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      Identification and characterization of variants and a novel 4 bp deletion in the regulatory region of SIX6, a risk factor for primary open‐angle glaucoma

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          Abstract

          Background

          Primary open‐angle glaucoma ( POAG) is a complex disease of multigenic inheritance and the most common subtype of glaucoma. SIX6 encodes a transcription factor involved in retina, optic nerve, and pituitary development. Previous studies showed a genetic association between the SIX6 locus and POAG, identifying risk alleles. Whether these alleles are present also in the south Indian population is unclear.

          Methods

          To address this question, the SIX6 gene and an already characterized and highly conserved SIX6 enhancer (Ch14:60974427‐60974430) were sequenced in two south Indian cohorts, respectively, composed of 65/65 and 200/200 POAG cases/age‐matched controls. We next used Taqman‐based allelic discrimination assay to genotype a common variant (rs33912345: c.421A>C) and the rs1048372 SNP in two cohorts, respectively, composed of 557/387 and 590/448 POAG cases/age‐matched controls. An additional cohort of 153 POAG cases was subsequently recruited to assess the association of the rs33912345:c.421A>C and rs10483727 variants with more prominent changes in two POAG 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 assays.

          Results

          We identified two known rare and two common variants in the SIX6 locus and a novel 4 bp 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 in the south Indian ethnicity but patients carrying the corresponding C or T risk alleles exhibited a dose‐dependent 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 assays demonstrated that the newly identified 4 bp deletion significantly reduced reporter expression in cells of the retinal ganglion and amacrine layers, where human SIX6 is expressed.

          Conclusion

          Altogether, our data further support the implication of SIX6 variants as POAG risk factors and implicates SIX6 haploinsufficiency in POAG pathogenesis.

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          Most cited references47

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          Aging, Cellular Senescence, and Cancer

          For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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            The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease.

            J. Kumar (2009)
            The sine oculis homeobox (SIX) protein family is a group of evolutionarily conserved transcription factors that are found in diverse organisms that range from flatworms to humans. These factors are expressed within, and play pivotal developmental roles in, cell populations that give rise to the head, retina, ear, nose, brain, kidney, muscle and gonads. Mutations within the fly and mammalian versions of these genes have adverse consequences on the development of these organs/tissues. Several SIX proteins have been shown to directly influence the cell cycle and are present at elevated levels during tumorigenesis and within several cancers. This review aims to highlight aspects of (1) the evolutionary history of the SIX family; (2) the structural differences and similarities amongst the different SIX proteins; (3) the role that these genes play in retinal development; and (4) the influence that these proteins have on cell proliferation and growth.
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              Genome-wide analysis of multiethnic cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

              Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located on chromosome 3q25.31 within the FNDC3B gene (p=4.19×10−08 for rs6445055), two on chromosome 9 (p=2.80×10−11 for rs2472493 near ABCA1 and p=6.39×10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best p=1.04×10−11 for rs747782). Separate meta-analyses of four independent POAG cohorts, totaling 4,284 cases and 95,560 controls, show that three of these IOP loci are also associated with POAG.
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                Author and article information

                Contributors
                pbovolenta@cbm.csic.es
                sundar@aravind.org
                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                27 April 2017
                July 2017
                : 5
                : 4 ( doiID: 10.1002/mgg3.2017.5.issue-4 )
                : 323-335
                Affiliations
                [ 1 ] Department of Molecular Genetics Aravind Medical Research Foundation Madurai India
                [ 2 ] Centro de Biología Molecular Severo Ochoa CSIC‐UAM Madrid Spain
                [ 3 ] CIBERER, ISCIII Madrid Spain
                [ 4 ] Glaucoma Clinic Aravind Eye Hospital Madurai India
                Author notes
                [*] [* ] Correspondence

                Periasamy Sundaresan, Department of Molecular Genetics, Aravind Medical Research Foundation, Aravind Eye Hospital, No‐1, Anna Nagar, Madurai – 625 020, Tamil Nadu, India. Tel: +91 4524356100; Fax: +91 452 2530984; E‐mail: sundar@ 123456aravind.org

                and

                Paola Bovolenta, Department of Development and Regeneration, CBMSO, c/Nicolas Cabrera 1, Cantoblanco, Madrid 28049, Spain. Tel: +34 91 196 4718; Fax: +34 91 196 4749; E‐mail: pbovolenta@ 123456cbm.csic.es

                Author information
                http://orcid.org/0000-0002-0599-8653
                Article
                MGG3290
                10.1002/mgg3.290
                5511802
                e857ac25-6606-4f6f-bf53-947ab2a5b8c8
                © 2017 Aravind Medical Research Foundation. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 02 January 2017
                : 20 March 2017
                : 21 March 2017
                Page count
                Figures: 4, Tables: 5, Pages: 13, Words: 9556
                Funding
                Funded by: AMRF
                Funded by: MINECO
                Award ID: BFU2010‐16031
                Award ID: BFU2013‐43213‐P
                Funded by: CIBERER
                Funded by: ISCIII
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                mgg3290
                July 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.4 mode:remove_FC converted:16.07.2017

                gene expression regulation,primary open‐angle glaucoma,six6,vertical cup to disc ratio,zebrafish

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