Genetic risk factors and retinal ganglion cell degeneration in primary open-angle glaucoma (POAG): A bird’s eye view

Barkur S. Shastry

Department of Biological Sciences, Oakland University, Rochester, USA.

DOI: 10.4236/abb.2013.45082                

Abstract

Glaucoma is an optic neuropathy and often associated with elevated intraocular pressure (IOP). It is the second leading cause of irreversible blindness worldwide and is characterized by the optic nerve degeneration and loss of retinal ganglion cells (RGCs). This may lead to loss of vision. The primary cause of glaucoma is unknown but several risk factors including elevated IOP and age have been suggested. In most population, primary open-angle glaucoma (POAG) is the most common type of glaucoma and is often associated with elevated IOP. Genetic analyses have identified at least 14 chromosomal loci but only three genes which when mutated can cause POAG have been well documented. These genes account for less than 5% of all POAG cases suggesting that more than 90% of the genetic contribution of POAG cases is unknown. RGC consists of cell body, axon and dendritic arbor and each of these three parts can independently degenerate. Several molecular signals such as oxidative stress, mitochondrial dysfunction, disruption of neurotrophic factor (NTF), dysfunction of immune system, glial activation and the release of tumor necrosis factor (TNF) have been found to be involved in the optic nerve degeneration. Therefore, therapies aimed at axonal and cell body protection may have a greater protective role in early or progressive glaucoma. In the future, an understanding of gene-gene and gene-environmental factor interaction as well as epigenetic regulation of gene expression by environmental factors may provide an opportunity to develop neuroprotective therapies and DNA based diagnostic tests.

Keywords

Degeneration, Gene, Mutation, Retina

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Quigley, H. (1996) Number of people with glaucoma worldwide. British Journal of Ophthalmology, 80, 389393. doi:10.1136/bjo.80.5.389
[2]	Shastry, B.S. (2011) Genetic risk factors in glaucoma. In: Berhardt, L.E. Ed., Advances in Medicine and Biology, Nova Science Publishers, Inc., New York, 71-87.
[3]	Shastry, B.S. (2013) Genetic susceptibility to primary angle-closure glaucoma. Discovery Medicine, 15, 17-22.
[4]	Shastry, B.S. (2013) Genetic susceptibility to normal tension glaucoma. British Journal of Medicine and Medical Research, 3, 372-382.
[5]	Shastry, B.S. (2013) Emerging concept of genetic and epigenetic contributions to the manifestation of glaucoma. In: Rumelt, S., Ed., Glaucoma: Basic and Clinical Aspects, InTech Inc., Israel, in press.
[6]	Munemasa, Y. and Kitaoka, Y. (2012) Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection. Frontiers in Cellular Neuroscience, 6, 60-72.
[7]	Quigley, H. (1993) Open-angle glaucoma. New England Journal of Medicine, 328, 1097-1106. doi:10.1056/NEJM199304153281507
[8]	Fuse, N. (2010) Genetic bases of glaucoma. Tohoku Journal of Experimental Medicine, 221, 1-10. doi:10.1620/tjem.221.1
[9]	Anderson, D.R., Drance, S.M. and Schulzer, M. (2001) Natural history of normal tension glaucoma. Ophthalmology, 108, 247-253. doi:10.1016/S0161-6420(00)00518-2
[10]	Wiggs, J.L. (2012) The cell and molecular biology of complex forms of glaucoma: updates on genetic, environmental and epigenetic risk factors. Investigative Ophthalmology & Visual Science, 53, 2467-2469. doi:10.1167/iovs.12-9483e
[11]	Gottfredsdottir, M.S., Sverrisson, T., Musch, D.C., et al. (1999) Chronic open-angle glaucoma and associated ophthalmic findings in monozygotic twins and their spouses in Iceland. Journal of Glaucoma, 8, 134-139. doi:10.1097/00061198-199904000-00009
[12]	Teikari, J.M. (1990) Genetic influences in open-angle glaucoma. International Ophthalmology Clinic, 30, 161168. doi:10.1097/00004397-199030030-00003
[13]	Liu, Y. and Allingham, R.R. (2011) Molecular genetics in glaucoma. Experimental Eye Research, 93, 331-339. doi:10.1016/j.exer.2011.08.007
[14]	Fingert, J.H. (2011) Primary open-angle glaucoma genes. Eye, 25, 587-595. doi:10.1038/eye.2011.97
[15]	Fingert, J.H., Stone, E.M., Sheffield, V.C., et al. (2002) Myocilin glaucoma. Survey of Ophthalmology, 47, 547561. doi:10.1016/S0039-6257(02)00353-3
[16]	Thorleifsson, G., Walters, G.B., Hewitt, A.W., et al. (2010) Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nature Genetics, 42, 906-909. doi:10.1038/ng.661
[17]	Wiggs, J.L., Kang, J.H., Yaspan, B.L., et al. (2011) Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma in Caucasian from the United States. Human Molecular Genetics, 20, 4707-4713. doi:10.1093/hmg/ddr382
[18]	Burdon, K.P., Macgregor, S., Hewitt, A.W., et al. (2011) Genome wide association study identifies susceptibility loci for open-angle glaucoma at TMCO1 and CDKN2BAS1. Nature Genetics, 43, 574-578. doi:10.1038/ng.824
[19]	Wiggs, J.L., Yaspan, B.L., Hauser, M.A., et al. (2012) common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. Public Library of Science Genetics, 8, e1002654.
[20]	Abo-Amero, K.K. Kondkar, A.A., Mousa, A., et al. (2012) Lack of association of SNP rs 4236601 near CAV1 and CAV2 with POAG in a Saudi cohort. Molecular Vision, 18, 1960-1965.
[21]	Kuehn, M.H., Wang, K., Roos, B., et al. (2011) Chromosome 7q31 POAG locus: ocular expression of caveolins and lack of association with POAG in a US cohort. Molecular Vision, 17, 430-435.
[22]	Sethi, A., Mao, W., Wordinger, R.J., et al. (2011) Transforming growth factor beta induces extracellular matrix protein cross-linking lysyl oxidase (LOX) gene in human trabecular meshwork cells. Investigative Ophthalmology & Visual Science, 52, 5240-5250. doi:10.1167/iovs.11-7287
[23]	Joe, M.K. and Tomarrev, S.I. (2010) Expression of myocilin mutant sensitizes cells to oxidative stress induced apoptosis: Implications to glaucoma pathogenesis. American Journal of Pathology, 176, 2880-2890. doi:10.2353/ajpath.2010.090853
[24]	He, Y., Leung, K.W., Zhou, Y.H., et al. (2009) Pro370Leu mutant myocilin impairs mitochondrial function in human trabecular meshwork cells. Molecular Vision, 15, 815-825.
[25]	Joe, M.K., Sohn, S., Hur, W., et al. (2003) Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochemical Biophysical Research Communication, 312, 592-600. doi:10.1016/j.bbrc.2003.10.162
[26]	Chalasani, M.L., Radha, V., Gupta, V., et al. (2007) A glaucoma associated mutant optineurin selectively induces death of retinal ganglion cells which is inhibited by antioxidants. Investigative Ophthalmology & Visual Science, 48, 1607-1614. doi:10.1167/iovs.06-0834
[27]	Kato, K., Sasaki, N., Matsunaga, S., et al. (2007) Cloning of canine myocilin cDNA and molecular analysis of the myocilin gene in Shiba Inu dogs. Veterinary Ophthalmology, 10, 53-62. doi:10.1111/j.1463-5224.2007.00530.x
[28]	Kato, K., Kamida, A., Sasaki, N., et al. (2009) Evaluation of the CYP1B1 gene as a candidate gene in beagles with open-angle glaucoma. Molecular Vision, 15, 2470-2474.
[29]	Kato, K., Sasaki, N., Gelatt, K.N., et al. (2009) Autosomal recessive primary open-angle glaucoma (POAG) in beagles is not associated with mutations in myocilin (MYOC) gene. Graefes Archives of Clinical and Experiments Ophthalmology, 247, 1435-1436. doi:10.1007/s00417-009-1053-2
[30]	Kato, K., Sasaki, N. and Shastry, B.S. (2012) Retinal ganglion cell (RGC) death in glaucomatous beagles is not associated with mutations in p53 and NTF4 genes. Veterinary Ophthalmology, 15, 8-12. doi:10.1111/j.1463-5224.2012.01024.x
[31]	Kang, J.H., Wiggs, J.L., Rosener, B.A., et al. (2010) Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interaction with sex and postmenopausal hormone use. Investigative Ophthalmology & Visual Science, 51, 971-979. doi:10.1167/iovs.09-4266
[32]	Stein, J.D., Pasguale, L.R. and Talwar, N. (2011) Geographic and climatic factors associated with exfoliation syndrome. Archives of Ophthalmology, 129, 1053-1060. doi:10.1001/archophthalmol.2011.191
[33]	Ahmed, F., Brown, K.M., Stephan, D.A., et al. (2004) Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. Investigative Ophthalmology & Visual Science, 45, 12471258. doi:10.1167/iovs.03-1123
[34]	Huang, W., Fileta, J., Guo, Y. and Grosskreutz, C.L. (2006) Down regulation of Thy1 in retinal ganglion cells in experimental glaucoma. Current Eye Research, 31, 265271.
[35]	Weishaupt, J.H., Klocker, N. and Bahr, M. (2005) Axotomy induced early down regulation of POU-IV class transcription factors Brn-3a and Brn-3b in retinal ganglion cells. Journal of Molecular Neuroscience, 26, 17-25. doi:10.1385/JMN:26:1:017
[36]	Yan, Z., Qugley, H.A., Pease, M.E., et al. (2007) Changes in gene expression in experimental glaucoma and optic nerve transection: The equilibrium between protective and detrimental mechanisms. Investigative Ophthalmology & Visual Science, 48, 5539-5548. doi:10.1167/iovs.07-0542
[37]	Soto, I., Oglesby, E., Buckingham, B.P., et al. (2008) Retinal ganglion cells down regulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. Journal of Neuroscience, 28, 548-561. doi:10.1523/JNEUROSCI.3714-07.2008
[38]	Morgan, J.E. (2002) Retinal ganglion cell shrinkage in glaucoma. Journal of Glaucoma, 11, 365-370. doi:10.1097/00061198-200208000-00015
[39]	Pelzel, H.R., Schlamp, C.L. and Nickells, R.W. (2010) Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. Biomedical Central Neuroscience, 11, 62. doi:10.1186/1471-2202-11-62
[40]	Chen, B. and Cepko, C.L. (2007) Requirement of histone deacetylase activity for the expression of critical photoreceptor gene. Biomedical Central Developmental Biology, 7, 78.
[41]	Chen, B. and Cepko, C.L. (2009) HDAC4 regulates normal survival in normal and diseased retinas. Science, 323, 256-259. doi:10.1126/science.1166226
[42]	Gaub, P., Joshi, Y., Wuttke, A., et al. (2011) The histone acetyltransferase p300 promotes intrinsic axonal regeneration. Brain, 134, 2134-2148. doi:10.1093/brain/awr142
[43]	Nickells, R.W. (2012) The cell and molecular biology of glaucoma: Mechanisms of retinal ganglion cell death. Investigative Ophthalmology & Visual Science, 53, 24762481.
[44]	Almasieh, M., Wilson, A.M., Morquette, B., et al. (2012) The molecular basis of retinal ganglion cell death in glaucoma. Progress in Retinal and Eye Research, 31, 152-181. doi:10.1016/j.preteyeres.2011.11.002
[45]	Schlamp, C.L., Li, Y., Dietz, J.A., et al. (2006) Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. Biomedical Central Neuroscience, 7, 66. doi:10.1186/1471-2202-7-66
[46]	Howell, G.R., Libby, R.T., Jacobs, T.C., et al. (2007) Axons and retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. Journal of Cell Biology, 179, 1523-1537. doi:10.1083/jcb.200706181
[47]	Harder, J.M. and Libby, R.T. (2011) BBC3 (PUMA) regulates developmental apoptosis but not axonal injury induced death in the retina. Molecular Neurodegeneration, 6, 50. doi:10.1186/1750-1326-6-50
[48]	Morrison, J.C., Dormann-Pease, M.E., Dunkelberger, G.R., et al. (1990) Op-tic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma. Archives of Ophthalmology, 108, 1020-1024. doi:10.1001/archopht.1990.01070090122053
[49]	Martin, K.R., Quigley, H., Valenta, D., et al. (2006) Optic nerve dynein motor protein distribution changes with intraocular pressure elevation in a rat model of glaucoma. Experimental Eye Research, 83, 255-262. doi:10.1016/j.exer.2005.11.025
[50]	Tezel, G. and Wax, M.B. (2000) Increased production of tumor necrosis factor alpha by glial cell exposed to stimulated ischemia or elevated hydrostatic pressure induced apoptosis in cultured retinal ganglion cells. Journal of Neuroscience, 20, 8693-8700.
[51]	Kitaoka, Y., Kitaoka, Y., Kwong, J.M., et al. (2006) TNF-alpha induced optic nerve degeneration and nuclear factor kappa Bp65. Investigative Ophthalmology & Visual Science, 47, 1448-1457. doi:10.1167/iovs.05-0299
[52]	Yang, X., Luo, C., Cai, J., et al. (2011) Neurodegenerative and inflammatory pathway components linked to TNF-alpha/TNFR1 signaling in the glaucomatous human retina. Investigative Ophthalmology & Visual Science, 52, 8442-8454. doi:10.1167/iovs.11-8152
[53]	Doh, S.H., Kim, J.H., Lee, K.M., et al. (2010) Retinal ganglion cell death induced by endoplasmic reticulum stress in a chronic glaucoma model. Brain Research, 1308, 158-166. doi:10.1016/j.brainres.2009.10.025
[54]	Tezel, G. (2006) Oxidative stress in glaucomatous neurodegeneration: Mechanisms and consequences. Progress in Retinal and Eye Research, 25, 490-513. doi:10.1016/j.preteyeres.2006.07.003
[55]	Yuki, K., Ozawa, Y., Yoshida, T., et al. (2011) Retinal ganglion cell loss in superoxide dismutase 1 deficiency. Investigative Ophthalmology & Visual Science, 52, 41434150. doi:10.1167/iovs.10-6294
[56]	Lieven, C.J., Schlieve, C.R., Hoegger, M.J., et al. (2006) Retinal ganglion cell axotomy induces an increase in intracellular superoxide anion. Investigative Ophthalmology & Visual Science, 47, 1477-1485. doi:10.1167/iovs.05-0921
[57]	Minton, A.Z., Phatak, N.R., Stankowska, D.L., et al. (2012) Endothelin B receptors contribute to retinal ganglion cell loss in a rat model of glaucoma. Public Library of Science One, 7, e43199.
[58]	Tonari, M., Kurimoto, T., Horie, T., et al. (2012) Blocking endothelin B receptor rescues retinal ganglion cells from optic nerve injury through suppression of neuroinflammation. Investigative Ophthalmology & Visual Science, 53, 3490-3500. doi:10.1167/iovs.11-9415
[59]	Lau, J., Dang, M., Hockmann, K., et al. (2006) Effects of acute delivery of endothelin-1 on retinal ganglion cell loss in the rat. Experimental Eye Research, 82, 132-145. doi:10.1016/j.exer.2005.06.002
[60]	Dong, C.J., Guo, Y., Agey, P., et al. (2008) Alpha 2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. Investigative Ophthalmology & Visual Science, 49, 4515-4522. doi:10.1167/iovs.08-2078
[61]	Lam, T.T., Alber, A.S., Kwong, J.M., et al. (1999) N-methyl-D-aspartate (NMDA)–Induced apoptosis in rat retina. Investigative Ophthalmology & Visual Science, 40, 23912397.
[62]	Kuribayashi, J., Kitaoka, Y., Munemasa, Y., et al. (2010) Kinesin-1 and degenerative changes in optic nerve axons in NMDA-Induced neurotoxicity. Brain Research, 1362, 133-140. doi:10.1016/j.brainres.2010.09.053
[63]	Michalska-Malecka, K. and Slowinska-Lozynska, L. (2012) Aggregation and deformability of erythrocytes in primary open-angle glaucoma (POAG): The assessment of arterial hypertension. Clinical Hemorheology Microcirculation, 51, 277-285.
[64]	Mao, W., Rubin, J.S., Anoruo, N., et al. (2012) SFRP1 promoter methylation and expression in human trabecular meshwork cells. Experimental Eye Research, 97, 130-136. doi:10.1016/j.exer.2012.01.003