Association of a single nucleotide polymorphism in the TIGR/MYOCILIN gene promoter with the severity of primary open‐angle glaucoma

Colomb, Evelyne; Nguyen, Thai; Béchetoille, A; Dascotte, J C; Valtot, F; Brézin, Antoine P.; Berkani, M; Copin, Bruno; Gomez, Lucienne; Polansky, Jon R.; Garchon, Henri‐Jean

doi:10.1034/j.1399-0004.2001.600308.x

Cited by 42 publications

(31 citation statements)

References 24 publications

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“…Some investigators suggest that MYOC promoter variants may influence the progression of glaucoma (10,11,29), while others disagree with this conclusion (2). Since human patients are currently offered genetic testing based on the presence of noncoding variants, the issue is very important.…”

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confidence: 99%

Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma

Gould

Miceli-Libby

Savinova

et al. 2004

Molecular and Cellular Biology

120

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Glaucoma is a leading cause of preventable blindness in the world (30,46). Elevated intraocular pressure (IOP) is one of the strongest known risk factors (41) and can cause glaucoma in animal models (6). IOP elevation in human glaucoma results from increased resistance to aqueous-humor drainage (36). Although the etiology of glaucoma is complex, the result is death of retinal ganglion cells and loss of vision (31). Primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States and affects up to 1 to 2% of people over 40 years of age (47).Multiple genetic loci are reported to contribute to POAG (32,34,42,49,51,52). Disease-associated mutations have been identified in the myocilin gene, MYOC (14, 43). Studies from a broad range of ethnic backgrounds generally agree that MYOC mutations are responsible for approximately 3% of adult-onset POAG and a greater proportion of juvenile-onset open-angle glaucoma (2, 14). Despite this, neither the normal function(s) of MYOC nor how MYOC mutations result in IOP elevation and glaucoma has been defined.MYOC has also been implicated in steroid-induced ocular hypertension with glaucoma. Steroid-induced ocular hypertension in response to glucocorticoid treatment occurs in as many as 40% of people treated with glucocorticoids (37, 53). MYOC is up regulated in cultured trabecular meshwork (TM; an ocular drainage structure) cells treated with glucocorticoids.Thus, MYOC was identified as a candidate to mediate glucocorticoid-induced glaucoma (26,28). Supporting this, IOP elevation (assessed as an increase in drainage structure resistance) is glucocorticoid inducible in some but not all human anterior segment perfusion cultured eyes. In these cultures, IOP elevation correlates with MYOC induction (8) and ultrastructural changes (9) in the TM. Cultured anterior segments that developed elevated IOP had MYOC induction, while those that did not develop elevated IOP had no MYOC induction (8). Similarly, monkeys treated with glucocorticoids develop ocular hypertension (13), and in at least some eyes glucocorticoids induce MYOC and cause ultrastructural changes in the TM (8).Further studies, which do not involve steroid use, also can support a role for elevated MYOC levels in IOP elevation and glaucoma. In some glaucoma patients, the TM has elevated MYOC levels and broadened MYOC distribution (24). Cultured human anterior segments perfused with recombinant MYOC are reported to develop elevated IOP, whereas those perfused with an equal amount of other proteins or denatured MYOC do not (12). Finally, in the albino Wistar rat strain, experimental IOP elevation did not induce ocular MYOC, suggesting that MYOC induction does not occur secondary to IOP elevation (1).Despite these circumstantial data, there is no direct in vivo evidence that elevated MYOC levels cause IOP elevation and glaucoma. The rat study mentioned above (1) does not exclude MYOC elevation as a secondary response to increased IOP in different settings (either in different genetic contexts or in respo...

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mentioning

confidence: 99%

Genetically Increasing Myoc Expression Supports a Necessary Pathologic Role of Abnormal Proteins in Glaucoma

Gould

Miceli-Libby

Savinova

et al. 2004

Molecular and Cellular Biology

120

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“…One of these changes, À83 G4A 20 has been shown to be associated to the Arg76Lys polymorphism, 21 but we have not detected it. All the patients showed increased IOP, and needed surgery to control it.…”

Section: Discussionmentioning

confidence: 42%

Mutations including the promoter region of myocilin/TIGR gene

et al. 2004

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Mutations in the MYOC/TIGR gene are responsible for autosomal dominant primary open angle glaucoma (POAG). Almost all mutations responsible for POAG have been detected in the coding region (in particular at exon 3). By using the techniques of PCR, SSCP, automated sequencing and restriction analysis, we have studied 79 patients suffering from glaucoma. We have found five patients with sequence variants in the consensus region of the promoter. These sequence variants might be involved in the altered association between the consensus region and the corresponding transcription factor. This possibility might be favouring the association of other transcription factors, which would operate as activators or inhibitors of the transcription, altering the MYOC/TIGR expression.

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“…However, it is sometimes difficult to distinguish between pathologic mutations and benign polymorphisms. For instance, one MYOC promoter variant, called MYOC.mt1, has been considered as a genetic marker for the risk of POAG progression [93]. But our study and another disproved an association of MYOC.mt1 with POAG progression [94,95].…”

Section: Available Genetic Markersmentioning

confidence: 64%