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. JohnEric Jorgenson, Anton M. Jetten

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number4877
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

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