Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

histopathological analysis of the trabecular meshwork of affected patients. Still, despite the fact that the causative role of mutant myocilin for some forms of glaucoma is known for 10 years, such data are currently missing.

REFERENCES

1.Stone, E. M., Fingert, J. H., Alward, W. L. M., Nguyen, T. D., Polansky, J. R., Sunden, S. L. F., Nishimura, D., Clark, A. F., Nystuen, A., Nichols, B. E., Mackey, D. A., Ritch, R., Kalenak, J. W., Craven, E. R. & Sheffield, V. C. (1997). Identification of a gene that causes primary open angle glaucoma. Science 275, 668–670.

2.Tamm, E. R. (2002). Myocilin and glaucoma: facts and ideas. Prog. Retin. Eye Res. 21, 395–428.

3.Tamm, E. R. & Polansky, J. (2001). The TIGR/MYOC gene and glaucoma: opportunities for new understandings. J. Glaucoma 10(Suppl 1), S9–S12.

4.Tamm, E. R. & Russell, P. (2001). The role of myocilin/TIGR in glaucoma. Results of the Glaucoma Research Foundation Catalyst Meeting in Berkeley, CA, March 2000. J. Glaucoma 10, 329–339.

5.Adam, M. F., Belmouden, A., Binisti, P., Brézin, A. P., Valtot, F., Béchetoille, A., Dascotte, J. -C., Copin, B., Gomez, L., Chaventre, A., Bach, J. -F. & Garchon, H. -J. (1997). Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma. Hum. Mol. Gen. 12, 2091–2097.

6.Swiderski, R. E., Ross, J. L., Fingert, J. H., Clark, A. F., Alward, W. L., Stone, E. M. & Sheffield, V. C. (2000). Localization of MYOC transcripts in human eye and optic nerve by in situ hybridization. Invest. Ophthalmol. Vis. Sci. 41, 3420–3428.

7.Karali, A., Russell, P., Stefani, F. H. & Tamm, E. R. (2000). Localization of myocilin/trabecular meshwork inducible glucocorticoid response protein in the human eye.

Invest. Ophthalmol. Vis. Sci. 41, 729–740.

8.Tamm, E., Russell, P., Epstein, D. L., Johnson, D. H. & Piatigorsky, J. (1999). Modulation of myocilin/TIGR expression in human trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 40, 2577–2582.

9.Tomarev, S. I., Wistow, G., Raymond, V., Dubois, S. & Malyukova, I. (2003). Gene expression profile of the human trabecular meshwork: NEIBank sequence tag analysis.

Invest. Ophthalmol. Vis. Sci. 44, 2588–2596.

10.Ohlmann, A., Goldwich, A., Flügel-Koch, C., Fuchs, A. V., Schwager, K. & Tamm, E. R. (2003). Secreted glycoprotein myocilin is a component of the myelin sheath in peripheral nerves. Glia 43, 128–140.

11.Goldwich, A., Baulmann, D. C., Ohlmann, A., Flugel-Koch, C., Schocklmann, H. & Tamm, E. R. (2005). Myocilin is expressed in the glomerulus of the kidney and induced in mesangioproliferative glomerulonephritis. Kidney Int. 67, 140–151.

12.Noda, S., Mashima, Y., Obazawa, M., Kubota, R., Oguchi, Y., Kudoh, J., Minoshima, S. & Shimizu, N. (2000). Myocilin expression in the astrocytes of the optic nerve head. Biochem. Biophys. Res. Commun. 276, 1129–1135.

13.Ricard, C. S., Agapova, O. A., Salvador-Silva, M., Kaufman, P. L. & Hernandez, M. R. (2001). Expression of myocilin/TIGR in normal and glaucomatous primate optic nerves.

Exp. Eye Res. 73, 433–447.

14.Ortego, J., Escribano, J. & Coca-Prados, M. (1997). Cloning and characterization of subtracted cDNAs from human ciliary body library encoding TIGR, a protein involved in juvenile open angle glaucoma with homology to myosin and olfactomedin. FEBS Lett. 413, 349–353.

15.Nguyen, T. D., Chen, P., Huang, W. D., Chen, H., Johnson, D. & Polansky, J. R. (1998). Gene structure and properties of TIGR, an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells. J. Biol. Chem. 273, 6341–6350.

16.Fingert, J. H., Ying, L., Swiderski, R., Nystuen, A. M., Arbour, N. C., Alward, W. L. M., Sheffiled, V. C. & Stone, E. M. (1998). Characterization and comparison of the human and mouse GLC1A glaucoma genes. Genome Res. 8, 377–384.

17.Swiderski, R. E., Ying, L., Cassell, M. D., Alward, W. L., Stone, E. M. & Sheffield, V. C. (1999). Expression pattern and in situ localization of the mouse homologue of the human MYOC (GLC1A) gene in adult brain. Brain Res. Mol. Brain Res. 68, 64–72.

18.Clark, A. F., Kawase, K., English-Wright, S., Lane, D., Steely, H. T., Yamamoto, T., Kitazawa, Y., Kwon, Y. H., Fingert, J. H., Swiderski, R. E., Mullins, R. F., Hageman, G. S., Alward, W. L., Sheffield, V. C. & Stone, E. M. (2001). Expression of the glaucoma gene myocilin (MYOC) in the human optic nerve head. FASEB J. 15, 1251–1253.

19.Knaupp, C., Flügel-Koch, C., Goldwich, A., Ohlmann, A. & Tamm, E. R. (2004). The expression of myocilin during murine eye development. Graefes Arch. Clin. Exp. Ophthalmol. 242, 339–345.

20.Takahashi, H., Noda, S., Imamura, Y., Nagasawa, A., Kubota, R., Mashima, Y., Kudoh, J., Oguchi, Y. & Shimizu, N. (1998). Mouse myocilin (Myoc) gene expression in ocular tissues. Biochem. Biophys. Res. Commun. 248, 104–109.

21.Torrado, M., Trivedi, R., Zinovieva, R., Karavanova, I. & Tomarev, S. I. (2002). Optimedin: a novel olfactomedin-related protein that interacts with myocilin. Hum. Mol. Genet. 11, 1291–1301.

22.Ahmed, F., Torrado, M., Johnson, E., Morrison, J. & Tomarev, S. I. (2001). Changes in mRNA levels of the Myoc/Tigr gene in the rat eye after experimental elevation of intraocular pressure or optic nerve transection. Invest. Ophthalmol. Vis. Sci. 42, 3165–3172.

23.Tomarev, S. I., Tamm, E. R. & Chang, B. (1998). Characterization of the mouse myoc/tigr gene. Biochem. Biophys. Res. Commun. 245, 887–893.

24.Taguchi, M., Kanno, H., Kubota, R., Miwa, S., Shishiba, Y. & Ozawa, Y. (2000). Molecular cloning and expression profile of rat myocilin. Mol. Genet. Metab. 70, 75–80.

25.Abderrahim, H., Jaramillo-Babb, V. L., Zhou, Z. & Vollrath, D. (1998). Characterization of the murine TIGR/myocilin gene. Mamm. Genome 9, 673–675.

26.Mertts, M., Garfield, S., Tanemoto, K. & Tomarev, S. I. (1999). Identification of the region in the N-terminal domain responsible for the cytoplasmic localization of Myoc/Tigr and its association with microtubules. Lab. Invest. 79, 1237–1245.

27.Kubota, R., Noda, S., Wang, Y., Minoshima, S., Asakawa, S., Kudoh, J., Mashima, Y., Oguchi, Y. & Shimizu, N. (1997). A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression and chromosomal mapping. Genomics 41, 360–369.

28.Wentz-Hunter, K., Ueda, J., Shimizu, N. & Yue, B. Y. (2002). Myocilin is associated with mitochondria in human trabecular meshwork cells. J. Cell Physiol. 190, 46–53.

29.Ueda, J., Wentz-Hunter, K. K., Cheng, E. L., Fukuchi, T., Abe, H. & Yue, B. Y. (2000). Ultrastructural localization of myocilin in human trabecular meshwork cells and tissues. J. Histochem. Cytochem. 48, 1321–1330.

30.Wentz-Hunter, K., Ueda, J. & Yue, B. Y. (2002). Protein interactions with myocilin. Invest. Ophthalmol. Vis. Sci. 43, 176–182.

31.Gobeil, S., Rodrigue, M. A., Moisan, S., Nguyen, T. D., Polansky, J. R., Morissette, J. & Raymond, V. (2004). Intracellular sequestration of hetero-oligomers formed by wild-type and glaucoma-causing myocilin mutants. Invest. Ophthalmol. Vis. Sci. 45, 3560–3567.

32.Sohn, S., Hur, W., Joe, M. K., Kim, J. H., Lee, Z. W., Ha, K. S. & Kee, C. (2002). Expression of wild-type and truncated myocilins in trabecular meshwork cells: their subcellular localizations and cytotoxicities. Invest. Ophthalmol. Vis. Sci. 43, 3680–3685.

33.Joe, M. K., Sohn, S., Hur, W., Moon, Y., Choi, Y. R. & Kee, C. (2003). Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochem. Biophys. Res. Commun. 312, 592–600.

34.Aroca-Aguilar, J. D., Sanchez-Sanchez, F., Ghosh, S., Coca-Prados, M. & Escribano, J. (2005). Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids Arg226 and Ile227. J. Biol. Chem. 280, 21043– 21051.

35.Vollrath, D. & Liu, Y. (2006). Temperature sensitive secretion of mutant myocilins. Exp. Eye Res. 82, 1030–1036.

36.Jacobson, N., Andrews, M., Shepard, A. R., Nishimura, D., Searby, C., Fingert, J. H., Hageman, G., Mullins, R., Davidson, B. L., Kwon, Y. H., Alward, W. L., Stone, E. M., Clark, A. F. & Sheffield, V. C. (2001). Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor. Hum. Mol. Genet. 10, 117–125.

37.Shepard, A. R., Jacobson, N., Sui, R., Steely, H. T., Lotery, A. J., Stone, E. M. & Clark, A. F. (2003). Characterization of rabbit myocilin: implications for human myocilin glycosylation and signal peptide usage. BMC Genet. 4, 5.

38.Goldwich, A., Ethier, C. R., Chan, D. W. & Tamm, E. R. (2003). Perfusion with the olfactomedin domain of myocilin does not affect outflow facility. Invest. Ophthalmol. Vis. Sci. 44, 1953–1961.

39.Malyukova, I., Lee, H. S., Fariss, R. N. & Tomarev, S. I. (2006). Mutated mouse and human myocilins have similar properties and do not block general secretory pathway.

Invest. Ophthalmol. Vis. Sci. 47, 206–212.

40.Fautsch, M. P., Vrabel, A. M., Peterson, S. L. & Johnson, D. H. (2004). In vitro and in vivo characterization of disulfide bond use in myocilin complex formation. Mol. Vis. 10, 417–425.

41.Russell, P., Tamm, E. R., Grehn, F. J., Picht, G. & Johnson, M. (2001). The presence and properties of myocilin in the aqueous humor. Invest. Ophthalmol. Vis. Sci. 42, 983–986.

42.Zillig, M., Wurm, A., Grehn, F. J., Russell, P. & Tamm, E. R. (2005). Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice.

Invest. Ophthalmol. Vis. Sci. 46, 223–234.

43.Rao, P. V., Allingham, R. R. & Epstein, D. L. (2000). TIGR/myocilin in human aqueous humor. Exp. Eye Res. 71, 637–641.

44.Filla, M. S., Liu, X., Nguyen, T. D., Polansky, J. R., Brandt, C. R., Kaufman, P. L. & Peters, D. M. (2002). In vitro localization of TIGR/MYOC in trabecular meshwork extracellular matrix and binding to fibronectin. Invest. Ophthalmol. Vis. Sci. 43, 151–161.

45.Li, Y., Aroca-Aguilar, J. D., Ghosh, S., Sanchez-Sanchez, F., Escribano, J. & CocaPrados, M. (2006). Interaction of myocilin with the C-terminal region of hevin. Biochem. Biophys. Res. Commun. 339, 797–804.

46.Karavanich, C. & Anholt, R. R. (1998). Evolution of olfactomedin. Structural constraints and conservation of primary sequence motifs. Ann. N. Y. Acad. Sci. 855, 294–300.

47.Karavanich, C. A. & Anholt, R. R. (1998). Molecular evolution of olfactomedin. Mol. Biol. Evol. 15, 718–726.

48.Yokoe, H. & Anholt, R. R. (1993). Molecular cloning of olfactomedin, an extracellular matrix protein specific to olfactory neuroepithelium. Proc. Natl. Acad. Sci. U.S.A. 90, 4655–4659.

49.Snyder, D. A., Rivers, A. M., Yokoe, H., Menco, B. P. & Anholt, R. R. (1991). Olfactomedin: purification, characterization, and localization of a novel olfactory glycoprotein.

Biochemistry 30, 9143–9153.

50.Fautsch, M. P. & Johnson, D. H. (2001). Characterization of myocilin-myocilin interactions.

Invest. Ophthalmol. Vis. Sci. 42, 2324–2331.

51.Hardy, K. M., Hoffman, E. A., Gonzalez, P., McKay, B. S. & Stamer, W. D. (2005). Extracellular trafficking of myocilin in human trabecular meshwork cells. J. Biol. Chem. 280, 28917–28926.

52.Perkumas, K. M., Hoffman, E. A., McKay, B. S., Allingham, R. R. & Stamer, W. D. (2007). Myocilin-associated exosomes in human ocular samples. Exp. Eye Res. 84, 209–212.

53.Stamer, W. D., Perkumas, K. M., Hoffman, E. A., Roberts, B. C., Epstein, D. L. & McKay, B. S. (2006). Coiled-coil targeting of myocilin to intracellular membranes. Exp. Eye Res. 83, 1386–1395.

54.Ricard, C. S., Mukherjee, A., Silver, F. L. & Wagenknecht, P. L. (2006). Canine myocilin is associated with lipid modified by palmitic acid. Mol. Vis. 12, 1427–1436.

55.Joe, M. K., Sohn, S., Choi, Y. R., Park, H. & Kee, C. (2005). Identification of flotillin-1 as a protein interacting with myocilin: implications for the pathogenesis of primary open-angle glaucoma. Biochem. Biophys. Res. Commun. 336, 1201–1206.

56.Fautsch, M. P., Bahler, C. K., Vrabel, A. M., Howell, K. G., Loewen, N., Teo, W. L., Poeschla, E. M. & Johnson, D. H. (2006). Perfusion of his-tagged eukaryotic myocilin increases outflow resistance in human anterior segments in the presence of aqueous humor.

Invest. Ophthalmol. Vis. Sci. 47, 213–221.

57.Clark, A. F., Steely, H. T., Dickerson, J. E., Jr., English-Wright, S., Stropki, K., McCartney, M. D., Jacobson, N., Shepard, A. R., Clark, J. I., Matsushima, H., Peskind, E. R., Leverenz, J. B., Wilkinson, C. W., Swiderski, R. E., Fingert, J. H., Sheffield, V. C. & Stone, E. M. (2001). Glucocorticoid induction of the glaucoma gene MYOC in human and monkey trabecular meshwork cells and tissues. Invest. Ophthalmol. Vis. Sci. 42, 1769–1780.

58.Shepard, A. R., Jacobson, N., Fingert, J. H., Stone, E. M., Sheffield, V. C. & Clark, A. F. (2001). Delayed secondary glucocorticoid responsiveness of MYOC in human trabecular meshwork cells. Invest Ophthalmol. Vis. Sci. 42, 3173–3181.

59.Gould, D. B., Miceli-Libby, L., Savinova, O. V., Torrado, M., Tomarev, S. I., Smith, R. S. & John, S. W. (2004). Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol. Cell Biol. 24, 9019–9025.

60.Peters, D. M., Herbert, K., Biddick, B. & Peterson, J. A. (2005). Myocilin binding to Hep II domain of fibronectin inhibits cell spreading and incorporation of paxillin into focal adhesions. Exp. Cell Res. 303, 218–228.

61.Bornstein, P. (2001). Thrombospondins as matricellular modulators of cell function. J. Clin. Invest. 107, 929–934.

62.Sage, E. H. & Bornstein, P. (1991). Extracellular proteins that modulate cell-matrix interactions. SPARC, tenascin, and thrombospondin. J. Biol. Chem. 266, 14831–14834.

63.Sage, H., Vernon, R. B., Funk, S. E., Everitt, E. A. & Angello, J. (1989). SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca+2-dependent binding to the extracellular matrix. J. Cell Biol. 109, 341–356.

64.Murphy-Ullrich, J. E. & Hook, M. (1989). Thrombospondin modulates focal adhesions in endothelial cells. J. Cell Biol. 109, 1309–1319.

65.Flügel-Koch, C., Ohlmann, A., Fuchshofer, R., Welge-Lussen, U. & Tamm, E. R. (2004). Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous eyes, and induction by TGF-beta1 and dexamethasone in vitro. Exp. Eye Res. 79, 649–663.

66.Rhee, D. J., Fariss, R. N., Brekken, R., Sage, E. H. & Russell, P. (2003). The matricellular protein SPARC is expressed in human trabecular meshwork. Exp. Eye Res. 77, 601–607.

67.Johnson, M. (2006). ‘What controls aqueous humour outflow resistance?’ Exp. Eye Res. 82, 545–557.

68.Ethier, C. R. (2002). The inner wall of Schlemm’s canal. Exp. Eye Res. 74, 161–172.

69.Kim, B. S., Savinova, O. V., Reedy, M. V., Martin, J., Lun, Y., Gan, L., Smith, R. S., Tomarev, S. I., John, S. W. & Johnson, R. L. (2001). Targeted disruption of the myocilin

gene (Myoc) suggests that human glaucoma-causing mutations are gain of function. Mol. Cell Biol. 21, 7707–7713.

70.Lütjen-Drecoll, E., May, C. A., Polansky, J. R., Johnson, D. H., Bloemendal, H. & Nguyen, T. D. (1998). Localization of the stress proteins B-crystallin and trabecular meshwork inducible glucocorticoid response protein in normal and glaucomatous trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 39, 517–525.

71.Fautsch, M. P., Bahler, C. K., Jewison, D. J. & Johnson, D. H. (2000). Recombinant TIGR/MYOC increases outflow resistance in the human anterior segment. Invest. Ophthalmol. Vis. Sci. 41, 4163–4168.

72.Caballero, M., Rowlette, L. L. & Borrás, T. (2000). Altered secretion of a TIGR/MYOC mutant lacking the olfactomedin domain. Biochim. Biophys. Acta 1502, 447–460.

73.Liu, Y. & Vollrath, D. (2004). Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma. Hum. Mol. Genet. 13, 1193–1204.

74.Yam, G. H., Gaplovska-Kysela, K., Zuber, C. & Roth, J. (2007). Aggregated myocilin induces russell bodies and causes apoptosis: implications for the pathogenesis of myocilincaused primary open-angle glaucoma. Am. J. Pathol. 170, 100–109.

75.Alward, W. L., Fingert, J. H., Coote, M. A., Johnson, A. T., Lerner, S. F., Junqua, D., Durcan, F. J., McCartney, P. J., Mackey, D. A., Sheffield, V. C. & Stone, E. M. (1998). Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene. N. Engl. J. Med. 338, 1022–1027.

76.Zhou, Z. & Vollrath, D. (1999). A cellular assay distinguishes normal and mutant TIGR/myocilin protein. Hum. Mol. Genet. 8, 2221–2228.

77.Caballero, M. & Borrás, T. (2001). Inefficient processing of an olfactomedin-deficient myocilin mutant: potential physiological relevance to glaucoma. Biochem. Biophys. Res. Commun. 282, 662–670.

78.Gobeil, S., Letartre, L. & Raymond, V. (2006). Functional analysis of the glaucoma-causing TIGR/myocilin protein: integrity of amino-terminal coiled-coil regions and olfactomedin homology domain is essential for extracellular adhesion and secretion. Exp. Eye Res. 82, 1017–1029.

79.Welihinda, A. A., Tirasophon, W. & Kaufman, R. J. (1999). The cellular response to protein misfolding in the endoplasmic reticulum. Gene Expr. 7, 293–300.

80.Hampton, R. Y. (2000). ER stress response: getting the UPR hand on misfolded proteins. Curr. Biol. 10, R518–R521.

81.Ellgaard, L. & Helenius, A. (2003). Quality control in the endoplasmic reticulum. Nat. Rev. Mol. Cell Biol. 4, 181–191.

82.Jana, N. R., Tanaka, M., Wang, G. & Nukina, N. (2000). Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum. Mol. Genet. 9, 2009–2018.

83.Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A. & Klein, W. L. (1998). Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U.S.A. 95, 6448–6453.

84.Johnston, J. A., Dalton, M. J., Gurney, M. E. & Kopito, R. R. (2000). Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U.S.A. 97, 12571–12576.

85.Beuret, N., Rutishauser, J., Bider, M. D. & Spiess, M. (1999). Mechanism of endoplasmic reticulum retention of mutant vasopressin precursor caused by a signal peptide truncation associated with diabetes insipidus. J. Biol. Chem. 274, 18965–18972.

86.Gould, D. B., Reedy, M., Wilson, L. A., Smith, R. S., Johnson, R. L. & John, S. W. (2006). Mutant myocilin nonsecretion in vivo is not sufficient to cause glaucoma. Mol. Cell Biol. 26, 8427–8436.

87.Senatorov, V., Malyukova, I., Fariss, R., Wawrousek, E. F., Swaminathan, S., Sharan, S. K. & Tomarev, S. (2006). Expression of mutated mouse myocilin induces open-angle glaucoma in transgenic mice. J. Neurosci. 26, 11903–11914.

functions. However, there is a huge gap between discovery of the DNA sequences of these genes and determination of the role of their encoded proteins in many complex and biological processes.

The glaucoma genetics field has equally been benefited by the Human Genome Project and by the discovery of these genes. During the 1990s, molecular genetics of glaucoma mainly involved family ascertainment, genome scans, and classical positional mapping by utilizing both conventional and unconventional methods of linkage analysis. Over the last few years, this type of investigation has intensified and, as of this writing, at least 24 different genetic loci have been linked to various forms of glaucoma (see Table 1). This method of gene mapping has been successful for identification of at least three genetic loci for primary congenital glaucoma (PCG), five loci for juvenile-onset primary open-angle glaucoma (JOAG), and at least, 16 other loci for adult-onset primary open-angle glaucoma (POAG). Additionally, various genome scans on different ethnic populations suggested a number of other chromosomal regions for JOAG and POAG, as well as other clinically related parameters, such as intraocular pressure (IOP) and cup-to-disk ratios. However, these mapping data are considered provisional and still require additional confirmation by other investigators. Likewise, a number of genetic loci have been associated with other forms

Table 1

Known Chromosomal Locations for Different Congenital and Open-Angle Forms of Glaucoma

of glaucoma including, pseudoexfoliation, angle closure, and many other glaucomarelated ocular conditions that still require further confirmation. Taken altogether, the existing number of genetic loci for various forms of glaucoma only presents a fraction of the total number of genes that are anticipated to be involved in this ever-evolving group of optic neuropathies. As our molecular understanding of these genetic loci are improved and as we get more in-depth knowledge in the biological processes that are involved in the etiology of this group of ocular disorders, our classification of glaucoma subtypes and our clinical options for management and treatment of these patients need to be continuously reevaluated. It is important to note that the molecular genetics study of glaucoma over the last decade or so has already made a significant contribution to our general knowledge of these complicated ocular conditions. Therefore, it is hoped that by reviewing the general role of three different glaucoma genes (CYP1B1, Optineurin, and WDR36) that have previously been identified by our group within the context of this chapter, we provide a general introduction for better understanding of these genes and their role in the etiology of glaucoma. A similar chapter on the only other glaucoma gene, Myocilin (MYOC), is also provided in this book.

CYTOCHROME P4501B1 (CYP1B1)

PCG or buphthalmos is an autosomal recessive disorder that results from developmental defects of the anterior ocular segment. PCG is a major cause of childhood blindness that manifests itself during late fetal and neonatal periods. It has also been termed isolated trabeculodysgeneses because of an abnormal development of trabecular meshwork (TM) and the anterior chamber angle that leads to obstruction of aqueous humor flow, high IOP, ocular enlargement, and corneal edema (1). The study of molecular genetics of PCG began in the mid 1990s (2). In our own group, we have sought potential genes responsible for glaucoma phenotypes by examining the genomic DNA of individual members in pedigrees in which multiply affected PCG subjects have been identified. Originally, we collected a large number of families from different ethnic populations and subsequently applied the methods of genetic linkage analysis to a panel of 17 Turkish kindred and mapped a major genetic locus (GLC3A) for this phenotype to chromosome 2p22.2 (2). Subsequently, this mapping was confirmed by other investigators and for many other populations around the world. The critical region at the GLC3A locus was carefully screened, and after excluding a number of potential candidate genes, eventually, we identified three different truncating mutations in the CYP1B1 gene in our PCG families (3). This was subsequently confirmed in studies of affected individuals in pedigrees from Saudi Arabia (4), Slovakia (5), and many other populations around the world. Hence, by using the procedure of genetic linkage and positional cloning, CYP1B1 became not only the first known, but also a major gene for both familial and sporadic cases of PCG (6,7). We have also mapped two other genetics loci for the PCG phenotype on 1p36 (GLC3B) (8) and 14q24.3 (GLC3C) (9) regions. However, so far only the defective PCG gene at the GLC3A locus (i.e., CYP1B1) has been identified (3) though extensive search is currently underway in our laboratories to clone the other two defective PCG genes at the GLC3B and

GLC3C loci.

Role of CYP1B1 in Various Eye Disorders

CYP1B1 is a xenobiotic-metabolizing enzyme with known roles in eye development and in PCG. Recently, the presence of CYP1B1 mutations in other eye diseases with anterior chamber malformations including Peter’s anomaly (10–13), Rieger’s anomaly (14), JOAG (15,16), and POAG (16,17) has been reported. This broad range of glaucoma phenotypes associated with CYP1B1 mutations suggests a key role for this molecule in the physiology and development of the eye.

CYP1B1 is a gene for PCG that was originally cloned from the 2p22.2 region (2). It is now well established that mutations in this gene (18) are the major causes of this phenotype (see Tables 2 and 3). Current estimates suggest that over 80% of familial and 30% of sporadic cases of PCG may have mutations in this one gene alone. As presented in Table 2, a large number of CYP1B1 mutations, including truncating, insertions, deletions, duplications, and non-synonymous amino acid substitutions have been reported in PCG cases (7). It is interesting that few exact mutations have been observed not only in PCG subjects but also in individuals affected with Peter’s and Rieger’s anomalies (see Table 2). Other CYP1B1 mutations lead to incomplete penetrance in certain PCG subjects (19) or cause either juvenile- (16) or adult-onset POAG (17). The biochemical and functional consequence for a number of these mutations have been extensively studied in detail and are briefly discussed below.

Recently, a co-occurrence of mutations in both CYP1B1 and MYOC shows an earlier onset and more severe glaucoma phenotype (20). Therefore, it was hypothesized that CYP1B1 may act as a potential modifier for the effects induced by mutations in other POAG genes. In a Canadian JOAG study, the combination of MYOC and CYP1B1 mutations caused an earlier onset of glaucoma than with MYOC mutations alone (20). Further, CYP1B1 mutations were found in 4.6% of JOAG patients who do not have MYOC mutations, indicating that the presence of mutant CYP1B1 probably has a stronger effect on the manifestation of glaucoma pathogenesis than MYOC alone (15). Recently, CYP1B1 mutations were also observed in 3% of Indian (16) and 10.9% of Spanish (17) adult-onset POAG cases. These studies showed some unique CYP1B1 mutations in JOAG (L345F and R523T) and POAG (S28W, Q144H, R145W, V409F, S515L, and D530G) subjects who have not previously been reported in any of the PCG subjects investigated from a worldwide population. Over 44 other CYP1B1 mutations

(7) are only reported in the PCG patients (see Table 2). A list of commonly reported CYP1B1 mutations in PCG, JOAG, and adult-onset POAG is presented in Table 3.

It is not clear at this point how heterozygous mutations (see Table 3) in an enzyme such as CYP1B1 could be responsible for the two phenotypes of JOAG and POAG that are both inherited as autosomal-dominant conditions. One explanation may be that the high frequency of CYP1B1 gene carriers in populations with high-recorded degrees of consanguinity is responsible for such observations. This is further complicated by the fact that a large number of normal siblings with two copies of CYP1B1 mutations in certain PCG families do not manifest any ocular conditions. Therefore, when two copies of CYP1B1 mutant alleles are not sufficient to produce any phenotypes in such normal siblings, it would be interesting to resolve how the presence of only one mutated CYP1B1 allele could be responsible for the clinical phenotypes of JOAG or POAG. Obviously, much work is still needed before the role of CYP1B1 gene mutations in