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Review Article Mechanisms of Disease

Primary Open-Angle Glaucoma
Young H. Kwon, M.D., Ph.D., John H. Fingert, M.D., Ph.D., Markus H. Kuehn, Ph.D., and Wallace L.M. Alward, M.D. N Engl J Med 2009; 360:1113-1124March 12, 2009 Article Glaucoma is a chronic, degenerative optic neuropathy that can be distinguished from most other forms of acquired optic neuropathy by the characteristic appearance of the optic nerve. In glaucoma, the neuroretinal rim of the optic nerve becomes progressively thinner, thereby enlarging the optic-nerve cup. This phenomenon is referred to as optic-nerve cupping. Its cause is the loss of retinal ganglion cell axons, along with supporting glia and vasculature. The remaining neuroretinal rim retains its normal pink color. In other optic neuropathies, the optic-nerve tissue loses its pink color and cupping does not develop. A rare exception is arteritic anterior ischemic optic neuropathy, in which cupping can occur.1 Patients with glaucoma typically lose peripheral vision and may lose all vision if not treated. Although glaucoma frequently occurs without an elevation of intraocular pressure, the disease is nonetheless classified according to anterior-segment variations that can elevate intraocular pressure. The anterior segment of the eye has its own circulatory system, which nourishes the crystalline lens and cornea, both of which lack a blood supply. Aqueous humor, produced by the ciliary body, circulates throughout the anterior chamber and drains through the trabecular meshwork in the iridocorneal angle, which is the angle formed by the iris and cornea (Figure 1Figure 1

Circulation of the Aqueous Humor.).2 Elevated intraocular pressure does not result from increased aqueous humor production but rather from reduced aqueous outflow. The glaucomas are classified by the appearance of the iridocorneal angle. There are open-angle, closed-angle, and developmental categories, which are further divided into primary and secondary types. Primary open-angle glaucoma can occur with or without elevated intraocular pressure; the latter is sometimes called normal-tension

glaucoma. Primary open-angle glaucoma includes both adult-onset disease (occurring after 40 years of age) and juvenile-onset disease (occurring between the ages of 3 and 40 years of age). Examples of secondary open-angle glaucomas include those associated with exfoliation or pigment-dispersion syndrome. Closed-angle glaucoma can be primary (e.g., pupillary block) or secondary (e.g., inflammatory or neovascular causes). Developmental forms of glaucoma include primary congenital glaucoma and glaucoma associated with syndromes (e.g., aniridia or the Axenfeld–Rieger syndrome). Primary open-angle glaucoma, the predominant form of glaucoma in Western countries, probably comprises several clinically indistinguishable diseases. In this review, we discuss primary open-angle glaucoma, in which the iridocorneal angle is open (unobstructed) and normal in appearance but aqueous outflow is diminished. We discuss the clinical features of primary open-angle glaucoma and mechanisms of elevated intraocular pressure and optic-nerve damage. To illustrate the mechanisms of elevated intraocular pressure, we focus on mutations in the myocilin (MYOC) gene. Approximately 4% of cases of adult-onset primary open-angle glaucoma and more than 10% of juvenile-onset cases are associated with MYOC mutations.3,4 These adult-onset cases feature an elevated intraocular pressure with resultant optic-nerve damage and visual loss, and they are clinically indistinguishable from cases of primary open-angle glaucoma in patients without MYOC mutations.5 To address the mechanisms of optic-nerve damage, we broaden the discussion to include primary open-angle glaucoma with elevated intraocular pressure, with or without MYOC mutations. Primary open-angle glaucoma is the second leading cause of blindness in the United States and the leading cause of blindness among black Americans.6 There is good evidence that black race, older age, elevated intraocular pressure, family history of primary open-angle glaucoma, myopia, and low diastolic perfusion pressure are risk

factors for primary open-angle glaucoma.6,7, (Table 1Table 1 Major Risk Factors Associated with Primary Open-Angle Glaucoma.). Among patients with an elevated intraocular pressure, a relatively thin central cornea is another major risk factor for the disease.14 Evidence for other risk factors (diabetes mellitus, elevated systolic blood pressure, and migraine, among others) is less consistent. 15 The main clinical features of primary open-angle glaucoma are an open iridocorneal angle and cupping of the optic-nerve head (or optic disk), with corresponding loss of visual field. Elevated intraocular pressure is not part of the clinical definition because primary open-angle glaucoma can occur when intraocular pressure is normal (typically 10 to 21 mm Hg). Nevertheless, elevated intraocular pressure is an important risk factor and is also considered to be a causative factor in glaucoma16; currently, it is the only modifiable causative factor. Many randomized clinical trials have shown that reducing intraocular pressure slows the onset and progression of glaucoma.17,18 Therefore, all current treatments of primary open-angle glaucoma are aimed at reducing intraocular pressure by medical or surgical means.19,20 The Case

which is in the GLC1E locus.32 but less is known about the role of WDR36.22 Subsequent linkage studies of other glaucoma pedigrees have mapped the chromosomal locations of 13 additional glaucoma-related genes (GLC1B through GLC1N).Presentation Case Presentation: Primary Open-Angle Glaucoma recounts a typical presentation of primary open-angle glaucoma (see Figure 2Figure 2 Optic Disks and Corresponding Visual Fields in a Patient with Primary Open-Angle Glaucoma and a MYOC Mutation.36 A central clinical feature of myocilin-associated glaucoma is elevated intraocular pressure. and some mutations cause higher intraocular pressure than others. including OPTN (encoding optineurin) and WDR36 (encoding a T-cell activation WD repeat-containing protein).34 Some MYOC mutations have been detected in a sufficient number of patients to allow identification of mutation-specific glaucoma phenotypes. which encodes the protein myocilin. and analyses of genetic markers in such pedigrees have mapped a glaucoma-related gene to a region of chromosome 1q designated GLC1A.27-31 Mutations in MYOC are among the most common causes of inherited eye disease with a known molecular basis. A variety of MYOC mutations have been detected in 3 to 5% of patients with adult-onset primary open-angle glaucoma in cohorts around the world. except that in the juvenile-onset form the intraocular pressure is often extremely high (frequently >40 mm Hg).35 In patients . Myocilin is produced in many tissues.3. Mutations in other genes. Mutations associated with juvenile-onset primary open-angle glaucoma lead to the greatest elevations in intraocular pressure — often more than 40 mm Hg. including age at onset and maximum intraocular pressure.23 The relevant gene at the GLC1A locus is MYOC (Online Mendelian Inheritance in Man number.25 the two ocular tissues that regulate intraocular pressure. adult-onset form of primary open-angle glaucoma has been explored by testing large cohorts of patients for mutations. It has the same clinical features as the adult-onset condition. Mutations associated with adult-onset primary open-angle glaucoma typically cause maximum pressures of 25 to 40 mm Hg.31. which is in the GLC1G locus.21 Large pedigrees with autosomal-dominant inheritance of juvenile-onset primary open-angle glaucoma have been reported. and see video showing an optic nerve examination). Juvenile-onset primary open-angle glaucoma is rare.26 In several studies of pedigrees. including the ciliary body24 and trabecular meshwork. OPTN. have also been studied as potential causes of primary open-angle glaucoma.27 The role of MYOC in the pathogenesis of the common. has been associated with a small fraction of cases of low-pressure glaucoma. 601652).35. mutations in MYOC were always coinherited with juvenile-onset primary open-angle glaucoma.33 These genes have recently been reviewed elsewhere. for examination results. a strong indication that MYOC is the glaucoma gene in the GLC1A locus.

e. 48 Glaucoma-associated mutations also reduce the secretion of myocilin in vitro and in vivo. MYOC mutations greatly reduce the quantity of myocilin that is secreted into the aqueous humor. MYOC mutations may prevent the secretion of myocilin by exposing a cryptic domain that directs proteins to peroxisomes. whereas benign sequence polymorphisms have no such effect.25. These effects suggest that MYOC mutations encode a protein that causes microscopic abnormalities in the structures of an otherwise normal-appearing iridocorneal angle..31 Myocilin has been detected in the trabecular meshwork.40-42 Recombinant myocilin protein. The N-terminal of myocilin has a signal sequence that targets proteins for secretion. MYOC mutations associated with glaucoma do alter the properties of the protein — disease-associated mutations reduce the solubility of myocilin in a detergent.43 MYOC mutations do not appear to cause glaucoma as a result of haploinsufficiency or overexpression.37 Wild-type myocilin protein is secreted. Secretion of myocilin is dramatically reduced in trabecular-meshwork cells cultured from patients with glaucoma-associated MYOC mutations. Indeed. glaucoma does not develop in mice with overexpression of myocilin or with deficient myocilin production. Analysis of its amino acid sequence has revealed functional domains. high intraocular pressure appears to be important not only for the onset of glaucoma but also for progression of the disease.25.with MYOC mutations. indicating that myocilin is secreted from trabecular-meshwork cells in vitro and that in vivo it is secreted from ocular tissues that may include the trabecular meshwork or ciliary body. including a leucine zipper domain for protein–protein interactions and two domains that can influence protein localization. which suggests that the peroxisomal targeting sequence is not functional under normal circumstances.47.38.38.39 It has also been found secreted in the growth medium of primary cultures of human trabecular-meshwork cells and in human and mouse aqueous humor. Arg46Stop)45 do not cause glaucoma.38. Similarly.46. which is the principal structure of the eye that regulates intraocular pressure.). and myocilin in medium from cultured cells can self-associate and form multimers. a family of secreted proteins with unknown function. myocilin in aqueous humor. especially the trabecular meshwork. whereas the last three amino acids at the C-terminal of myocilin encode a sequence that directs intracellular proteins to peroxisomes. The function of myocilin is unknown.40 Similarly. The vast majority of glaucoma-associated MYOC mutations lie within a large segment of myocilin protein that is homologous to olfactomedin proteins. These results suggest that disease-causing mutations alter the myocilin protein in such a way that it disrupts the regulation of intraocular pressure. Deficiencies in myocilin production resulting from a hemizygous deletion44 or a presumed homozygous null mutation (i. and there is evidence that mutant myocilin may be retained within the intracellular space by means of an abnormal association with .40 supporting the idea that failure to secrete myocilin is a central feature in the pathogenesis of myocilin-associated glaucoma (Figure 3Figure 3 Proposed Pathways for Normal Secretion of Myocilin into the Aqueous Humor and for Secretion Reduced by a MYOC Mutation.

these animal models will facilitate studies of the effects of MYOC mutations on the health and numbers of trabecular-meshwork cells and the organization of the extracellular structure of the trabecular meshwork. We limit the discussion to recent literature.53 Mutant myocilin that accumulates in the intracellular space may be toxic to trabecular-meshwork cells.57. The optic-nerve head consists of axons projected from retinal ganglion cells. The finding that aqueous humor outflow is reduced in patients with MYOC mutations supports this hypothesis. A reduction in cellularity and alterations in the architecture of the trabecular meshwork have been observed in glaucoma.55.54 The development of animal models of myocilin-associated glaucoma50. and oligodendrocytes (the oligodendrocytes are present only in the postlaminar region and are important in postlaminar axon myelination). and subcellular levels.59-61 Elevated intraocular pressure has direct effects on retinal ganglion cells. initiating a cascade of events that begins with loss of function in these cells.proteins of the peroxisome-targeting system.56 provides new tools for exploring the effects of mutations in the myocilin gene on the structure and function of the outflow pathway at the tissue. which damages the outflow pathway and results in elevated intraocular pressure. astrocytes.51 Endothelial cells of the trabecular meshwork maintain its structure and facilitate the outflow of aqueous humor from the eye by remodeling this porous tissue and preventing debris from occluding the outflow pathway.). a collagenous structure with sievelike openings (Figure 4AFigure 4 The OpticNerve Head and Proposed Events Leading to Retinal Ganglion-Cell Death in Glaucoma.58 We outline several key mechanisms of optic-nerve damage that are caused by elevated intraocular pressure. Injury or death of trabecular-meshwork cells has been implicated in the pathogenesis of open-angle glaucoma. In particular. cellular.50 Regardless of the mechanism of retention. The optic-nerve head also contains retinal vasculature (the central retinal artery and vein) and such glial elements as microglia.49 Other studies in mice have shown that mutations in the murine myocilin gene (Myoc) can inhibit secretion of myocilin and cause some signs of glaucoma without a cryptic targeting domain. The lamina cribrosa separates unmyelinated prelaminar retinal ganglioncell axons from myelinated postlaminar retinal ganglion-cell axons. It is generally believed that elevated intraocular pressure — regardless of its cause — triggers a common set of cellular events. thereby elevating intraocular pressure and eventually damaging the optic nerve. more comprehensive reviews of the subject can be found elsewhere. decreased secretion and increased accumulation of intracellular myocilin appear to be initial steps in the pathogenesis of myocilinassociated glaucoma. Axonal transport decreases in the presence of elevated intraocular pressure.62 The reduced retrograde axoplasmic flow can stress retinal ganglion cells and cause their death from .51. which exit the eye through the lamina cribrosa.52 and these changes may increase resistance to aqueous outflow. although damage that is independent of elevated intraocular pressure may also occur in primary open-angle glaucoma.

87 In a mouse model of glaucoma. and these changes can have biomechanical effects on the opticnerve head that in turn increase stress on retinal ganglion-cell axons. including increased synthesis of collagen IV.87 These morphologic findings are accompanied by changes in the composition of the extracellular matrix of the opticnerve head. even in the absence of elevated intraocular pressure. The biomechanical consequences of these changes are believed to strain retinal ganglion-cell axons.74.94.95 Clinical observations have indicated that the optic-nerve head. the lamina cribrosa bows posteriorly (Figure 4C). which further compromises their function. make the cup larger and deeper.81 Glial cells in the optic-nerve head (microglia and astrocytes) become activated in response to the elevated intraocular pressure in glaucoma82-85 (Figure 4B).83.91 Cupping of the optic-nerve head results from the loss of prelaminar tissue and posterior deformation of the lamina cribrosa. These changes in the lamina cribrosa.88. activated glial cells released tumor necrosis factor α (TNF-α).99 In these mice. and this accumulation causes cellular stress and malfunction. proteoglycans. and presumably also in human glaucoma.76-79 and increased expression of markers of hypoxia and glial activation. Activated astrocytes synthesize molecules that lead to degradation and remodeling of the extracellular matrix. is the initial site of glaucomatous damage.65. The presence of TNF-α in human glaucomatous retina90 and optic-nerve head91 has been detected by immunohistochemical analysis. These results suggest that TNF-α can be a mediator of damage of retinal ganglion-cell axons when intraocular pressure is elevated. and soon thereafter.92 This change is accompanied by microglial proliferation.69-73 The use of microarray technology in animal models has shown that changes in the geneexpression profile of the retina occur rapidly in response to elevated intraocular pressure.86.96 In animal models. this evidence suggests that glial activation and TNF-α are important mediators of damage to retinal ganglion-cell axons.75 These changes include decreased expression of many genes specific to retinal ganglion cells74.86. In the DBA2/J mouse strain.93 Subsequently. the . adhesion molecules.87. and antioxidant treatments have some benefit in animal models.88 Deletion of the genes encoding TNF-α or its receptor increased the survival of retinal ganglion cells in this model.89 Intravitreal injection of TNF-α causes loss of retinal ganglion-cell axons and subsequently loss of entire cells.68 In glaucoma. a proinflammatory cytokine. combined with the eventual loss of prelaminar tissue.62-64 If blood perfusion at the optic-nerve head is persistently reduced. even though the soma of the retinal ganglion cells appears normal. and matrix metalloproteinases and a loss of gap-junction communication that accompanies astrocyte activation.deprivation of neurotrophic factors such as brain-derived neurotrophic factor. Three-dimensional histomorphometric studies of primates with experimentally induced glaucoma raised the possibility that one of the early changes in the structure of the optic-nerve head in glaucoma is the thickening — rather than thinning — of prelaminar tissue. axonal shrinkage and decreased retrograde transport occur. proteins and lipids with oxidative modifications accumulate in the retina and optic-nerve head. and more specifically the lamina cribrosa. damage to retinal ganglion-cell axons precedes the death of the cells97. elevated intraocular pressure develops spontaneously at 7 to 9 months of age. Collectively.88.90.98 (Figure 4B and 4C).80.65-67 tissue hypoxia can induce the formation and accumulation of reactive oxygen species in the retina.

97 Thus. Most. and these processes may further contribute to the degeneration of retinal ganglion cells. glial expression of major-histocompatibility-complex (MHC) class II molecules108 and synthesis of components of the complement cascade109. if not all. a process distinct from the adaptive immune response and more akin to a reaction of the innate immune system. perhaps involving excessive synthesis of extracellular matrix material83. Altermatt Professorship. The most important risk factor for glaucoma is elevated intraocular pressure. Hadley Glaucoma Research Fund and Research to Prevent Blindness. the degradation of the retinal ganglion-cell axon and soma may involve separate mechanisms. of the loss of retinal ganglion cells in the glaucomatous retina occurs through apoptosis. glial cells phagocytose cellular debris and initiate a scar response after retinal ganglion-cell death.110 occur as retinal ganglion-cell death continues. we provide treatment for the only known risk factor that can be modified.102. the ganglion-cell axons that make up the optic nerve are damaged by a variety of factors. elevated intraocular pressure.103 Axonal damage and chronic stress result in the death of retinal ganglion cells.104. Because the optic-nerve damage in glaucoma is not yet amenable to direct treatment. . although there is indirect evidence of inflammatory processes. a major cause of blindness.86. and Dr.105 Inhibition of apoptosis by deletion of the Bax gene in a mouse model of glaucoma almost completely rescues the retinal ganglion-cell soma. As more is understood about the molecular biology of the trabecular meshwork and optic nerve in health and disease.81 Instead. damage to retinal ganglion-cell axons occurs despite the absence of the collagenous lamina cribrosa plates typically found in primates. Retinal ganglion-cell death is not accompanied by prominent infiltration of mononuclear cells. suggesting that damage to the axons occurs in an area that corresponds to the lamina cribrosa in primates. Inflammation-like glial activity is frequently observed in degenerative disorders of the central nervous system and is referred to as neuroinflammation.97 However.77. Blodi Chair.100 By means of noninvasive direct imaging of apoptotic cell death.retinal ganglion-cell axons proximal to the point of myelination survive. In glaucoma. Coupled with thinning and further posterior bowing of the lamina cribrosa. and Leonard A.77. our ability to treat glaucoma will likely improve.107 In glaucoma.106 it has been possible to observe progressive loss of retinal ganglion-cell axons and cell bodies in a rat model of glaucoma. Dr. but axons are not preserved.100 In DBA/2 mice. as seen clinically in advanced glaucoma (Figure 4D). deep cup.101 This finding suggests that a cellmediated mechanism underlies the damage. Supported in part by grants from the Marlene S. Alward received support from the Frederick C. as indicated by the presence of autoantibodies against retinal antigens in patients with glaucoma.95 or elevation of intra-axonal calcium levels resulting from overexpression of ephrin-B2 (a receptor tyrosine kinase in glioma cells). retinal ganglion cells survive for only about 1 to 2 months after axonal degeneration. Kwon received support from the Clifford M. and Ruth M. apoptotic loss of the retinal ganglion cells results in a large.94. only some of which are understood.

4 Aldred MA. Low prevalence of MYOC mutations in UK primary open-angle glaucoma patients limits the utility of genetic testing. 1 Hayreh SS. Liebmann JM. Address reprint requests to Dr.108:1586-1594 CrossRef | Web of Science | Medline 2. Zimmerman MB. Biomedicine: a new angle on ocular development. and Dr. Science 2003. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. A case-control comparison of the clinical characteristics of glaucoma and ocular hypertensive patients with and without the myocilin Gln368Stop mutation. Optic disc morphology after arteritic anterior ischemic optic neuropathy. Am J Ophthalmol 2002. University of Iowa.. et al. for her assistance with the preparation of the manuscript.Ph. Hum Genet 2004. We thank Patricia Duffel. et al. Hill A. Kwon at University of Iowa Health Care. Fingert reports receiving grant support from Alcon Research and holding several unlicensed patents related to gene discovery in glaucoma. From the Department of Ophthalmology and Visual Sciences. Alward reports holding an unlicensed patent for the diagnosis of MYOC mutations. Iowa City.. Iowa City. 200 Hawkins Dr.299:1527-1528 CrossRef | Web of Science | Medline 3. 5 Graul TA.8:899-905 CrossRef | Web of Science | Medline 4.115:428-431 CrossRef | Web of Science | Medline 5.134:884-890 CrossRef | Web of Science | Medline . References 1. R.. 3 Fingert JH. M.Dr. et al. IA 52242. Hum Mol Genet 1999. 2 Alward WL. Jonas JB. Ophthalmology 2001. Baumber L. Heon E. No other potential conflict of interest relevant to this article was reported.A. Kwon YH.

Primary open angle glaucoma. Hypertension. gender.112:69-73 CrossRef | Web of Science | Medline 12.47:4254-4261 CrossRef | Web of Science | Medline 9. Quigley HA. Lee KE. Refractive errors. 12 Mitchell P. et al. Sommer A. Sandbach J. Philadelphia: J. 2000:128-40. Hourihan F. and primary open-angle glaucoma: a population-based assessment. eds. Ophthalmology . 7. Ophthalmology 1999. Quigley HA. Duane's clinical ophthalmology. Katz J.106:2010-2015 CrossRef | Web of Science | Medline 13. 8 Rudnicka AR. Variations in primary open-angle glaucoma prevalence by age. Mt-Isa S. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Survey. Javitt JC. 6 Kwon YH.113:216-221 CrossRef | Web of Science | Medline 11.6. Open angle glaucomas. Katz J. Arch Ophthalmol 1994. 10 Tielsch JM. 13 Wong TY. 7 Alward WLM. Klein BE. In: Alward WLM. intraocular pressure. Knudtson M. perfusion pressure. Katz J. Caprioli J. Arch Ophthalmol 1995. St. Cook DG. Jaeger EA. 11 Tielsch JM. and race: a Bayesian metaanalysis. 8. ed. In: Tasman W. Owen CG. Klein R. Tielsch JM. Ashby D. Javitt JC.109:1090-1095 CrossRef | Web of Science | Medline 10. Sommer A. Louis: Mosby. 1999:1-30. Invest Ophthalmol Vis Sci 2006. Family history and risk of primary open angle glaucoma: the Baltimore Eye Survey. Lippincott. 9 Sommer A. The relationship between glaucoma and myopia: the Blue Mountains Eye Study. Glaucoma: the requisites in ophthalmology. and glaucoma in a white population. Arch Ophthalmol 1991. Wang JJ.B.

16 Bahrami H. Lancet 2004. Philadelphia: Lippincott Williams & Wilkins. 2005:170-90.110:211-217 CrossRef | Web of Science | Medline 14. In: Allingham RR. N Engl J Med 1998. 18 Kass MA. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Leske MC. Medical management of glaucoma. Shields MB. Moroi SE. 19 Alward WL. 14 Gordon MO.120:1268-1279 Web of Science | Medline 18. Arch Ophthalmol 2002. Arch Ophthalmol 2002. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Brandt JD. Shields' textbook of glaucoma. Primary open-angle glaucoma. Freedman S. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. et al. Arch Ophthalmol 2002. Hyman L.120:714-720 Web of Science | Medline 15. 20 Weinreb RN. Ophthalmic Epidemiol 2006.2003. Higginbotham EJ. Khaw PT. 15 Clinical epidemiology of glaucoma. Shafranov G. Damji KF. Causal inference in primary open angle glaucoma: specific discussion on intraocular pressure.363:1711-1720 CrossRef | Web of Science | Medline 21. Heuer DK. Beiser JA. Bengtsson B. Hussein M. et al.13:283-289 CrossRef | Web of Science | Medline 17.339:1298-1307 Full Text | Web of Science | Medline 20. 5th ed. Bengtsson B. 21 .120:701-713 Web of Science | Medline 19. 17 Heijl A. 16.

27 Stone EM.125:30-37 CrossRef | Web of Science | Medline 24. Escribano J. Alward WL. Richards JE. Noda S. A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning. Cloning and characterization of subtracted cDNAs from a human ciliary body library encoding TIGR. et al. Genetic etiologies of glaucoma. et al. and chromosomal mapping. Coca-Prados M. et al. Stone EM. Ophthalmologica 1997. et al. tissue expression. Clinical phenotype of juvenileonset primary open-angle glaucoma linked to chromosome 1q. Fauss DJ. 25 Polansky JR. FEBS Lett 1997. 23 Wiggs JL. 22 Sheffield VC. Alward WL. 26 Kubota R. 24 Ortego J.63:1549-1552 CrossRef | Web of Science | Medline .Johnson AT. Science 1997.41:360-369 CrossRef | Web of Science | Medline 27. Genetic linkage of familial open angle glaucoma to chromosome 1q21-q31. Fingert JH.4:47-50 CrossRef | Web of Science | Medline 23. Allingham RR. et al.413:349-353 CrossRef | Web of Science | Medline 25. Wang Y. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma. Arch Ophthalmol 2007.275:668-670 CrossRef | Web of Science | Medline 28. a protein involved in juvenile open angle glaucoma with homology to myosin and olfactomedin.103:808-814 Web of Science | Medline 22. Identification of a gene that causes primary open angle glaucoma. 28 Wiggs JL. Vollrath D. Boehnke M. Chen P. Ophthalmology 1996. Am J Hum Genet 1998. Nat Genet 1993. et al.211:126-139 CrossRef | Web of Science | Medline 26. Genomics 1997.

Wiggs JL.14:725-733 CrossRef | Web of Science | Medline 34. DaSilva A.338:1022-1027 Full Text | Web of Science | Medline 36. Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma. Invest . Adult-onset primary open-angle glaucoma caused by mutations in optineurin. 36 Allingham RR.48:73-94 CrossRef | Medline 35. Child A. 35 Alward WLM. Myocilin glaucoma. Hitchings R. et al. De La Paz MA. Hum Mol Genet 1997. Spaeth G. Binisti P. Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22. 31 Fingert JH. Stone EM.47:547-561 CrossRef | Web of Science | Medline 32. Brice G. Science 2002. Belmouden A. 33 Monemi S. Int Ophthalmol Clin 2008.295:1077-1079 CrossRef | Web of Science | Medline 33. Novel TIGR/MYOC mutations in families with juvenile onset primary open angle glaucoma. 34 Challa P. Surv Ophthalmol 2002.1. et al. Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma. Glaucoma genetics. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). Coote MA. Child A. et al. Hum Mol Genet 2005.35:989992 CrossRef | Web of Science | Medline 30. 29 Stoilova D. Alward WL. et al. Sheffield VC. et al. et al. 32 Rezaie T. J Med Genet 1998. Fingert JH.6:2091-2097 CrossRef | Web of Science | Medline 31. N Engl J Med 1998. 30 Adam MF.29.

Polansky JR. Andrews M. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. an olfactomedin-related glycoprotein cloned from glucocorticoid-induced trabecular meshwork cells. 38 Nguyen TD. 41 O'Brien TE. Bloemendal H. J Biol Chem 1998. 42 Wordinger RJ. Hum Mol Genet 2001. Nguyen TD. Polansky JR. 37 Fingert JH.39:517525 Web of Science | Medline 40. 43 . Huang WD. Metheney CD. Chen P. Johnson D. Gene structure and properties of TIGR. Localization of the stress proteins alpha B-crystallin and trabecular meshwork inducible glucocorticoid response protein in normal and glaucomatous trabecular meshwork. Genome Res 1998. May CA. Invest Ophthalmol Vis Sci 1998. Polansky JR. Swiderski RE.273:6341-6350 CrossRef | Web of Science | Medline 39.Ophthalmol Vis Sci 1998.19:517-524 CrossRef | Web of Science | Medline 42. 40 Jacobson N. Clark AF.8:377-384 Web of Science | Medline 38. Shepard AR. Johnson DH. 39 Lutjen-Drecoll E. et al. et al.39:2288-2295 Web of Science | Medline 37. Chen H.18:629-667 CrossRef | Web of Science | Medline 43.10:117-125 CrossRef | Web of Science | Medline 41. Non-secretion of mutant proteins of the glaucoma gene myocilin in cultured trabecular meshwork cells and in aqueous humor. Characterization and comparison of the human and mouse GLC1A glaucoma genes. Prog Retin Eye Res 1999. Ying L. Curr Eye Res 1999. Immunofluorescence method for quantifying the trabecular meshwork glucocorticoid response (TIGR) protein in trabecular meshwork and Schlemm's canal cells.

et al. Savinova OV. 45 Lam DS. Mol Cell Biol 2001. Expression of mutated mouse myocilin induces open-angle glaucoma in transgenic mice. 46 Kim BS. Invest Ophthalmol Vis Sci 2000. 47 Gould DB. Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma.8:2221-2228 CrossRef | Web of Science | Medline 49. Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function. Reedy MV. Mol Cell Biol 2004. Intracellular sequestration of heterooligomers formed by wild-type and glaucoma-causing myocilin mutants. Rodrigue MA.24:9019-9025 CrossRef | Web of Science | Medline 48. Malyukova I.Gobeil S. et al. et al.16:609-617 CrossRef | Web of Science | Medline 50. Hum Mol Genet 2007. Hum Mol Genet 1999. Fariss R. Savinova OV. 44 Wiggs JL.21:7707-7713 CrossRef | Web of Science | Medline 47.41:1386-1391 Web of Science | Medline 46. et al. Miceli-Libby L. et al. Millar JC. Vollrath D. Truncations in the TIGR gene in individuals with and without primary open-angle glaucoma. 48 Zhou Z. Molecular and clinical evaluation of a patient hemizygous for TIGR/MYOC.45:3560-3567 CrossRef | Web of Science | Medline 44. et al. Invest Ophthalmol Vis Sci 2004. J Neurosci . Leung YF. Jacobson N. Arch Ophthalmol 2001. 49 Shepard AR. A cellular assay distinguishes normal and mutant TIGR/myocilin protein.119:1674-1678 Web of Science | Medline 45. Chua JK. 50 Senatorov V. Vollrath D. Glaucoma-causing myocilin mutants require the peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure. Moisan S.

Craig JE. 51 Alvarado J. Sivalingam E. J Glaucoma 2003. The glaucomas.49:1932-1939 CrossRef | Web of Science | Medline 56.87:257-267 CrossRef | Web of Science | Medline 57. In: Ritch R.2006. Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals. 2nd ed. Rohen JW. St.91:564-579 Web of Science | Medline 52. Histopathology of 150 trabeculectomy specimens in glaucoma. 53. Heersink S. Trans Ophthalmol Soc U K 1976. Murphy C. Grinchuk O. Ophthalmology 1984.26:11903-11914 CrossRef | Web of Science | Medline 51.96:245-255 Medline 54. Weinreb S. 1996:89-123. McLean IW. 53 Rodrigues MM.12:237-242 CrossRef | Web of Science | Medline 55. Tonography demonstrates reduced facility of outflow of aqueous humor in myocilin mutation carriers. Distribution of axonal and glial elements in the rhesus optic nerve head studied by electron microscopy. Morphology of aqueous outflow pathways in normal and glaucomatous eyes. 52 Lütjen-Drecoll E. Am J Ophthalmol 1976. Juster R. Shields MB. et al. Tomarev SI. 57 Minckler DS. Krupin T. Exp Eye Res 2008. Transgenic mice expressing the Tyr437His mutant of human myocilin protein develop glaucoma. et al. van der Straaten D. 54 Wilkinson CH. 56 Paper W. Tso MO. Kroeber M. 55 Zhou Y. Spaeth GL. Elevated amounts of myocilin in the aqueous humor of transgenic mice cause significant changes in ocular gene expression. Louis: Mosby.82:179-187 Web of Science | Medline . Invest Ophthalmol Vis Sci 2008. eds.

et al.26:45-55 CrossRef | Web of Science | Medline 62. Invest Ophthalmol Vis Sci 2000. 2005:1-10. Duane's foundations of clinical ophthalmology. Zack DJ. Rao NA. 60 Vrabec JP. Rubin RM. Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Philadelphia: Lippincott Williams & Wilkins. Cringle SJ. Bass L.41:3460-3466 Web of Science | Medline 63. 65 . Ophthalmol Clin North Am 2005. Kwon YH. Zack DJ. McKinnon SJ. Levin LA. Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection. Kerrigan-Baumrind LA. In: Tasman W. Quigley HA.41:764-774 Web of Science | Medline 64. Morgan WH. eds. 59 Kuehn MH. Eye 2007. Invest Ophthalmol Vis Sci 2000. Tezel G. Yu DY. Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. 64 Balaratnasingam C. The neurobiology of cell death in glaucoma. Jaeger EA. Retinal ganglion cell death in glaucoma: mechanisms and neuroprotective strategies. 63 Pease ME. Fingert JH.18:383-395 CrossRef | Medline 60. Anatomy and embryology of the optic nerve. 58 Zhang J. Axonal transport and cytoskeletal changes in the laminar regions after elevated intraocular pressure.48:3632-3644 CrossRef | Web of Science | Medline 65. 61 Wax MB. 59. Mol Neurobiol 2002. McKinnon SJ.21:Suppl 1:S11-S14 CrossRef | Web of Science | Medline 61. Invest Ophthalmol Vis Sci 2007.58. 62 Quigley HA. Matich G.

14:224-233 Web of Science | Medline 68. Sanez DA. Free Radic Biol Med 2004. 69 Tezel G. Ritch R. Peng PH. Yang X. Grieshaber MC. Invest Ophthalmol Vis Sci 2007. Invest Ophthalmol Vis Sci 2005. Ma MC. Crowston JG. Sande P. 68 Ko ML. 70 Liu Q.37:803-812 CrossRef | Web of Science | Medline 72. Dynamic changes in reactive oxygen species and antioxidant levels in retinas in experimental glaucoma. Oxygen and blood flow: players in the pathogenesis of glaucoma.48:4580-4589 CrossRef | Web of Science | Medline 71. Luo C. Ju WK. Keller Sarmiento MI.46:3177-3187 CrossRef | Web of Science | Medline 70. Accelerated aging in glaucoma: immunohistochemical assessment of advanced glycation end products in the human retina and optic nerve head. Rao NA. Invest Ophthalmol Vis Sci 2007. Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head.48:1201- . Mol Vis 2008. Arch Ophthalmol 2004. 72 Tezel G. 71 Moreno MC. Retinal oxidative stress induced by high intraocular pressure. Cai J.Rajendram R. Wax MB. 66 Tezel G. 67 Mozaffarieh M. Yang X. Br J Ophthalmol 2007. et al. Chen CF. Flammer J. Oxidative stress is an early event in hydrostatic pressure induced retinal ganglion cell damage. Neuroglobin in normal retina and retina from eyes with advanced glaucoma. Rosenstein RE.39:365-373 CrossRef | Web of Science | Medline 69.91:663-666 CrossRef | Web of Science | Medline 66. Free Radic Biol Med 2005. Proteomic identification of oxidatively modified retinal proteins in a chronic pressure-induced rat model of glaucoma.122:1348-1356 CrossRef | Web of Science | Medline 67. Campanelli J.

Gene Ther 2009. Oglesby E. Mol Vis . Grosskreutz CL. Downregulation of Thy1 in retinal ganglion cells in experimental glaucoma. et al. Li Y.45:1247-1258 CrossRef | Web of Science | Medline 76. Johnson EC. Clark AF. Ahn JH. Retinal ganglion cells downregulate gene expression and lose their axons within the optic nerve head in a mouse glaucoma model. 77 Soto I. Johnson EC. 79 Schlamp CL. Morrison JC. Redox proteins thioredoxin 1 and thioredoxin 2 support retinal ganglion cell survival in experimental glaucoma. Gene expression profile of the adult human retinal ganglion cell layer. Caprioli J.31:265-271 CrossRef | Web of Science | Medline 79. Brown KM.16:17-25 CrossRef | Web of Science | Medline 74. Changes in Thy1 gene expression associated with damaged retinal ganglion cells. Guo Y. Curr Eye Res 2006. Mol Vis 2006. Tomarev SI. Pease ME. Changes in gene expression in experimental glaucoma and optic nerve transection: the equilibrium between protective and detrimental mechanisms.48:5539-5548 CrossRef | Web of Science | Medline 75. 73 Munemasa Y. Kwong JM. Stephan DA. Morrison JC. 75 Ahmed F. et al. Piri N. J Neurosci 2008. Kuehn MH. 76 Kim CY. Nickells RW. Fileta J. Quigley HA. Kwon YH.12:1640-1648 Web of Science | Medline 77.28:548-561 CrossRef | Web of Science | Medline 78. Buckingham BP. Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. 78 Huang W. Invest Ophthalmol Vis Sci 2004. Invest Ophthalmol Vis Sci 2007. 74 Yang Z.1211 CrossRef | Web of Science | Medline 73.

Physiol Genomics 2004. Horner PJ. 80 Steele MR. Hernandez MR. Prog Retin Eye Res 2000. Calkins DJ. Salvador-Silva M. Vetter ML.17:157-169 CrossRef | Web of Science | Medline 86. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling.2001. 84 Hernandez MR. Varela HJ. Glia 2001. Exp Eye Res 1999. 85 Yang P. Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma. Agapova OA.38:45-64 CrossRef | Web of Science | Medline 85. Ricard CS. Agapova O. DNA microarray analysis of gene expression in human optic nerve head astrocytes in response to hydrostatic pressure. Glia 2002. et al. Parker A.19:297-321 CrossRef | Web of Science | Medline . Enhanced tenascin expression associated with reactive astrocytes in human optic nerve heads with primary open angle glaucoma.33:205-216 CrossRef | Web of Science | Medline 84. Yang P. Curr Opin Ophthalmol 2004. The immune system and glaucoma. 82 Pena JD.68:29-40 CrossRef | Web of Science | Medline 83. Inman DM. 81 Tezel G. Differential gene expression in astrocytes from human normal and glaucomatous optic nerve head analyzed by cDNA microarray. Salvador-Silva M. Aoi S. Hernandez MR. Ricard CS.7:192-201 Web of Science | Medline 80. Invest Ophthalmol Vis Sci 2006. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human optic nerve head astrocytes. Wax MB. Ricard CS. 83 Agapova OA.15:80-84 CrossRef | Medline 82. 86 Hernandez MR.47:977-985 CrossRef | Web of Science | Medline 81.

91 Yan X. Edward DP. 90 Tezel G. Doser TA. Wax MB. 3-D histomorphometry of the normal and early glaucomatous monkey optic nerve head: prelaminar neural tissues and cupping. Downs JC. Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. 93 Johnson EC. Kwong JM. Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model. 89 Kitaoka Y. 87 Burgoyne CF.48:31613177 CrossRef | Web of Science | Medline . Bellezza A.42:1787-1794 Web of Science | Medline 91. 88 Nakazawa T. J Neurosci 2006.118:666-673 Web of Science | Medline 92. TNF-alpha-induced optic nerve degeneration and nuclear factor-kappaB p65. Invest Ophthalmol Vis Sci 2006. Cepurna WO. Morrison JC. Invest Ophthalmol Vis Sci 2001. Wax MB. Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Downs JC. Tezel G. Matsubara A. Invest Ophthalmol Vis Sci 2007.47:1448-1457 CrossRef | Web of Science | Medline 90.48:5068-5084 CrossRef | Web of Science | Medline 93. Li LY. 92 Yang H. TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Ross-Cisneros FN. J Glaucoma 2008. Patil RV. Burgoyne CF.17:318-328 CrossRef | Web of Science | Medline 88. et al. et al. Invest Ophthalmol Vis Sci 2007. Arch Ophthalmol 2000. Jia L. Thompson H. Premise and prediction: how optic nerve head biomechanics underlies the susceptibility and clinical behavior of the aged optic nerve head. Nakazawa C.87.26:12633-12641 CrossRef | Web of Science | Medline 89.

97 Howell GR. Hernandez MR. 99 Jakobs TC.7:66-66 CrossRef | Web of Science | Medline 99. Jakobs TC. 96 Quigley HA. J Cell Biol 2005. Ben Y. J Cell Biol 2007.1:17-26 CrossRef | Web of Science | Medline 101. 100 Libby RT. Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric.55:1085-1098 CrossRef | Web of Science | Medline 95. Parker A. Li Y. 95 Morrison JC. Dorman-Pease ME. Juarez S.108:1020-1024 CrossRef | Web of Science | Medline 96. Arch Ophthalmol 1990. Li Y. Pressure induces loss of gap junction communication and redistribution of connexin 43 in astrocytes.94. Savinova OV. 101 .179:1523-1537 CrossRef | Web of Science | Medline 98. Libby RT. Dietz JA. Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. John SW. Masland RH. Glia 2007. PLoS Genet 2005. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. Dunkelberger GR.18:39-57 CrossRef | Web of Science | Medline 97. Quigley HA. Neuronal death in glaucoma. et al. 94 Malone P. Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. BMC Neurosci 2006. et al.171:313-325 CrossRef | Web of Science | Medline 100. Janssen KT. Nickells RW. Libby RT. 98 Schlamp CL. Prog Retin Eye Res 1999. Miao H. Optic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma.

Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis.48:5567-5581 CrossRef | Web of Science | Medline 103. Patil RV. Kerrigan LA. Lutjen-Drecoll E. Induction of HLA-DR expression in human lamina cribrosa astrocytes by cytokines and .36:774-786 Web of Science | Medline 106. Agapova O. TUNEL-positive ganglion cells in human primary open-angle glaucoma. et al.115:1031-1035 CrossRef | Web of Science | Medline 105. Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Invest Ophthalmol Vis Sci 2001. et al.42:2303-2314 Web of Science | Medline 104.1:14-14 CrossRef | Medline 108. Sretavan DW. Luong V. Invest Ophthalmol Vis Sci 1995. Wax MB. Morphology of the murine optic nerve. Increased elastin expression in astrocytes of the lamina cribrosa in response to elevated intraocular pressure. Quigley HA. Gabelt BT. Invest Ophthalmol Vis Sci 2002. 102 Du J. Guo L. 107 Streit WJ. Nickells RW. Pease ME. 105 Quigley HA. Pease ME. Tezel G. 104 Kerrigan LA. Zack DJ.May CA.101:13352-13356 CrossRef | Web of Science | Medline 107. Yang P. 108 Yang J. Zack DJ. Upregulation of EphB2 and ephrin-B2 at the optic nerve head of DBA/2J glaucomatous mice coincides with axon loss. Fu C. Invest Ophthalmol Vis Sci 2007. Griffin WS. 103 Pena JD.43:2206-2212 Web of Science | Medline 102. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004. Mrak RE. Hernandez MR. Proc Natl Acad Sci U S A 2004. Smith SD. Arch Ophthalmol 1997. Thibault DJ. Tran T. 106 Cordeiro MF.

2012. Yang X. Kim CY. Ostojic J. 279-290 CrossRef 3. (2012) The role of TGF-β in the pathogenesis of primary open-angle glaucoma.42:365-371 Web of Science | Medline 109. 2 Rudolf Fuchshofer. Cell and Tissue Research 347:1. Ronald D. Tamm.47:1024-1029 CrossRef | Web of Science | Medline 110. Retinal synthesis and deposition of complement components induced by ocular hypertension. Complement component 1Q (C1Q) upregulation in retina of murine. 109 Stasi K. 110 Kuehn MH. primate. (2012) 3D simulation of the aqueous flow in the human eye. Orestis Vardoulis. Exp Eye Res 2006. Yue.83:620-628 CrossRef | Web of Science | Medline Citing Articles (41) 1.simulated ischemia. 223-258. 5299-5307 CrossRef 5.T. Journal of Pharmaceutical Sciences 100:12. Pamulapati. et al. Cellular and Molecular Biology of Optineurin. Reda Hasballa. Invest Ophthalmol Vis Sci 2001. Sylvain Roy. . Nagel D. Schoenwald. (2011) Ocular hypotensive action of a novel tetrahydroquinoline analog in rabbit: Physicochemical evaluation. Medical Engineering & Physics CrossRef 2. Philippe Reymond.J. and human glaucomatous eyes. 1 Adan Villamarin. et al. Invest Ophthalmol Vis Sci 2006. 4 Chandrasena R. 5 . 3 Hongyu Ying. Nikolaos Stergiopulos. Ernst R. Beatrice Y. CrossRef 4.

Tomarev. Anja K. (2011) Depletion of optineurin in RGC-5 cells derived from retinal neurons causes apoptosis and reduces the secretion of neurotrophins. Kevin Bugge. (2011) Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. Ernst R. 3392-3402 CrossRef 6. Catherine Creuzot-Garcher. (2011) Amyloid Fibril Formation by the Glaucoma-Associated Olfactomedin Domain of Myocilin. (2011) 24S-hydroxycholesterol and cholesterol-24Shydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma.Heung Sun Kwon. promotes cell migration through activation of integrin-focal adhesion kinase-serine/threonine kinase signaling pathway. 6 Susan D. Kuehn. Abbot F. 3542-3553 CrossRef 11. Orwig. Darryl Y. Sheffield. Searby. Nishimura. Chemistry and Physics of Lipids 164:6. 7 Christiane Sippl. Aging Health 7:5. Rand Allingham. 9 Mukhtar Bizrah. Bosserhoff. (2011) Myocilin. Perry. 8 Yutao Liu. Tamm. 719-733 CrossRef 10. Experimental Eye Research 93:5. R. Raquel L. Christopher W. 331-339 CrossRef 9. Zode. (2011) Glaucoma and Alzheimer’s disease in the elderly. Lionel Bretillon. Li Guo. Laura Y. Ingeborg Schmidt-Krey. Kim. Lieberman. Charles C. Journal of Molecular Biology CrossRef 7. 669-680 CrossRef 8. Michael G. Journal of Cellular Physiology 226:12. Markus H. Kabhilan Mohan. Anderson. 10 Gulab S. Dietmar Fischer. Rong Zhang. Sinisa D. 11 Cynthia Fourgeux. Clark. Journal of Clinical Investigation 121:9. Stanislav I. Stone. Grozdanic. Maria Francesca Cordeiro. Turnage. Niyazi Acar. a glaucomaassociated protein. Katherine C. Douglas Vollrath. Val C. Experimental Eye Research 93:4. (2011) Molecular genetics in glaucoma. Alain Bron. 496- . Edwin M.

Robbert P van Manen. Zegers. W. 2482-2494 CrossRef 16. Turnage. F. H. 15 J. J. A. J. (2011) Common genetic variants associated with open-angle glaucoma. N. A. Stefansson. (2011) The Stability of Myocilin Olfactomedin Domain Variants Provides New Insight into Glaucoma as a Protein Misfolding Disorder. Hofman. van Koolwijk. W. C. Jansonius. Thorleifsson. (2011) Potential for Linezolid-Related Blindness: A Review of Spontaneous Adverse Event Reports. M. t. H. M. 585-590 CrossRef 17. Scheetz. Jacoline. Pharmacotherapy 31:6. L. R. Oostra. Cynthia L. Mullins. J. Wolfs. R. Samuel L Aitken. Stone. R. Y. A. 14 W. Jonasson.499 CrossRef 12. Uitterlinden. B. Kwon. P. V. van Duijn. Nicole Burns. L. de Jong. H. Human Molecular Genetics 20:12. T. Lieberman. Welgen-Lussen. Rivadeneira. C. S. T. Amin. F. T. M. Biochemistry 50:26. Kirwan. K. D. Ramdas. H. (2011) WITHDRAWN: Reprint of: Mechanisms of retinal ganglion cell injury and defense in glaucoma. Walters. G. H. 5824-5833 CrossRef 13. 12 J. L. Human Molecular Genetics 20:12. Danyi Wang. Alward. V. N. B. C. G. Weisschuh. Bergen. L. 17 . C. A. Wassink. C. Fingert. Reis. A. F. Stone. Gibson. Klaver. J. E. Cree. Walker. B. C. F. U. Lotery. N. Raquel L. Roos. K. Bennett. Davis. Lemij. A. Experimental Eye Research CrossRef 14. R. M. J. Chandler A. Thorsteinsdottir. 2464-2471 CrossRef 15. (2011) Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. U. B. Katherine C. L. Sheffield. Mardin. G. E. Robin. F. W. Pasutto. Janssen. Vingerling. F. 16 Jack Brown. A. J. M. C. Y. Gramer. E. M. R. 13 Juan Qu. C. A. Grosskreutz. A. B. E. R. G. S.

231-237 CrossRef 24. Eye 25:5. Osman. Lee. 1932-1942 Full Text 20. 1017-1023 CrossRef 18. Nicole Weisschuh. Alan E. Michal Kowalski. Azad. Hauser. Val C. Malgorzata Stanczyk. Rand Allingham. (2011) Evaluation of oxidative stress markers in pathogenesis of primary open-angle glaucoma. 23 Ireneusz Majsterek. (2011) A Critical Appraisal and Comparison of the Quality and Recommendations of Glaucoma Clinical Practice Guidelines. Guttmacher. Eugen Gramer. 18 Chun Ding. Sheffield. Friedrich E Kruse. Gregory. Ronald Roepman. 21 Khaled K. Bernhard HF Weber. Ivan Goldberg. Experimental and Molecular Pathology 90:2. Ophthalmic Genetics1-5 CrossRef 22. Christian Y Mardin. Stef Letteboer.. André Reis. . (2011) Genomics and the Eye. Edwin M. Essam A. R. Szaflik. (2011) Lack of association between LOXL1 gene polymorphisms and primary open angle glaucoma in the Saudi Arabian population.. Experimental Eye Research 92:6. Ning Tian. Abu-Amero. 512-520 CrossRef 19.Yvonne Ou. (2011) Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma. Francesca Pasutto. 22 Lorena Fernández-Martínez. European Journal of Human Genetics 19:4. Bernd Rautenstrauss. 587-595 CrossRef 21. (2011) Effect of general anesthetics on IOP in elevated IOP mouse model. Michael A. (2011) Primary open-angle glaucoma genes. Paul P. Kurowska. Anna Kaminska. 445-451 CrossRef 23. Jacek P. Jan Blaszczyk. Anna K. 19 Feero. Ophthalmology 118:6. 24 . New England Journal of Medicine 364:20. Paulo A Ferreira. 20 J H Fingert. Ping Wang. Jerzy Szaflik.. . W. Al-Obeidan. Katarzyna Malinowska. Clive Migdal. Mohammad T. Saleh A. Stone.

Tae-Woo Kim. 30 Phulwinder K. Seok Hwan Kim.Harry A Quigley. Ian B. American Journal of Ophthalmology 151:2. . (2011) Mild systemic hypoxia and photopic visual field sensitivity. Acta Ophthalmologica 89:2. Seung-Sik Hwang. (2010) Biomarkers of primary open-angle glaucoma. Sung Jun Kim. P. Beatrice YJT Yue. 422435 CrossRef 28. E. (2011) Lack of WDR36 leads to preimplantation embryonic lethality in mice and delays the formation of small subunit ribosomal RNA in human cells in vitro. Bosl. Adrian G. The Lancet 377:9774. M. 29 Paul A Knepper. Meinel. Genetics of Glaucoma. James Duggan. (2011) Comparison of the Correlations Between Optic Disc Rim Area and Retinal Nerve Fiber Layer Thickness in Glaucoma and Nonarteritic Anterior Ischemic Optic Neuropathy. Thomas E. M. (2010) Stem cell marker olfactomedin 4: critical appraisal of its characteristics and role in tumorigenesis. Andrew J. Stewart. Dong Myung Kim. 761-775 CrossRef 31. R Rand Allingham. 26 Min Hee Suh. (2011) Glaucoma. Expert Review of Ophthalmology 5:6.e1 CrossRef 27. M. (2010) Neuroprotection in glaucoma – Is there a future role?. Cancer and Metastasis Reviews 29:4. M. CrossRef 29. 2010. Cummins. Gallenberger. . Kroeber. 731-742 CrossRef 30. Milkereit. Human Molecular Genetics 20:3. Francesca Cordeiro. Salt. R. R. Hardingham. e199-e204 CrossRef 26. Zele. 27 M. Wegner. D. John R Samples. 31 Abeir Baltmr. Tamm. Ki Ho Park. 28 Yutao Liu. Shereen Nizari. Jennifer E. 1367-1377 CrossRef 25. 25 Beatrix Feigl. M. Grover. 277-286.

38 Monique P. 36 Myung Kuk Joe. 554-566 CrossRef 32. Li Jia Chen. e62 CrossRef 33.J. The American Journal of Pathology 176:6. 48-53 CrossRef 34. Tomarev. (2010) Linking structure and function in glaucoma. Fredette. (2009) Bimatoprost.Experimental Eye Research 91:5. 371-386 CrossRef 36. (2010) Carnitine reduces the lipoperoxidative damage of the membrane and apoptosis after induction of cell stress in experimental glaucoma. Current Opinion in Ophthalmology 21:2. Wheat. M. (2010) Expression of Myocilin Mutants Sensitizes Cells to Oxidative Stress-Induced Apoptosis. 33 Juan Qu. G Risuleo. Curran. Grosskreutz. (2010) Glaucoma in Latinos/Hispanics. C De Seta. 100-105 CrossRef 38. Harwerth. Danyi Wang. 39 . 35 Timothy YY Lai. G Scarsella. 32 N Calandrella. Clement CY Tham. Drugs & Aging 26:12. Cell Death and Disease 1:8. (2010) Development of novel drugs for ocular diseases: possibilities for individualized therapy. Stanislav I. 2880-2890 CrossRef 37. Rohit Varma. Progress in Retinal and Eye Research 29:4. Gary HF Yam. Personalized Medicine 7:4. 34 R. Experimental Eye Research 91:1.S. Chi Pui Pang. Cynthia L. Anderson.L. 37 Elma Kim. 1049-1071 CrossRef 39. D.R. J. (2010) Mechanisms of retinal ganglion cell injury and defense in glaucoma. 249-271 CrossRef 35.

2679-2680 Full Text Letters . Naoki Nakaya. G. G. 122-138 CrossRef 40. Mantelli. Centofanti. Aloe. S. Bonini. R.Stanislav I. Bucci. F. (2009) Olfactomedin DomainContaining Proteins: Possible Mechanisms of Action and Functions in Normal Development and Pathology. (2009) Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. L. Levi-Montalcini. Tomarev. Parisi. Manni. M. V. 41 (2009) Primary Open-Angle Glaucoma. M. 40 A. New England Journal of Medicine 360:25. V. 13469-13474 CrossRef 41. Molecular Neurobiology 40:2. Lambiase. L. Proceedings of the National Academy of Sciences 106:32. Colafrancesco.