Abstract
In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve cross-section were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of ~18.5 (p genome-wide ~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes—CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)—passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.
Highlights
Glaucoma is a complex, multifactorial, neurodegenative disease that targets axons of retinal ganglion cells (RGCs) and is the leading cause of irreversible blindness worldwide (Standefer, 2004)
Damage to the optic nerve (ON), which is comprised of the axons of RGCs, leads to loss of visual field in glaucoma
In the D2 parent mutations in Tyrp1 and Gpnmb have been reported as being causative for the pigmentary dispersion glaucoma that leads to ON damage (John et al, 1998)
Summary
Multifactorial, neurodegenative disease that targets axons of retinal ganglion cells (RGCs) and is the leading cause of irreversible blindness worldwide (Standefer, 2004). Intraocular pressure (IOP) is a major contributing factor to glaucoma, elevated IOP is not detectable in all cases. In POAG, optic nerve (ON) axonal damage and IOP are highly heritable, and the genetic risk of elevated IOP and POAG are partially shared (Van Koolwijk et al, 2007; Carbonaro et al, 2008). It is highly likely that a subset of gene variants modulate the risk of RGC axon damage in an independent manner, and thereby directly affect the onset of glaucoma, rate of axon necrosis, and response to therapeutic interventions such as nicotinamide (Williams et al, 2017). Identification of additional sequence variants, and associated molecular and cellular processes that modulate glaucoma endophenotypes in animals and humans can definitely provide critical insights, as well as new targets for therapeutic intervention (Chintalapudi et al, 2017)
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