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Saidas Nair, Chitrangda Srivastava, Swanand Koli, Hong Soon Kang, Yien-Ming Kuo, Helene Choquet, Alexandra Badea, Eric Jorgenson, Anton Jetten; Krüppel-like zinc finger transcription factor GLIS1 regulates intraocular pressure by maintaining trabecular meshwork function. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2742.
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Genome-wide association study (GWAS) previously conducted by both us and others have detected an association of GLIS3 variants with high intraocular pressure (IOP) and primary angle-closure glaucoma. These findings provided the basis for determining the potential contribution of GLIS3 along with other GLIS family members in the pathogenesis of glaucoma. To this end, we characterized the glaucoma relevant phenotypes of mouse mutants representing all three Krüppel-like zinc finger transcriptional factor GLI-similar (GLIS), of these Glis1 deficient mice exhibited elevated IOP, a major risk factor of glaucoma. Here, we have characterized the role of GLIS1 in the pathogenesis of elevated IOP and glaucoma.
Glis1-deficient mice (Glis1-KO) and wild-type (WT) mice were aged and their IOP measured between ages 1 to 10 months employing a Tonolab. Aqueous humor (AqH) outflow was monitored in vivo employing the Gadolinium (Gd)-enhanced MRI. Histological and electron microscopy examination was performed to assess the structural and morphological changes of the ocular drainage tissues due to the loss of GLIS1 function. Glis1 expression was assessed in the ocular tissues by qPCR and RNAscope in situ hybridization. RNA-Seq analysis of ocular drainage tissue from Glis1-KO and WT mice was performed to identify potential downstream targets of Glis1. Finally, we determined the association of GLIS1 SNPs with primary open-angle glaucoma (POAG) utilizing a combined GERA and UK-Biobank cohorts.
Here, we demonstrate that Glis1-KO mice develop elevated IOP starting as early as at 2 months of age. The Gd-enhanced MRI revealed that reduced AqH drainage contributed to elevated IOP. Histopathological analysis showed progressive degeneration and dysfunction of the trabecular meshwork (TM), a tissue in which Glis1 is highly expressed. RNA-Seq analysis provided insight into Glis1 dependent pathways needed for proper maintenance of the TM layer. Finally, we found a significant association of a GLIS1 SNP, rs941125 with POAG.
Our study identifies transcription factor GLIS1 as a novel and critical regulator of TM function and maintenance, AqH dynamics, and IOP. Overall, our data suggest that the risk allele of human GLIS1 confers susceptibility towards developing POAG likely by impacting the TM layer and contributing to elevated IOP.
This is a 2020 ARVO Annual Meeting abstract.
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