Loss of PRSS56 function leads to ocular angle defects and increased susceptibility to high intraocular pressure

Abstract

Glaucoma is a leading cause of blindness affecting up to million people worldwide. High intraocular pressure (IOP) is a major risk factor for glaucoma. Inefficient aqueous humor (AqH) outflow resulting from structural or functional alterations in ocular drainage tissues are well established to cause high IOP, but the genes and pathways involved are poorly understood. We previously demonstrated that mutations in the gene encoding the serine protease PRSS56 induces ocular angle-closure and high IOP in mice and identified reduced ocular axial length as a potential contributing factor. Here we show that Prss56-/mice also exhibits an abnormal iridocorneal angle configuration characterized by a posterior shift of ocular drainage structures relative to the ciliary body and iris. Notably, we show that retina-derived PRSS56 is required between postnatal days 13 and 18 for proper iridocorneal configuration and that abnormal positioning of the ocular drainage tissues is not dependent on ocular size reduction in Prss56-/mice. Furthermore, we demonstrate that the genetic context modulates the severity of IOP elevation in Prss56 mutant mice and describe a progressive degeneration of ocular drainage tissues that likely contributes to the exacerbation of the high IOP phenotype observed on the C3H/HeJ genetic background. Finally, we identified five rare PRSS56 variants associated with human primary congenital glaucoma, a condition characterized by abnormal development of the ocular drainage structures. Collectively, our findings point to a role for PRSS56 in the development and maintenance of ocular drainage tissues and IOP homeostasis, and provide new insights into glaucoma pathogenesis.

Quantification and image-derived phenotyping of retinal ganglion cell nuclei in theneemouse model of congenital glaucoma

“…Several mouse models relevant to early onset developmental forms of glaucoma have been described (Akula et al, 2020;Chang et al, 2001;Chen and Gage, 2016;Ishibashi et al, 1999;Iwao et al, 2009;Kroeber et al, 2010;Labelle-Dumais et al, 2020;Lachke et al, 2011;Smith et al, 2000;Thomson et al, 2017;Tolman et al, 2021). Among them, many studies have focused on phenotypes of the anterior segment and there have been relatively few in depth studies of RGC damage.…”

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

“…Samples were embedded in glycol methacrylate, and serial sagittal sections (2 μm) passing through the optic nerve were cut and stained with hematoxylin and eosin (H&E). Ten similarly spaced sections corresponding to the peripheral, mid- peripheral and central regions (passing through the optic nerve) of the eye were evaluated 81 . Both angles of a section were considered for evaluation.…”

“…Ten similarly spaced sections corresponding to the peripheral, mid-peripheral and central regions (passing through the optic nerve) of the eye were evaluated 81 . Both angles of a section were considered for evaluation.…”

Updates on Genes and Genetic Mechanisms Implicated in Primary Angle-Closure Glaucoma

“… 204 Furthermore, Prss56 -/- mice have been recently shown to exhibit ocular angle defects and increased risk of high IOP. 205 The study suggested a critical role for PRSS56 in the development and maintenance of ocular drainage tissues and IOP homeostasis. 205 …”

“… 205 The study suggested a critical role for PRSS56 in the development and maintenance of ocular drainage tissues and IOP homeostasis. 205 …”