Intracellular Sequestration of Hetero-oligomers Formed by Wild-Type and Glaucoma-Causing Myocilin Mutants

Gobeil, Stéphane; Rodrigue, Marc-André; Moisan, Steve; Nguyen, Thai; Polansky, Jon R.; Morissette, Jean; Raymond, Vincent

doi:10.1167/iovs.04-0300

Cited by 93 publications

(88 citation statements)

References 43 publications

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“…Studies of both cell culture and human tissue have shown that the abnormal protein that is produced by myocilin mutations is poorly secreted and is retained within trabecular meshwork cells. [37][38][39][40] Accumulation of abnormal myocilin protein may be toxic to trabecular meshwork cells and may lead to their dysfunction or death, which may ultimately produce decreased aqueous outflow, elevated IOP, and glaucoma. 41,42 Animal models harboring myocilin mutations have been developed and are beginning to reveal the specific molecular steps that lead from mutations in myocilin to the elevated IOP that is characteristic of myocilin-related glaucoma.…”

Section: Myocilin (Myoc Omim #601652)mentioning

confidence: 99%

Primary open-angle glaucoma genes

Fingert

2011

Eye

191

175

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A substantial fraction of glaucoma has a genetic basis. About 5% of primary open angle glaucoma (POAG) is currently attributed to single-gene or Mendelian forms of glaucoma (ie glaucoma caused by mutations in myocilin or optineurin). Mutations in these genes have a high likelihood of leading to glaucoma and are rarely seen in normal subjects. Other cases of POAG have a more complex genetic basis and are caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. These factors are more frequently detected in patients with POAG, but are also commonly observed in normal subjects. Additional genes that may be important in glaucoma pathogenesis have been investigated using quantitative traits approaches. Such studies have begun to identify genes that control the magnitude of important quantitative features of glaucoma that may also be important risk factors for POAG, such as central corneal thickness. Each of these different approaches to study glaucoma genetics is providing new insights into the pathogenesis of POAG.

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Section: Myocilin (Myoc Omim #601652)mentioning

confidence: 99%

Primary open-angle glaucoma genes

Fingert

2011

Eye

191

175

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“…30,31 Such detergent-insoluble MYOC aggregates cannot be secreted by the cells. 30,31 In the present work, we generated CHO-K1 and HEK293 cells stably expressing C-terminal GFP-tagged WT or mutant MYOC to initially verify the effect of an additional transient expression of FLAG-tagged WT MYOC on the solubility and secretion of the formed MYOC complexes. In previous studies, it was shown that MYOC tagged with GFP was secreted with a similar efficiency as MYOC without any tag.…”

Section: Heteromeric Complexes Of Wt and Mutant Myoc Form Rough Er-dementioning

confidence: 99%

“…21,28,29 In agreement with this, several missense and truncated mutant MYOCs have been shown to interact with WT MYOCs to form heteromeric protein aggregates resulting in a block of secretion of WT MYOCs as well. 25,30,31 MYOC-secreting TM cells are phagocytotically active and keep the outflow drainage along the TM clean of deposits of particulate matter of various origin. 7,[32][33][34] We reasoned that a disturbance of the phagocytotic capacity of the TM cell population could be a pathogenetic factor in the development of MYOC-caused POAG.…”

mentioning

confidence: 99%

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Yam

Gaplovská-Kyselá

Zuber

et al. 2007

The American Journal of Pathology

120

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Primary open-angle glaucoma with elevated intraocular pressure is a leading cause of blindness worldwide. Mutations of myocilin are known to play a critical role in the manifestation of the disease. Misfolded mutant myocilin forms secretion-incompetent intracellular aggregates. The block of myocilin secretion was proposed to alter the extracellular matrix environment of the trabecular meshwork, with subsequent impediment of aqueous humor outflow leading to elevated intraocular pressure. However, the molecular pathogenesis of myocilin-caused glaucoma is poorly defined. In this study, we show that heteromeric complexes composed of wild-type and mutant myocilin were retained in the rough endoplasmic reticulum, aggregating to form inclusion bodies typical of Russell bodies. The presence of myocilin aggregates induced the unfolded protein response proteins BiP and phosphorylated endoplasmic reticulum-localized eukaryotic initiation factor-2␣ kinase (PERK) with the subsequent activation of caspases 12 and 3 and expression of C/EBP homologous protein (CHOP)/GADD153, leading to apoptosis. Our findings identify endoplasmic reticulum stress-induced apoptosis as a pathway to explain the reduction of trabecular meshwork cells in patients with myocilincaused glaucoma. As a consequence, the phagocytotic capacity of the remaining trabecular meshwork cell population would be insufficient for effective cleaning of aqueous humor, constituting a major pathogenetic factor for the development of Glaucoma is a heterogeneous group of optic neuropathies characterized by a progressive degeneration of the optic nerve resulting in an irreversible loss of vision. 1After age-related macular degeneration, it is the second leading cause of severe vision loss or blindness.2 It is expected that ϳ4% of the world population older than the age of 40 will develop glaucoma. Primary open-angle glaucoma (POAG) is the most common form of the disease.2 In most cases of POAG, the aqueous humor outflow from the anterior eye chamber is impeded, resulting in an elevated intraocular pressure (IOP) and causing ganglion cell death in the neural retina.3,4 Hence, impaired outflow drainage along the trabecular meshwork (TM) and Schlemm's canal seems to be central in the pathogenesis of POAG. 3,4

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“…The identity of the constructs was confirmed by sequencing. Wild-type myocilin cDNA and four myocilin mutants (P370L, Y437H, I477N, and N480K) were cloned into the pRcCMV vector 30 and were kindly provided by Dr. V. Raymond (Molecular Endocrinology and Oncology Research Center, Laval University Hospital Research Center, Qué bec City, Qué bec, Canada).…”

Section: Plasmidsmentioning

confidence: 99%

Expression of Myocilin Mutants Sensitizes Cells to Oxidative Stress-Induced Apoptosis

Margetis

Tomarev

2010

The American Journal of Pathology

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Mutations in the myocilin gene are associated with juvenile and adult-onset primary open-angle glaucoma. However, the pathogenic mechanisms of myocilin-induced glaucoma are still largely unknown. To investigate these mechanisms, we developed stably transfected HEK293 cell lines expressing wild-type or mutant (Y437H and I477N) myocilins under an inducible promoter. Expression of two mutant myocilins led to different levels of endoplasmic reticulum stress and increased apoptosis after treatment of cells with hydrogen peroxide. The Y437H mutant myocilin cell line showed the highest sensitivity to the oxidant treatment. Several antioxidant genes were downregulated in the Y437H mutant myocilin cell line , but not in other cell lines. The Y437H mutant myocilin cell line also produced more reactive oxygen species than other cell lines examined. Consistent with the data obtained in cultured cells , the endoplasmic reticulum stress marker , 78 kDa glucoseregulated protein , was up-regulated , whereas antioxidant proteins , paraoxonase 2 and glutathione peroxidase 3 , were down-regulated in the eye angle tissue of 18-month-old transgenic mice expressing Y437H myocilin mutant. In addition , a pro-apoptotic factor , CCAAT/enhancer-binding protein-homologous protein , was up-regulated in the aged transgenic mouse angle tissue. Our results suggest that expression of mutated myocilins may have a sensitization effect , which can lead to a severe phenotype in combination with oxidative stress. Mutant myocilins may confer different sensitivity to oxidative stress depending on the mutation. (Am J Pathol

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Intracellular Sequestration of Hetero-oligomers Formed by Wild-Type and Glaucoma-Causing Myocilin Mutants

Cited by 93 publications

References 43 publications

Primary open-angle glaucoma genes

Primary open-angle glaucoma genes

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Expression of Myocilin Mutants Sensitizes Cells to Oxidative Stress-Induced Apoptosis

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