Chromosome 9p21 primary open‐angle glaucoma susceptibility locus: a review

Ng, Soo Khai; Casson, Robert J.; Burdon, Kathryn P.; Craig, Jamie E

doi:10.1111/ceo.12234

Cited by 37 publications

(33 citation statements)

References 67 publications

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“…Furthermore, the group of downregulated genes included KLF‐7 and PTPRO that encoded a Kruppel‐like transcriptional regulator and receptor protein tyrosine phosphatases , respectively, both involved in axon growth and guidance. Examination of DEG within the “CDK activity” GO term revealed that expression of CDKN2A and CDKN2B , co‐localized on chromosome 9p21 , remained upregulated in patient‐specific clones versus controls in the RGC stage as in the RPC stage (Fig. C, F).…”

Section: Resultsmentioning

confidence: 99%

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

et al. 2017

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Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls. The decrease in the number of RGC generation is accompanied by repressed developmental expression of RGC regulatory genes. The SIX6 risk allele RGCs display short and simple neurites, reduced expression of guidance molecules, and immature electrophysiological signature. In addition, these cells have higher expression of glaucoma-associated genes, CDKN2A and CDKN2B, suggesting an early onset of the disease phenotype. Consistent with the developmental abnormalities, the SIX6 risk allele RGCs display global dysregulation of genes which map on developmentally relevant biological processes for RGC differentiation and signaling pathways such as mammalian target of rapamycin that integrate diverse functions for differentiation, metabolism, and survival. The results suggest that SIX6 influences different stages of RGC differentiation and their survival; therefore, alteration in SIX6 function due to the risk allele may lead to cellular and molecular abnormalities. These abnormalities, if carried into adulthood, may make RGCs vulnerable in glaucoma. Stem Cells 2017;35:2239-2252.

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Section: Resultsmentioning

confidence: 99%

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

et al. 2017

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“…One of the primary reasons we chose to highlight this pathway, was that it was one of the few to depict the interaction between the 3 major genes within the 9p21 chromosomal region, CDKN2A , CDKN2B , and CDKN2B-AS1 . These genes have been consistently shown to be associated with the development of glaucoma in several GWAS and genotyping studies (Janssen et al, 2013; Ng et al, 2014). CDKN2B-AS1 encodes a long non-coding RNA (termed CDKN2B-AS1 or ANRIL) that is transcribed in the antisense direction of the CDKN2A-CDKN2B gene cluster, which encodes p16 (CDKN2A) and p15 (CDKN2B) proteins (Holdt et al, 2013; Jarinova et al, 2009; Visel et al, 2010).…”

Section: Pathway Analysis and Functional Annotationmentioning

confidence: 99%

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

Danford

Verkuil

Choi

et al. 2017

Progress in Retinal and Eye Research

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Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the “POAGome.” We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-β signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-β signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.

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“…The gene encoding p16INK4a , CDKN2A , lies within the INK4/ARF tumor suppressor locus on human chromosome 9p21; this is the most significant region to be identified as having an association with POAG in different population samples (Ng, Casson, Burdon, & Craig, ). Although the molecular mechanism of many of these associations is yet to be described, we have shown that one of them especially highly correlates with the presence of another top risk variant of glaucoma—Six6 rs33912345.…”

Section: Discussionmentioning

confidence: 99%

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

et al. 2019

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Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimics events occurring in human glaucoma. Senescence‐related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence‐associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix‐degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.

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Chromosome 9p21 primary open‐angle glaucoma susceptibility locus: a review

Cited by 37 publications

References 67 publications

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

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