Ocular Expression and Distribution of Products of the POAG-Associated Chromosome 9p21 Gene Region

Glyn Chidlow,Jamie E Craig,David P Dimasi,Shiwani Sharma,Kathryn P Burdon,John P M Wood,Robert J Casson,Balraj Mittal

doi:10.1371/journal.pone.0075067

Glyn Chidlow, Jamie E Craig + Show 6 more

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https://doi.org/10.1371/journal.pone.0075067

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Abstract

It has recently been shown that there are highly significant associations for common single nucleotide polymorphisms (SNPs) near the CDKN2B-AS1 gene region at the 9p21 locus with primary open angle glaucoma (POAG), a leading cause of irreversible blindness. This gene region houses the CDKN2B/p15INK4B , CDKN2A/p16INK4A and p14ARF (rat equivalent, p19ARF) tumour suppressor genes and is adjacent to the S-methyl-5′-thioadenosine phosphorylase (MTAP) gene. In order to understand the ocular function of these genes and, therefore, how they may be involved in the pathogenesis of POAG, we studied the distribution patterns of each of their products within human and rat ocular tissues. MTAP mRNA was detected in the rat retina and optic nerve and its protein product was localised to the corneal epithelium, trabecular meshwork and retinal glial cells in both human and rat eyes. There was a very low level of p16INK4A mRNA present within the rat retina and slightly more in the optic nerve, although no protein product could be detected in either rat or human eyes with any of the antibodies tested. P19ARF mRNA was likewise only present at very low levels in rat retina and slightly higher levels in the optic nerve. However, no unambiguous evidence was found to indicate expression of specific P19ARF/p14ARF proteins in either rat or human eyes, respectively. In contrast, p15INK4B mRNA was detected in much higher amounts in both retina and optic nerve compared with the other genes under analysis. Moreover, p15INK4B protein was clearly localised to the retinal inner nuclear and ganglion cell layers and the corneal epithelium and trabecular meshwork in rat and human eyes. The presented data provide the basis for future studies that can explore the roles that these gene products may play in the pathogenesis of glaucoma and other models of optic nerve damage.

Highlights

Glaucoma is a leading cause of irreversible blindness and manifests as an age-related, progressive optic neuropathy with a poorly understood pathogenesis and limited treatment options [1]
There was a broadly similar level of methyl-59-thioadenosine phosphorylase (MTAP) mRNA across the different tissues
In light of previous work defining the importance of gene products from the 9p21 locus in diseases such as coronary heart disease [21,22,23], diabetes [21,46], atherosclerosis [26] and cancer [24,25], the systematically validated discovery that single nucleotide polymorphisms (SNPs) from this region are associated with primary open-angle glaucoma (POAG) is of great significance [7,8,11,12,13,14,15,16,17,18,19,20]

Summary

Introduction

Glaucoma is a leading cause of irreversible blindness and manifests as an age-related, progressive optic neuropathy with a poorly understood pathogenesis and limited treatment options [1]. It affects approximately 2.5% of the general population over 40 years of age, with the prevalence increasing exponentially thereafter [2,3]. The most common form of glaucoma is primary open-angle glaucoma (POAG), which has a poorly understood cause and pathogenesis but which makes up approximately 74% of all cases [3] This particular form of glaucoma is usually treated by lowering intraocular pressure (IOP).

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