Clinical Features and Course of Patients with Glaucoma with the E50K Mutation in the Optineurin Gene

Aung, Tin; Rezaie, Tayebeh; Okada, Koji; Viswanathan, Ananth C.; Child, Anne H.; Brice, Glen; Bhattacharya, Siladitya; Lehmann, Ordan J.; Sarfarazi, Mansoor; Hitchings, Roger A.

doi:10.1167/iovs.04-1133

Cited by 134 publications

(87 citation statements)

References 41 publications

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“…Therefore, it is less likely that the younger patients were detected earlier in the progress of the disease than the older ones. Aung et al 30 reported the mutation of optineurin gene is associated with the early onset (mean age of 40.8 years), more severe form of NTG. This result also could be interpreted as the early onset NTG has a distinct genetic pathogenesis from the late onset NTG.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the association between 677C>T and 1298A>C 5,10-methylenetetra- hydrofolate reductase gene polymorphisms and normal-tension glaucoma

Woo

Kim

et al. 2007

Eye

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Purpose Homozygous polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and resultant hyperhomocysteinaemia have been established as an independent risk factor for vascular diseases. There are evidences that vascular abnormalities are involved in the pathogenesis and progression of normaltension glaucoma (NTG). In the present study, we were to find out the associations between 677C4T and 1298A4C polymorphisms of the MTHFR gene and NTG. Methods This was a retrospective, casecontrolled study enrolling 78 NTG patients and 100 controls. DNA from peripheral blood lymphocytes was extracted and the genotypes of polymorphisms (677C4T and 1298A4C) in the MTHFR gene were determined using PCR followed by restriction enzyme digestion. The frequencies of the polymorphic genotypes in the patients with NTG and controls were compared. Results The frequencies of the polymorphisms of the MTHFR gene (677C4T and 1298A4C) in the NTG patients were not significantly different from those of controls. But the younger NTG patients (age at diagnosis p45 years) showed significantly higher prevalence of 677C4T polymorphism than the older NTG patients (age at diagnosis 445 years) (TT genotype, 38.9 vs 11.9%, P ¼ 0.006, OR ¼ 4.71, 95% CI ¼ 1.49-14.9) and than the younger control subgroup (TT genotype, 38.9 vs 6.1%, P ¼ 0.001, OR ¼ 9.86, 95% CI ¼ 2.23-42.4). Conclusions The 677C4T polymorphism was significantly associated with NTG in the younger patients, while 1298A4C polymorphism was not. This suggests that 677C4T polymorphism of the MTHFR gene can be a genetic risk factor of NTG in Korean population.

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Section: Discussionmentioning

confidence: 99%

Investigation of the association between 677C>T and 1298A>C 5,10-methylenetetra- hydrofolate reductase gene polymorphisms and normal-tension glaucoma

Woo

Kim

et al. 2007

Eye

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“…Interestingly, NPG subjects who had E50K mutation were reported clinically to suffer glaucomatous defects more severe than those without this mutation. 46 It is also of note that PROSITE analysis 47 indicates that introduction of Glu 50 3 Lys mutation results in no particular changes either in the structure or the conformation of OPTN (data not shown). The E50K mutation may conceivably affect the protein activity or property by other mechanisms such as posttranslational phosphorylation.…”

Section: Studies Of Optineurin a Glaucoma Gene 1985mentioning

confidence: 91%

Studies of Optineurin, a Glaucoma Gene

Park

Shen

Samaraweera

et al. 2006

The American Journal of Pathology

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Optineurin (OPTN) has recently been linked to glaucoma, a major cause of blindness worldwide. Mutations in OPTN such as Glu 503 Lys (E50K) have been reported in patients, particularly those with normal pressure glaucoma. Here, we show that the endogenous OPTN was not secreted in two ocular cell types, human trabecular meshwork and retinal pigment epithelial cells. It localized instead in the cytoplasm in a diffuse pattern without a distinct association with the Golgi apparatus. When overexpressed, however, wild-type OPTN-green fluorescent protein (GFP) formed foci especially around the Golgi, colocalizing partially with the common endocytic pathway marker transferrin receptor in both cell types. Fragmentation of the Golgi was also observed. On nocodazole treatment, the OPTN foci were dispersed into the cytoplasm. Overexpression of mutant OPTN E50K -GFP resulted in a greater number (P < 0.0055) and size of the foci, compared with the wild type, and the Golgi alteration was potentiated. Cell loss observed in OPTN-expressing cultures was also more pronounced in OPTN E50K -GFP compared with that of wild-type OPTN-GFP counterparts (P < 0.01). This study highlights a possible role of OPTN in vesicle trafficking and Golgi integrity. It also provides insights into the possible mechanisms why E50K would exhibit a propensity toward the development of glaucoma.

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“…24,25 The Glu50Lys (E50K) mutation, found in Caucasian and Hispanic populations, 25 seems to be associated with a more progressive and severe disease in patients with normal tension glaucoma. 26 The human optineurin gene codes for a 577-amino acid protein that contains multiple coiled-coil domains and a C-terminal zinc finger. 27,28 The optineurin protein from different species has high amino acid homology.…”

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confidence: 99%

Differential Effects of Myocilin and Optineurin, Two Glaucoma Genes, on Neurite Outgrowth

Koga

Shen

Park

et al. 2010

The American Journal of Pathology

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Myocilin and optineurin are two genes linked to glaucoma , a major blinding disease characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. To investigate the effects of force-expressed wild-type and mutant myocilin and optineurin on neurite outgrowth in neuronal cells , we transiently transfected cells with pEGFP-N1 (mock control) as well as myocilin and optineurin plasmids including pMYOC WT -EGFP, pMYOC P370L -EGFP, pMYOC 1-367 -EGFP, pOPTN WT -EGFP , and pOPTN E50K -EGFP. PC12 cells transfected with pEGFP-N1 produced , as anticipated, long and extensive neuritis on nerve growth factor induction. The neurite length in those cells transfected with myocilin constructs was shortened and the number of neurites was also reduced. A similar inhibitory effect on neurite outgrowth was also elicited by myocilin transfection in RGC5 cells. In contrast , neither transfection of the optineurin constructs pOPTN WT -EGFP and pOPTN E50K -EGFP nor the myocilin and optineurin small-interfering RNA treatments induced significant alterations in neurite outgrowth. Transfection with the wild-type optineurin construct , but not with that of the wild-type myocilin, increased the apoptotic activity in cells. These results demonstrated that the two glaucoma genes , myocilin and optineurin, exhibited differential effects on neurite outgrowth. They may contribute to the development of neurodegenerative glaucoma via distinct mechanisms.

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Clinical Features and Course of Patients with Glaucoma with the E50K Mutation in the Optineurin Gene

Cited by 134 publications

References 41 publications

Investigation of the association between 677C>T and 1298A>C 5,10-methylenetetra- hydrofolate reductase gene polymorphisms and normal-tension glaucoma

Investigation of the association between 677C>T and 1298A>C 5,10-methylenetetra- hydrofolate reductase gene polymorphisms and normal-tension glaucoma

Studies of Optineurin, a Glaucoma Gene

Differential Effects of Myocilin and Optineurin, Two Glaucoma Genes, on Neurite Outgrowth

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