A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis

Yeming Yang,Xiao Li,Bo Chang,Patsy M Nishina,Xianjun Zhu,Bernie Fitzmaurice,Xuyang Liu,Wenjing Liu,Jieping Wang,Junkai Tan,Kuanxiang Sun,Wanli Tian

doi:10.1038/s41419-021-04331-1

Abstract

Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotypes and for developing therapeutic strategies. Here, we report the discovery of a new mouse model of early-onset glaucoma that bears a transversion substitution c. G344T, which results in a missense mutation, p. R115L in PITX2. The mutation causes an elevation in intraocular pressure (IOP) and progressive death of retinal ganglion cells (RGC). These ocular phenotypes recapitulate features of pathologies observed in human glaucoma. Increased oxidative stress was evident in the inner retina. We demonstrate that the mutant PITX2 protein was not capable of binding to Nuclear factor-like 2 (NRF2), which regulates Pitx2 expression and nuclear localization, and to YAP1, which is necessary for co-initiation of transcription of downstream targets. PITX2-mediated transcription of several antioxidant genes were also impaired. Treatment with N-Acetyl-L-cysteine exerted a profound neuroprotective effect on glaucoma-associated neuropathies, presumably through inhibition of oxidative stress. Our study demonstrates that a disruption of PITX2 leads to glaucoma optic pathogenesis and provides a novel early-onset glaucoma model that will enable elucidation of mechanisms underlying the disease as well as to serve as a resource to test new therapeutic strategies.

Highlights

Glaucoma, affecting 70 million people worldwide, is a group of neurodegenerative diseases characterized by the progressive death of retinal ganglion cells (RGCs) and atrophic excavation of the optic nerve, resulting in irreversible loss of vision [1, 2]
intraocular pressure (IOP) is maintained through a balance between aqueous humor secretion, by the ciliary body (CB), and drainage through the trabecular meshwork (TM), a porous tissue located in the iridocorneal angle [5]
Taken together, based on the transcriptome results, we propose that the rapid RGC loss and optic nerve (ON) dystrophy in mutant retina results from the elevated IOP caused by anterior segment dysgenesis, and to the compromised antioxidant capacity caused by impaired PITX2 transcriptional activity of antioxidant genes

Summary

Introduction

Glaucoma, affecting 70 million people worldwide, is a group of neurodegenerative diseases characterized by the progressive death of retinal ganglion cells (RGCs) and atrophic excavation of the optic nerve, resulting in irreversible loss of vision [1, 2]. An increased resistance to aqueous humor drainage can arise from developmental malformations of ocular structures and lead to early-onset glaucoma. Early-onset glaucoma cases generally have strong genetic contributions and many disease-causing mutations that lead to pathogenesis have been identified [6]. It should be noted that glaucoma is a complex, heterogeneous disease likely to be the consequence of the interaction of multiple genes This underlying complexity may hinder efforts to identify glaucoma-associated genes (or related mutations) and to uncover their pathogenic mechanisms. Identification of monogenic murine glaucoma models, may assist in addressing both of these issues To this end, the Eye Mutant Resource screening program at The Jackson Laboratory (JAX) identified a glaucoma model caused by a mutation in Pitx

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Results

Conclusion