This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.

 

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    Glaucoma is a multi-factorial eye disease in which the intraocular pressure (IOP) of the eye elevates to a point where the optic nerve, the main pathway by which vision information is sent to the brain, becomes irreversibly damaged.  Elevated IOP is caused by a build up of excess fluid in the eye that does not drain properly.  As the fibers of the optic nerve are damaged by increased pressure, both the amount and quality of information sent to the brain decreases and vision loss occurs (3), gradually causing "tunnel vision."  Unfortunately, glaucoma has no warning signs or symptoms and often individuals do not know they have the disease until vision loss has already occurred which is why many refer to it as the "silent eye disease."  Currently, glaucoma is designated as the second highest cause of blindness worldwide as it affects nearly 70 million people (1).  It is estimated that this number will rise to somewhere near 80 million by the year 2020 (2).  The prevalence of glaucoma is greater among blacks (4.7%) than whites and produces damage at an earlier age and induces blindness at a greater rate for them as well (3).  Additionally, in India, glaucoma is the cause of roughly 12.8% of total blindness, affecting 12 million people (2).
     The most common form of glaucoma is primary open angle glaucoma (POAG).  POAG is typically associated with an IOP that consistently remains above 22 mm Hg (normal range: 10-21 mm Hg); however, POAG can also occur when pressure lies within the normal range but optic nerve damage can still take place (1).  Many genes have been attributed to POAG, each with varying levels of effect, revealing the complexity of this disease.  Of the 25 chromosomal loci that have been linked to POAG, only mutations in the following four genes have been identified in POAG: MYOC, OPTN, WDR36, and NTF4 (2).
    The MYOC gene encodes for the protein, myocilin.  Myocilin, a secretory protein of 504 amino acids (7), is found in two structures of the eye that regulate IOP, trabecular meshwork and the ciliary body (6) as well as the sclera, choroid, cornea, iris, lamina cribosa, retina, and optic nerve (2).  As for non-ocular expression of myocilin, this protein is found in various types of muscles, the small intestine, thymus, prostate, stomach, trachea, bone marrow, and brain to name a few (2); however, overall, its function is not yet well characterized (6).  The structure of the MYOC gene involves two introns and a promoter region that separate three exons which contain the coding information (7).  MYOC also consists of two major domains.  One of these domains is a myosin-like domain near the N-terminus and the other is an olfactomedin-like domain near the C-terminus (2).  Mutations in MYOC accounts for 2-5% of POAG patients worldwide (2) as MYOC polymorphisms tend to increase the IOP in POAG patients (1).  Most mutations in MYOC that have been linked to glaucoma are missense mutations and have been mapped to exon 3 (see figure below).  Elevation of IOP may also be due to an obstruction of outflow caused by an accumulation of myocilin in the extracellular matrix (7). 



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Fig. 1 - The distrubution of disease-causing mutations across the MYOC gene.  The boxes are representative of myocilin's three exons separated by introns (lines) (8).

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Fig. 2 - Intraocular eye pressure builds up and forces stress on the optic nerve.
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Fig. 3 - Excess fluid builds up in the eye if drainage pathways become blocked.
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References:
1. Fuse, Nobuo. "Genetic Bases for Glaucoma." 
The Tohoku Journal of Experimental Medicine 221 (2010): 1-10. PubMed. Web. 22 Jan. 2011
http://www.jstage.jst.go.jp/article/tjem/221/1/1/_pdf
2. Rao, Kollu N., Srujana Nagireddy, and Subhabrata Chakrabarti. "Complex Genetic Mechanisms in Glaucoma: An Overview." 
Indian Journal of Opthamology 59.7 (2011): 31-42. PubMed. Web. 22 Jan. 2011.
http://www.ijo.in/article.asp?issn=0301-4738;year=2011;volume=59;issue=7;spage=31;epage=42;aulast=Rao 
3.  American Optometric Association. 
Answers To Your Questions About Glaucoma. St. Louis: American Optometric Association. Print.
4.  http://www.forbes.com/2009/06/26/life-saving-devices-technology-personal-monitors_slide_7.html
5.  http://www.youtube.com/watch?v=OJMEfGFbFMI
6.  "MYOC - Myocilin, Trabecular Meshwork Inducible Glucocorticoid Response - Genetics Home Reference." Genetics Home Reference - Your Guide to Understanding Genetic Conditions. 6 Feb. 2011. Web. 08 Feb. 2011. http://ghr.nlm.nih.gov/gene/MYOC
7.  Saura, Maria, Montse Cabana, Carmen Ayuso, and Diana Valverde. "European Journal of Human Genetics - Mutations including the Promoter Region of Myocilin//TIGR Gene." Nature Publishing Group : Science Journals, Jobs, and Information. 13 Oct. 2004. Web. 08 Feb. 2011. http://www.nature.com/ejhg/journal/v13/n3/full/5201299a.html
8.  Fingert, John H., Elise Heon, Jefferey M. Liebmann, Tetsuya Yamamoto, Jaime E. Craig, Julian Rait, Kazuhide Kawase, Sek-Tien Hoh, Yvonne M. Buys, Joanne Dickinson, Robin R. Hockey, Donna Williams-Lyn, Graham Trope, Yoshiaki Kitazawa, Robert Ritch, David A. Mackey, Wallace L.M. Alward, Val C. Sheffield, and Edwin M. Stoned. "Analysis of Myocilin Mutations in 1703 Glaucoma Patients From Five Different Populations — Hum Mol Genet." Oxford Journals | Life Sciences & Medicine | Human Molecular Genetics. 14 Mar. 1999. Web. 08 Feb. 2011. http://hmg.oxfordjournals.org/content/8/5/899.full
9. McMahon, C., Semina, E.V., Link, B.A. "Using zebrafish to study the complex genetics of glaucoma." Comparative Biochemistry and Physiology Part C: Toxicology and Parmacology. vol 138-3. July 2004. Web. 24 Feb 2011. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W89-4CDJG6X-1&_user=443835&_coverDate=07%2F31%2F2004&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000020958&_version=1&_urlVersion=0&_userid=443835&md5=525db1a96bf7be7620dabbcd34c426f9&search#toc2
10. Kubota, R., Noda, S., Wang, Y., Minoshima, S., Asakawa, S., Kudoh, J., Mashima, Y., Oguchi, Y., Shimizu, N. "A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression, and chromosomal mapping." Genomics. vol 41-3.1 May 1997, Pages 360-369 Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan. http://www.sciencedirect.com.ezproxy.library.wisc.edu/science?_ob=ArticleURL&_udi=B6WG1-45M8YTG-C5&_user=443835&_coverDate=05%2F01%2F1997&_rdoc=1&_fmt=high&_orig=gateway&_origin=gateway&_sort=d&_docanchor=&view=c&_acct=C000020958&_version=1&_urlVersion=0&_userid=443835&md5=1562ae0f98031b9d89c1c8377a859b1e&search





Katy Potts
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Last updated 05-15-2011

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