GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

K. Saidas Nair, Chitrangda Srivastava, Robert V. Brown, Swanand Koli, Hélène Choquet, Hong Soon Kang, Yien-Ming Kuo, Sara A. Grimm, Caleb Sutherland, Alexandra Badea, G. Allan Johnson, Yin Zhao, Jie Yin, Kyoko Okamoto, Graham Clark, Terete Borrás, Gulab Zode, Krishnakumar Kizhatil, Subhabrata Chakrabarti, Simon W. M. John, Eric Jorgenson and Anton M. Jetten ()
Additional contact information
K. Saidas Nair: University of California, San Francisco
Chitrangda Srivastava: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Robert V. Brown: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Swanand Koli: University of California, San Francisco
Hélène Choquet: Kaiser Permanente Northern California, Division of Research
Hong Soon Kang: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Yien-Ming Kuo: University of California, San Francisco
Sara A. Grimm: Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health
Caleb Sutherland: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Alexandra Badea: Duke University
G. Allan Johnson: Duke University
Yin Zhao: University of California, San Francisco
Jie Yin: Kaiser Permanente Northern California, Division of Research
Kyoko Okamoto: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health
Graham Clark: The Jackson Laboratory
Terete Borrás: University of North Carolina School of Medicine
Gulab Zode: University of North Texas Health Science Center
Krishnakumar Kizhatil: The Jackson Laboratory
Subhabrata Chakrabarti: Brien Holden Eye Research Centre, L. V. Prasad Eye Institute
Simon W. M. John: The Jackson Laboratory
Eric Jorgenson: Regeneron Pharmaceuticals, Inc
Anton M. Jetten: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10−6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

Date: 2021
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DOI: 10.1038/s41467-021-25181-7

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