":{"date-parts":[[2017,7]]},"abstract":"Abstract<\/jats:title>Background<\/jats:title>Primary open\u2010angle glaucoma (POAG<\/jats:styled-content>) is a complex disease of multigenic inheritance and the most common subtype of glaucoma. SIX<\/jats:styled-content>6<\/jats:italic> encodes a transcription factor involved in retina, optic nerve, and pituitary development. Previous studies showed a genetic association between the SIX<\/jats:styled-content>6<\/jats:italic> locus and POAG<\/jats:styled-content>, identifying risk alleles. Whether these alleles are present also in the south Indian population is unclear.<\/jats:p><\/jats:sec>Methods<\/jats:title>To address this question, the SIX<\/jats:styled-content>6<\/jats:italic> gene and an already characterized and highly conserved SIX<\/jats:styled-content>6<\/jats:italic> enhancer (Ch14:60974427\u201060974430) were sequenced in two south Indian cohorts, respectively, composed of 65\/65 and 200\/200 POAG<\/jats:styled-content> cases\/age\u2010matched controls. We next used Taqman\u2010based allelic discrimination assay to genotype a common variant (rs33912345: c.421A>C) and the rs1048372 SNP<\/jats:styled-content> in two cohorts, respectively, composed of 557\/387 and 590\/448 POAG<\/jats:styled-content> cases\/age\u2010matched controls. An additional cohort of 153 POAG<\/jats:styled-content> cases was subsequently recruited to assess the association of the rs33912345:c.421A>C and rs10483727 variants with more prominent changes in two POAG<\/jats:styled-content> diagnostic parameters: retinal nerve fiber layer thickness and vertical cup\/disc ratio, using spectral domain optical coherence tomography. The activity of the newly identified enhancer variants was assessed by transgenesis in zebrafish and luciferase<\/jats:italic> assays.<\/jats:p><\/jats:sec>Results<\/jats:title>We identified two known rare and two common variants in the SIX<\/jats:styled-content>6<\/jats:italic> locus and a novel 4\u00a0bp deletion in the analyzed enhancer. Contrary to previous studies, we could not establish a significant association between the rs10483727 and rs33912345:c.421A>C variants and PAOG<\/jats:styled-content> in the south Indian ethnicity but patients carrying the corresponding C or T risk alleles exhibited a dose\u2010dependent reduction of the thickness of the retinal nerve fiber layer and a significant increase in the vertical cup\/disc ratio. Transgenesis in zebrafish and luciferase<\/jats:italic> assays demonstrated that the newly identified 4\u00a0bp deletion significantly reduced reporter expression in cells of the retinal ganglion and amacrine layers, where human SIX<\/jats:styled-content>6<\/jats:italic> is expressed.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Altogether, our data further support the implication of SIX<\/jats:styled-content>6<\/jats:italic> variants as POAG<\/jats:styled-content> risk factors and implicates SIX<\/jats:styled-content>6<\/jats:italic> haploinsufficiency in POAG<\/jats:styled-content> pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.290","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T04:13:43Z","timestamp":1493352823000},"page":"323-335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification and characterization of variants and a novel 4\u00a0bp deletion in the regulatory region of SIX<\/scp>6<\/i>, a risk factor for primary open\u2010angle glaucoma"],"prefix":"10.1002","volume":"5","author":[{"given":"Mohd Hussain","family":"Shah","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics Aravind Medical Research Foundation Madurai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noemi","family":"Tabanera","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa CSIC\u2010UAM Madrid Spain"},{"name":"CIBERER, ISCIII Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subbaiah Ramasamy","family":"Krishnadas","sequence":"additional","affiliation":[{"name":"Glaucoma Clinic Aravind Eye Hospital Madurai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manju R.","family":"Pillai","sequence":"additional","affiliation":[{"name":"Glaucoma Clinic Aravind Eye Hospital Madurai India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Bovolenta","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa CSIC\u2010UAM Madrid Spain"},{"name":"CIBERER, ISCIII Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0599-8653","authenticated-orcid":false,"given":"Periasamy","family":"Sundaresan","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics Aravind Medical Research Foundation Madurai India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,4,27]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms161226135"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12046"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3482"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.681254"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22051"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183653"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004372"},{"key":"e_1_2_6_9_1","first-page":"3518","article-title":"First\u2010degree Consanguinity as a risk factor to developing primary open\u2010angle Glaucoma in Mexican families","volume":"54","author":"Chavez E.","year":"2013","journal-title":"Invest. 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