Open angle glaucoma in soluble guanylate cyclase α1-deficient mice and its association with the GUCY1A3/GUCY1B3 locus in humans

Abstract

Primary open angle glaucoma (POAG) is a leading cause of blindness, due to irreversible retinal ganglion cell (RGC) loss with optic nerve (ON) degeneration. Currently, there is no cure for POAG and available therapies offer incomplete protection, highlighting the need for novel drug targets. Although several POAG risk factors have been identified, including elevated intraocular pressure (IOP) and genetic factors, the molecular signaling pathways involved remain largely unknown. Impaired nitric oxide (NO) signaling has been implicated in the pathogenesis of POAG. Here, we report that mice lacking the α 1 subunit of the NO receptor soluble guanylate cyclase (sGC α 1 - / - mice) represent a novel animal model of POAG. sGC α 1 - / - mice develop moderate increases in IOP, a decrease in aqueous humor outflow rate, thinning of the retinal nerve fiber layer (RNFL), and loss of ON axons in the context of an open iridocorneal angle, all features of POAG. Importantly, a targeted gene association study in POAG patients with incident paracentral vision loss, a subtype of POAG thought to be associated with vascular dysregulation, identified a locus containing the genes encoding the α 1 and β 1 subunits of sGC. Our findings provide new insights into the genetics and biology of POAG, demonstrating that a well-characterized signaling pathway (NO-cGMP) is involved in the pathogenesis of POAG. In addition, identifying sGC α 1 - / - mice as a unique model for POAG, provides a tool for investigators to test new strategies for disease prevention, potentially informing the clinical development of existing cGMP-elevating therapeutic compounds for treatment of POAG.