Other entities represented in this entry:
SNOMEDCT: 77075001; ICD10CM: H40.11; ICD9CM: 365.11; DO: 1070;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p13 | Glaucoma 1, open angle, E | 137760 | Autosomal dominant | 3 | OPTN | 602432 |
A number sign (#) is used with this entry because of evidence that this form of adult-onset primary open angle glaucoma (POAG), designated GLC1E, is caused by heterozygous mutation in the OPTN gene (602432) on chromosome 10p13.
Quigley (1993) reviewed adult-onset primary open angle glaucoma, which combines a particular abnormal appearance of the optic disc (optic nerve head) with a slowly progressive loss of visual sensitivity. Many patients with glaucoma have intraocular pressures above the normal range, although this cannot be considered part of the definition of the disease, since some patients have normal intraocular pressures. Changes in the optic disc, either inherited or acquired, contribute to the development of the disorder, which leads to visual loss from increasing nerve fiber layer atrophy. Quigley et al. (1994) stated that POAG should be reviewed as a multifactorial disorder.
Genetic Heterogeneity of Primary Open Angle Glaucoma
Other forms of primary open angle glaucoma include GLC1A (137750), caused by mutation in the MYOC gene (601652) on chromosome 1q24; GLC1B (606689) on chromosome 2cen-q13; GLC1C (601682) on chromosome 3q21-q24; GLC1D (602429) on chromosome 8q23; GLC1F (603383), caused by mutation in the ASB10 gene (615054) on chromosome 7q36; GLC1G (609887), caused by mutation in the WDR36 gene (609669) on chromosome 5q22; GLC1H (611276), caused by mutation in the EFEMP1 gene (601548) on chromosome 2p16; GLC1I (609745) on chromosome 15q11-q13; GLC1J (608695) on chromosome 9q22; GLC1K (608696) on chromosome 20p12; GLC1L (see 137750) on chromosome 3p22-p21; GLC1M (610535) on chromosome 5q22; GLC1N (611274) on chromosome 15q22-q24; GLC1O (613100), caused by mutation in the NTF4 gene (162662) on chromosome 19q13; GLC1P (177700), caused by an approximately 300-kb duplication on chromosome 12q24, most likely involving the TBK1 gene (604834).
Nail-patella syndrome (NPS; 161200), which is caused by mutation in the LMX1B gene (602575) on chromosome 9q34, has open angle glaucoma as a pleiotropic feature.
Other Forms of Glaucoma
For a general description and a discussion of genetic heterogeneity of congenital forms of glaucoma, see GLC3A (231300).
See 606657 for a discussion of normal tension glaucoma (NTG) or normal pressure glaucoma (NPG), a subtype of POAG.
See 618880 for a discussion of primary closed-angle glaucoma.
Tanito et al. (2004) described the use of a digitized laser slit lamp that uses a helium-neon laser as a light source in detecting reduction of posterior pole retinal thickness in glaucoma. Posterior pole retinal thickness was found to be decreased in early and moderate stage POAG. Reduction of perifoveal retinal thickness was correlated with visual field loss.
In a study of 4,319 subjects in the Beijing Eye Study stratified into several myopia subgroups, Xu et al. (2007) found that marked to high myopia with a myopic refractive error exceeding -6 diopters was associated with a high prevalence of glaucomatous optic neuropathy.
Using topical application of dexamethasone, Armaly (1966) concluded that subjects can be divided into 3 classes according to the response of intraocular pressure--high, intermediate, and low. He interpreted these 3 phenotypes to correspond to the 3 genotypes of a 2-allele system.
Southren et al. (1985) presented evidence for an alteration in cortisol metabolism in primary open angle glaucoma. Changes in 2 enzymes were found: a greater than 100-fold increase in cortisol delta-4-reductase and a 4-fold or greater decrease in 3-oxidoreductase activities. The increase of the former activity appeared to be the result of increased synthesis of the enzyme. In normal mammalian tissues, cortisol is metabolized by delta-4-reductase to dihydrocortisol and then by 3-oxidoreductase to tetrahydrocortisol with no significant accumulation of dihydrocortisol. The intermediate 5-beta-dihydrocortisol that accumulates in human trabecular meshwork (TM) at the angle of the anterior chamber in cases of POAG potentiates effects of glucocorticoids in raising intraocular pressure in rabbits.
Yang et al. (2001) analyzed T-cell subsets and levels of cytokine IL2 (147680) and soluble IL2 receptor (see, e.g., 147730) in the peripheral blood of patients with normal pressure glaucoma and primary open angle glaucoma and compared them to values in age-matched controls. They found increased frequency of CD8+/HLA-DR+ lymphocytes in patients with NPG and increased CD3+/CD8+ lymphocytes in both NPG and POAG patients. CD5+ lymphocytes were higher only in POAG patients. The mean concentration of soluble IL2R was higher in NPG and POAG patients than in controls although the IL2 concentration was similar in patients and controls. Also, the reactivity of T lymphocytes to the nonspecific reagent phytohemagglutinin was reduced significantly in both NPG and POAG patients. The authors concluded that the immune system might play an important role in initiation or progression of glaucomatous optic neuropathy in some patients.
Although POAG has traditionally been associated with high intraocular pressure (IOP), glaucoma is considered a multifactorial disorder. Ferreira et al. (2004) measured the total reactive antioxidant potential (TRAP) and the activities of antioxidant enzymes in the aqueous humor of 24 POAG patients and 24 controls. The authors found that superoxide dismutase (SOD; 147450) activity, glutathione peroxidase (GPX; 138320) activity, and TRAP might be useful oxidative stress markers in the aqueous humor of glaucoma patients.
Gherghel et al. (2005) found that patients with newly diagnosed POAG exhibited low levels of circulating glutathione, suggesting a general compromise of the antioxidative defense system.
Transforming growth factor beta-2 (TGFB2; 190220) is present at elevated levels in the aqueous humor of patients with POAG. Studies have shown that TGFB2 influences cultured trabecular meshwork cells. Gottanka et al. (2004) found that TGFB2 reduced outflow facility when perfused into cultured human anterior segments. Furthermore, TGFB2 affected the extracellular matrix (ECM) of the trabecular meshwork in a manner that was consistent with the observed reduction in outflow facility. Although the distribution of accumulated fibrillar material was different in these perfused eyes than that in POAG, the difference could have been due to variation in biomechanical environment for trabecular meshwork cells in cultured anterior segments compared with the living eye. Overall, the results supported the hypothesis that elevated TGFB2 levels in the aqueous humor played a role in the pathogenesis of the ocular hypertension in POAG.
Vranka et al. (2015) reviewed the development and function of the ECM in the trabecular meshwork and the involvement of the ECM and the TGFB2 gene in glaucoma.
Xue et al. (2007) found that human trabecular meshworks from glaucoma donors exhibited significantly higher activity levels of the calcification marker alkaline phosphatase (ALP) than their matched counterparts with normal eyes. Dexamethasone (Dex) and TGFB2, both of which are associated with glaucoma, significantly induced the upregulation of ALP activity in 2 trabecular meshwork primary cell lines. Silencing the inhibitor of calcification matrix Gla (MGP; 154870) by siRNA resulted in ALP activity that was increased by 197%. Xue et al. (2007) concluded that the increased activity of the calcification marker ALP in glaucomatous trabecular meshworks might be indicative of an underlying mineralization process during development of the disease. Inhibition of the calcification mechanism represented by the presence of active MGP appeared to be compromised in glaucomatous tissue.
Wordinger et al. (2007) studied the effects of altered bone morphogenetic protein signaling on intraocular pressure in POAG. They found that human trabecular meshwork synthesized and secreted BMP4 (112262) as well as expressed the BMP receptor subtypes BMPR1 (see 601299) and BMPR2 (600799). TM cells responded to exogenous BMP4 by phosphorylating SMAD signaling proteins (see 601595). Cultured human TM cells treated with TGFB2 significantly increased fibronectin (FN; 135600) levels, and BMP4 blocked this FN induction. There was significant elevation of mRNA and protein levels of the BMP antagonist Gremlin (GREM1; 603054) in glaucomatous TM cells. In addition, Gremlin was present in human aqueous humor. Gremlin blocked the negative effect of BMP4 on TGFB2 induction of FN. Addition of recombinant Gremlin to the medium of ex vivo perfusion-cultured human eye anterior segments caused the glaucoma phenotype of elevated IOP. Wordinger et al. (2007) concluded that these results were consistent with the hypothesis that, in POAG, elevated expression of Gremlin by TM cells inhibited BMP4 antagonism of TGFB2 and led to increased extracellular matrix deposition and elevated IOP.
Wang et al. (2006) assessed endothelin B receptor (EDNRB; 131244) expression in human glaucomatous optic nerves and the spatial relationship between EDNRB and astrocytes. The frequency of positive EDNRB immunoreactivity was significantly higher in human glaucomatous optic nerves as compared with age-matched controls (9/16 vs 1/10). EDNRB colocalized with astrocytic processes and was quantitatively higher in the glaucomatous eyes. Wang et al. (2006) concluded that increased EDNRB immunoreactivity in diseased optic nerves and its association with astrocytes suggested that the glia-endothelin system might be involved in the pathologic mechanisms of neuronal degeneration.
Polak et al. (2007) investigated the ocular blood flow response to systemic nitric oxide synthase (NOS; see 163731) inhibition in 12 patients with POAG and age-matched controls. POAG patients showed an abnormal blood flow response in the optic nerve head and the choroid as compared with controls, despite a comparable increase in systemic blood pressure. Polak et al. (2007) suggested that the NO system may be an attractive target for therapeutic interventions in glaucoma.
Bahler et al. (2008) studied the effects of 2 prostaglandin analogs, latanaprost free acid and prostaglandin E1 (PGE1), on outflow facility in cultured human anterior segments. They studied cultured anterior segments to eliminate the uveoscleral pathway and enable a direct assessment of trabecular outflow. Histologic changes indicated that prostaglandins have a direct trabecular meshwork effect.
Studies in families with and without cases of glaucoma led Armaly et al. (1968) to the conclusion that intraocular pressure and outflow facility are multifactorial in determination and that open angle glaucoma is probably multifactorial also. Schwartz et al. (1972) found low concordance in a twin study of effect of corticosteroids on intraocular pressure and concluded that inheritance is multifactorial.
The adult-onset primary open angle glaucoma usually has its onset after the age of 50 and is probably inherited as a complex trait, without an obvious segregation pattern.
Klein et al. (2004) investigated the family aggregation and heritability of risk indicators of primary open angle glaucoma. Heritability estimates were 0.36 for intraocular pressure, 0.55 for optic cup diameter, 0.57 for optic disc diameter, and 0.48 for cup-to-disc ratio. Correlations for the optic disc parameters were compatible with the amount of gene sharing in relative pairs of different degrees. The authors concluded that risk indicators for open angle glaucoma correlated highly in families, and the patterns were consistent with the hypothesis of genetic determinants of these factors.
Hewitt et al. (2007) performed a 2-stage study in a population-based sample of twins to determine the principal heritable components of visible optic nerve head structures that might be involved in the etiology of common blinding diseases such as glaucoma. Their results suggested that the shape and size of the optic disc and cup are more heritable and should receive a greater priority for quantification than should vascular features.
Coulehan et al. (1980) found that black participants in a glaucoma screening program had higher mean intraocular pressures, more frequent pathologic disc changes, and more new cases of glaucoma discovered than did whites matched for sex and age. In a 3-year period, blacks accounted for 23% of hospitalizations for chronic open angle glaucoma in 10 Pennsylvania counties, rather than the expected 6.3%. Among those hospitalized for open angle glaucoma, blacks were younger than whites.
Sarfarazi et al. (1998) identified a locus, designated GLC1E, in the 10p15-p14 region in a large British family with a classic form of normal tension glaucoma (606657). Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum lod score of 10 at a recombination fraction of 0.00 was obtained with D10S1216, 21 other markers provided significant values varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, lod scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Mutations in the OPTN gene were found to be a cause of POAG linked to chromosome 10p (Rezaie et al., 2002).
Nemesure et al. (2003) noted that 6 named loci contributing to POAG susceptibility had been identified by genetic linkage studies performed predominantly in Caucasian families. They evaluated the genetic component of POAG in a population of African descent in Barbados, West Indies, and found evidence of POAG loci located on chromosomes 2q and 10p.
Mapping by Genome Scan
Wiggs et al. (2000) performed a 2-stage genome scan using an initial pedigree set of 113 affected sib pairs and a second pedigree set of 69 affected sib pairs. In the combined data analysis, 5 regions (2, 14, 17p, 17q, and 19) produced a multipoint lod score greater than 2.0 between microsatellite markers and POAG. Multipoint analysis using ASPEX also showed significant results on chromosomes 2, 14, 17p, 17q, and 19.
Associations Pending Confirmation
Burdon et al. (2011) performed a genomewide association study in 590 patients with advanced POAG, with replication in an additional 334 patients with advanced OAG, 465 patients with less-severe POAG, and 93 cases from another glaucoma cohort. They found association with a SNP (rs4656461) located approximately 6.5 kb downstream of the TMCO1 gene (614123) on chromosome 1q24.1 (combined p = 6.00 x 10(-14); odds ratio, 1.51), and with a SNP (rs4977756) in the CDKN2BAS gene (613149) on chromosome 9p21 (combined p = 1.35 x 10(-14); odds ratio, 1.39). Burdon et al. (2011) also demonstrated retinal expression of genes at both loci in human ocular tissue.
Exclusion Studies
In 18 families with POAG in the United States, Allingham et al. (1998) excluded 2cen-q13 as the site of the mutation causing POAG.
Open angle glaucoma accounts for approximately 3% of blindness in white and 7.9% in black American populations (Quigley and Vitale, 1997). The disorder is diagnosed clinically by 3 tests to reveal characteristic glaucomatous optic nerve damage, characteristic visual field loss, and increased IOP. Normal or low tension glaucoma (606657) is a form of open angle glaucoma in which the typical glaucomatous cupping of the optic nerve head and visual field loss are present, but in which the recorded IOPs are consistently within the statistically normal range of less than 22 mm Hg. This form may account for about one-fifth of primary open angle glaucoma, although a single screening test may record normal tension glaucoma in more than one-half of cases.
Rezaie et al. (2002) identified mutations in the OPTN gene (602432.0001-602432.0005) in patients with adult-onset POAG. They found that mutations in OPTN account for 17% of patients with hereditary POAG, including individuals with normal intraocular pressure.
Chalasani et al. (2007) explored functional features of optineurin and its mutants. The E50K mutation (602432.0001) acquired the ability to induce cell death selectively in retinal ganglion cells. This cell death was mediated by oxidative stress. Chalasani et al. (2007) concluded that these findings raised the possibility of antioxidant use for delaying or controlling some forms of glaucoma.
Exclusion Studies
Nemesure et al. (2003) did not find support for myocilin (MYOC; 601652) or optineurin as a causative gene in an Afro-Caribbean population known to have relatively high rates of POAG.
Leung et al. (2000) found no abnormality of the TISR/oculomedin coding sequence or proximal promoter mutation in 110 Chinese patients with primary open angle glaucoma.
Open angle glaucoma is characterized by loss of retinal ganglion cells (RGCs), cupping of the optic disc, and defects in the visual field. Increased intraocular pressure (IOP) is the major known risk factor that produces glaucoma and glaucoma-like damage to the optic nerve and RGCs in experimental primate models. Harwerth et al. (1999) used argon laser treatments to the trabecular meshwork in 1 eye of each of 10 rhesus monkeys to create successful experimental glaucoma. Elevated intraocular pressure, followed by ganglion cell loss and visual field defects, ensued. However, other factors may interact with IOP to modulate its effect on the optic nerve. Disturbances of blood flow in the optic nerve head may be such a factor. Chauhan et al. (2004) described a model of chronic endothelin-1 (ET1; 131240) administration to the rat optic nerve and evaluated its effect on RGC and axon survival. ET1 led to a mean reduction in optic nerve blood flow of 68%. This resulted in a time-dependent loss of RGCs and their axons without apparent change in the optic disc topography.
Johnson et al. (2007) studied global gene expression changes in the optic nerve head (ONH) in a rat model of glaucoma with unilateral sustained IOP elevation. Microarray analysis identified more than 2,000 significantly regulated genes. For 225 of these genes, the changes were greater than 2-fold. The most significantly affected gene classes were cell proliferation, immune response, lysosome, cytoskeleton, extracellular matrix, and ribosome. A 2.7-fold increase in ONH cellularity confirmed glaucoma model cell proliferation. By quantitative PCR, increases in levels of periostin (608777), collagen VI (see 120220), and TGFB1 (190180) were linearly correlated to the degree of IOP-induced injury. For cyclin D1 (168461), fibulin-2 (135820), tenascin C (187380), TIMP1 (305370), and aquaporin-4 (600308), correlations were significantly nonlinear, displaying maximum changes with focal injury.
Borras et al. (2015) demonstrated that inhibiting the trabecular meshwork RhoA (165390) pathway by delivering a mutated, dominant-negative RhoA gene (scAAV2.dnRhoA) inside a long-expressing recombinant virus reduced nocturnal elevation of IOP in rats. By visual inspection, human trabecular meshwork cells infected with scAAV2.dnRhoA showed diminished stress fiber formation. A single-dose injection of scAAV2.dnRhoA into rat eyes prevented elevation of IOP during the nocturnal cycle for at least 4 weeks.
Sarfarazi (1997) reviewed advances concerning the molecular genetics of glaucomas. At the time of their review, 2 loci, GLC3A (231300) and GLC3B (600975), had been identified for primary congenital glaucoma, and mutations had been identified in the cytochrome p450 CYP1B1 gene (601771) in the former. The GLC1A locus had been identified for juvenile-onset primary open angle glaucoma, and mutations in MYOC (601652) identified. Furthermore, 2 loci, GLC1B (606689) and GLC1C (601682), had been identified for late-onset chronic open angle glaucoma by linkage studies.
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