# 606657

GLAUCOMA, NORMAL TENSION, SUSCEPTIBILITY TO


Alternative titles; symbols

NTG
GLAUCOMA, NORMAL PRESSURE, SUSCEPTIBILITY TO; NPG


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number		 Inheritance Phenotype
mapping key		 Gene/Locus Gene/Locus
MIM number
3q29 {Glaucoma, normal tension, susceptibility to} 606657 3 OPA1 605290
10p13 {Glaucoma, normal tension, susceptibility to} 606657 3 OPTN 602432

▼ TEXT

A number sign (#) is used with this entry because of evidence that susceptibility to normal tension glaucoma is associated with a particular intronic polymorphism of the optic atrophy-1 gene (OPA1; 605290) and mutation in the OPTN gene (602432).

▼ Clinical Features

Glaucoma is the second most common cause of blindness worldwide (Thylefors et al., 1995; Quigley, 1996). It is characterized by progressive loss of optic nerve axons and visual field damage. Most glaucoma in Caucasian and African American populations is of the primary open angle glaucoma (POAG) type (see 137760), in which elevated intraocular pressure (IOP) is a major feature (Sommer et al., 1991). Normal tension glaucoma (NTG) is an important subtype of POAG, in which the IOP is consistently within the statistically normal population range. NTG accounts for approximately one-third of all POAG cases (Bonomi et al., 1998). Because the IOP is normal when measured and patients often have good central vision, NTG is underdiagnosed and the condition presents late.


▼ Biochemical Features

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.


▼ Molecular Genetics

Association with OPA1

Because different mutations in the same gene may cause widely different phenotypes and because autosomal dominant optic atrophy (165500) due to mutation in the OPA1 gene shows a similar optic neuropathy in the absence of raised IOP, Aung et al. (2002) hypothesized that the OPA1 gene represents an excellent candidate gene for NTG. In a study of 2 cohorts of NTG patients, they found a strong association with a combination of 2 single nucleotide polymorphisms (SNPs) in intron 8 of the OPA1 gene (605290.0010).

In 137 patients with primary open angle glaucoma (POAG), including 67 with high tension glaucoma (HTG) and 70 with NTG, and 75 controls from the northeast of England, Yu-Wai-Man et al. (2010) analyzed 3 SNPs in the OPA1 gene and found significant association between the T allele at IVS8+4C-T and the risk of developing NTG (odds ratio, 2.04; p = 0.004) but not HTG. Logistic regression analysis confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR, 29.75; p = 0.001). Yu-Wai-Man et al. (2010) concluded that the CT/TT compound genotype in intron 8 of the OPA1 gene is a strong genetic risk determinant for NTG but not HTG.

Association with OPTN

Rezaie et al. (2002) identified a missense mutation (602432.0004) in the OPTN gene resulting in susceptibility to normal tension glaucoma.


▼ REFERENCES

  1. Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Krawczak, M., Thiselton, D. L., Alexander, C., Votruba, M., Brice, G., Child, A. H., Francis, P. J., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum. Genet. 110: 52-56, 2002. [PubMed: 11810296, related citations] [Full Text]

  2. Bonomi, L., Marchini, G., Marraffa, M., Bernardi, P., De Franco, I., Perfetti, S., Varotto, A., Tenna, V. Prevalence of glaucoma and intraocular pressure distribution in a defined population: the Egna-Neumarkt study. Ophthalmology 105: 209-215, 1998. [PubMed: 9479277, related citations] [Full Text]

  3. Quigley, H. A. Number of people with glaucoma worldwide. Brit. J. Ophthal. 80: 389-393, 1996. [PubMed: 8695555, related citations] [Full Text]

  4. Rezaie, T., Child, A., Hitchings, R., Brice, G., Miller, L., Coca-Prados, M., Heon, E., Krupin, T., Ritch, R., Kreutzer, D., Crick, R. P., Sarfarazi, M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295: 1077-1079, 2002. [PubMed: 11834836, related citations] [Full Text]

  5. Sommer, A., Tielsch, J. M., Katz, J., Quigley, H. A., Gottsch, J. D., Javitt, J., Singh, K. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Survey. Arch. Ophthal. 109: 1090-1095, 1991. [PubMed: 1867550, related citations] [Full Text]

  6. Thylefors, B., Negrel, A.-D., Pararajasegaram, R., Dadzie, K. Y. Global data on blindness. Bull. WHO 73: 115-121, 1995. [PubMed: 7704921, related citations]

  7. Yang, J., Patil, R. V., Yu, H., Gordon, M., Wax, M. B. T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am. J. Ophthal. 131: 421-426, 2001. [PubMed: 11292402, related citations] [Full Text]

  8. Yu-Wai-Man, P., Stewart, J. D., Hudson, G., Andrews, R. M., Griffiths, P. G., Birch, M. K., Chinnery, P. F. OPA1 increases the risk of normal but not high tension glaucoma. J. Med. Genet. 47: 120-125, 2010. [PubMed: 19581274, related citations] [Full Text]


Contributors:
Marla J. F. O'Neill - updated : 8/25/2010
Ada Hamosh - updated : 2/13/2002
Creation Date:
Victor A. McKusick : 1/30/2002
Edit History:
wwang : 08/26/2010
terry : 8/25/2010
ckniffin : 10/27/2004
terry : 6/27/2002
terry : 6/27/2002
carol : 2/13/2002
carol : 1/30/2002
carol : 1/30/2002

# 606657

GLAUCOMA, NORMAL TENSION, SUSCEPTIBILITY TO


Alternative titles; symbols

NTG
GLAUCOMA, NORMAL PRESSURE, SUSCEPTIBILITY TO; NPG


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number		 Inheritance Phenotype
mapping key		 Gene/Locus Gene/Locus
MIM number
3q29 {Glaucoma, normal tension, susceptibility to} 606657 3 OPA1 605290
10p13 {Glaucoma, normal tension, susceptibility to} 606657 3 OPTN 602432

TEXT

A number sign (#) is used with this entry because of evidence that susceptibility to normal tension glaucoma is associated with a particular intronic polymorphism of the optic atrophy-1 gene (OPA1; 605290) and mutation in the OPTN gene (602432).

Clinical Features

Glaucoma is the second most common cause of blindness worldwide (Thylefors et al., 1995; Quigley, 1996). It is characterized by progressive loss of optic nerve axons and visual field damage. Most glaucoma in Caucasian and African American populations is of the primary open angle glaucoma (POAG) type (see 137760), in which elevated intraocular pressure (IOP) is a major feature (Sommer et al., 1991). Normal tension glaucoma (NTG) is an important subtype of POAG, in which the IOP is consistently within the statistically normal population range. NTG accounts for approximately one-third of all POAG cases (Bonomi et al., 1998). Because the IOP is normal when measured and patients often have good central vision, NTG is underdiagnosed and the condition presents late.


Biochemical Features

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.


Molecular Genetics

Association with OPA1

Because different mutations in the same gene may cause widely different phenotypes and because autosomal dominant optic atrophy (165500) due to mutation in the OPA1 gene shows a similar optic neuropathy in the absence of raised IOP, Aung et al. (2002) hypothesized that the OPA1 gene represents an excellent candidate gene for NTG. In a study of 2 cohorts of NTG patients, they found a strong association with a combination of 2 single nucleotide polymorphisms (SNPs) in intron 8 of the OPA1 gene (605290.0010).

In 137 patients with primary open angle glaucoma (POAG), including 67 with high tension glaucoma (HTG) and 70 with NTG, and 75 controls from the northeast of England, Yu-Wai-Man et al. (2010) analyzed 3 SNPs in the OPA1 gene and found significant association between the T allele at IVS8+4C-T and the risk of developing NTG (odds ratio, 2.04; p = 0.004) but not HTG. Logistic regression analysis confirmed a strong association between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR, 29.75; p = 0.001). Yu-Wai-Man et al. (2010) concluded that the CT/TT compound genotype in intron 8 of the OPA1 gene is a strong genetic risk determinant for NTG but not HTG.

Association with OPTN

Rezaie et al. (2002) identified a missense mutation (602432.0004) in the OPTN gene resulting in susceptibility to normal tension glaucoma.


REFERENCES

  1. Aung, T., Ocaka, L., Ebenezer, N. D., Morris, A. G., Krawczak, M., Thiselton, D. L., Alexander, C., Votruba, M., Brice, G., Child, A. H., Francis, P. J., Hitchings, R. A., Lehmann, O. J., Bhattacharya, S. S. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Hum. Genet. 110: 52-56, 2002. [PubMed: 11810296] [Full Text: https://dx.doi.org/10.1007/s00439-001-0645-7]

  2. Bonomi, L., Marchini, G., Marraffa, M., Bernardi, P., De Franco, I., Perfetti, S., Varotto, A., Tenna, V. Prevalence of glaucoma and intraocular pressure distribution in a defined population: the Egna-Neumarkt study. Ophthalmology 105: 209-215, 1998. [PubMed: 9479277] [Full Text: http://linkinghub.elsevier.com/retrieve/pii/S0161-6420(98)92665-3]

  3. Quigley, H. A. Number of people with glaucoma worldwide. Brit. J. Ophthal. 80: 389-393, 1996. [PubMed: 8695555] [Full Text: http://bjo.bmj.com/cgi/pmidlookup?view=long&pmid=8695555]

  4. Rezaie, T., Child, A., Hitchings, R., Brice, G., Miller, L., Coca-Prados, M., Heon, E., Krupin, T., Ritch, R., Kreutzer, D., Crick, R. P., Sarfarazi, M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295: 1077-1079, 2002. [PubMed: 11834836] [Full Text: http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=11834836]

  5. Sommer, A., Tielsch, J. M., Katz, J., Quigley, H. A., Gottsch, J. D., Javitt, J., Singh, K. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Survey. Arch. Ophthal. 109: 1090-1095, 1991. [PubMed: 1867550] [Full Text: https://jamanetwork.com/journals/jamaophthalmology/fullarticle/vol/109/pg/1090]

  6. Thylefors, B., Negrel, A.-D., Pararajasegaram, R., Dadzie, K. Y. Global data on blindness. Bull. WHO 73: 115-121, 1995. [PubMed: 7704921]

  7. Yang, J., Patil, R. V., Yu, H., Gordon, M., Wax, M. B. T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am. J. Ophthal. 131: 421-426, 2001. [PubMed: 11292402] [Full Text: http://linkinghub.elsevier.com/retrieve/pii/S000293940000862X]

  8. Yu-Wai-Man, P., Stewart, J. D., Hudson, G., Andrews, R. M., Griffiths, P. G., Birch, M. K., Chinnery, P. F. OPA1 increases the risk of normal but not high tension glaucoma. J. Med. Genet. 47: 120-125, 2010. [PubMed: 19581274] [Full Text: http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=19581274]


Contributors:
Marla J. F. O'Neill - updated : 8/25/2010
Ada Hamosh - updated : 2/13/2002
Creation Date:
Victor A. McKusick : 1/30/2002
Edit History:
wwang : 08/26/2010
terry : 8/25/2010
ckniffin : 10/27/2004
terry : 6/27/2002
terry : 6/27/2002
carol : 2/13/2002
carol : 1/30/2002
carol : 1/30/2002