Abstract
Purpose :
Glaucoma is a multifactorial, neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs), optic nerve (ON) damage, and subsequent vision loss. Current treatment regimens focus on lowering intraocular pressure (IOP); however, it is known that some patients continue to experience RGC death despite adequate IOP reduction, suggesting that glaucoma is influenced by myriad genetic factors. It is crucial to identify alternative therapeutics to halt the progression of RGC death for more effective glaucoma prevention and treatment.
Methods :
We use systems genetics analysis to identify a quantitative trait locus (QTL) that modulates the number of live and evidently healthy axons in optic nerves of a large family of recombinant inbred strains. Within that QTL, we also define a set of high priority positional candidate genes, a subset of which are likely to modulate ON resilience and health, based on stringent criteria. A large cohort of the BXD family was aged to between 13 and 19 months of age. ONs from 75 BXD strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of intact axons per ON cross-section were counted and averaged for each strain (GeneNetwork trait BXD_24793). ON and retina sections were stained for Nphp3 localization using immunohistochemistry.
Results :
Numbers of intact axons per nerve ranged from 25,000 to more than 77,000. Linear mixed model mapping defines a locus on chromosome 9 between 97.27 and 106.02 Mb with a –logP linkage of 4.88. Of 850 positional candidates, one gene—nephronophthisis 3 (Nphp3)—passed stringent criteria and is highlighted here as a high priority candidate for follow-up analyses. Overall, this gene was significantly correlated with a higher number of intact axons per ON and a protective D allele effect.
Conclusions :
Systems genetics has identified Nphp3 as a key player in ON axon health in BXD mice. Nphp3 is a ciliary protein implicated in inherited kidney disease leading to end-stage renal failure. Nephronophthisis is a group of inherited disorders that also exhibit retinal degeneration, and cilia play a role in IOP regulation by trabecular meshwork cells. Cilia have also been found to be essential to RGC axonal regeneration following axotomy. Further investigation should take an interest in the role of Nphp3 and cilia in conferring resilience to glaucomatous ON damage.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.