AUTHOR=Stiemke Andrew B. , Sah Eric , Simpson Raven N. , Lu Lu , Williams Robert W. , Jablonski Monica M. 

TITLE=Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.00031

DOI=10.3389/fgene.2020.00031

ISSN=1664-8021

ABSTRACT=<p>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 (<italic>p</italic> genome-wide ~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including <italic>Gpnmb</italic>, <italic>Tyrp1, Cdh11, Pou6f2,</italic> and <italic>Cacna2d1</italic>. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes—<italic>CDC42 binding protein kinase beta</italic> (<italic>Cdc42bpb</italic>); <italic>eukaryotic translation initiation factor 5</italic> (<italic>Eif5</italic>); <italic>BCL2-associated athanogene 5</italic> (<italic>Bag5</italic>); <italic>apoptogenic 1, mitochondrial</italic> (<italic>Apopt1</italic>); <italic>kinesin light chain 1</italic> (<italic>Klc1</italic>); <italic>X-ray repair cross complementing 3</italic> (<italic>Xrcc3</italic>); <italic>protein phosphatase 1, regulatory subunit 13B</italic> (<italic>Ppp1r13b</italic>); and <italic>transmembrane protein 17</italic>9 (<italic>Tmem179</italic>)—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 &gt;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.</p>