Inefficient Processing of an Olfactomedin-Deficient Myocilin Mutant: Potential Physiological Relevance to Glaucoma

Caballero, Montserrat; Borrás, Teresa

doi:10.1006/bbrc.2001.4624

Cited by 72 publications

(75 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…E323K and D380A mutations were studied because of their strong association with familial glaucoma (37,41,49). In accordance with previous studies, we found that myocilin mutations promoted the accumulation of the protein in the ER as insoluble aggregates (16,18,25). However, a fraction of mutant molecules was clearly detected in the cellular soluble fraction, raising the possibility that they are secreted.…”

Section: Discussionsupporting

confidence: 92%

“…7, A-C, insoluble cellular fraction lanes), in agreement with previous works (16,18,25). Interestingly, a fraction of mutant myocilins were also detected as intracellular soluble molecules (Fig.…”

Section: Expression Of Mutant Pathogenic Myocilins In Cultured Cellsupporting

confidence: 92%

“…Over recent years, some of these events have been unraveled and have shown, for instance, that mutant forms of myocilin are not secreted in cultured cells; rather, they accumulate intracellularly as misfolded proteins. This leads to endoplasmic reticulum stress and to potential cytotoxicity (16,18,25,26). Although certain molecular mechanisms such as homoallelic complementation, haploinsuffiency, or negative dominant effect have been proposed to explain the pathogenesis of myocilin glaucoma, most experimental evidence supports the gain of function theory (27)(28)(29).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227

Aroca-Aguilar

Sánchez-Sánchez

Ghosh

et al. 2005

Journal of Biological Chemistry

114

View full text Add to dashboard Cite

Myocilin is a secreted glycoprotein of unknown function that is ubiquitously expressed in many human organs, including the eye. Mutations in this protein produce glaucoma, a leading cause of blindness worldwide. To explore the biological role of myocilin and the pathogenesis of glaucoma, we have analyzed the expression of recombinant wild type and four representative pathogenic myocilin mutations (E323K, Q368X, P370L, and D380A) in transiently transfected cell lines derived from ocular and nonocular tissues. We found that wild type myocilin undergoes an intracellular endoproteolytic processing at the C terminus of Arg 226. This cleavage predicts the production of two fragments, one of 35 kDa containing the C-terminal olfactomedin-like domain, and another of 20 kDa containing the N-terminal leucine zipper-like domain. Here we have analyzed the 35-kDa processed fragment, and we have found that it is co-secreted with the nonprocessed protein. Western immunoblot analyses showed that human aqueous humor and some ocular tissues also contain the processed 35-kDa myocilin, indicating that the endoproteolytic cleavage occurs in vivo. Mutant myocilins accumulated in the endoplasmic reticulum of transfected cells as insoluble aggregates. Interestingly, the four pathogenic myocilins inhibited the endoproteolytic processing with varying efficiency. Furthermore, the mutation P370L, which produces the most severe glaucoma phenotype, also elicited the most potent endoproteolytic cleavage inhibition. We propose that the endoproteolytic processing might regulate the activity of myocilin and that the inhibition of the processing by pathogenic mutations impairs the normal role of myocilin.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Expression Of Mutant Pathogenic Myocilins In Cultured Cellsupporting

confidence: 92%

mentioning

confidence: 99%

See 1 more Smart Citation

Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227

Aroca-Aguilar

Sánchez-Sánchez

Ghosh

et al. 2005

Journal of Biological Chemistry

114

View full text Add to dashboard Cite

show abstract

“…[57][58][59] It is known that most POAG-causing mutants of MYOC, unlike WT MYOC, are misfolded and retained intracellularly, resulting in blockade of its secretion. [23][24][25][26][27]30,60 The impeded secretion of aggregated MYOC has been proposed to cause alterations of the extracellular matrix along the TM outflow pathway and to obstruct aqueous humor outflow. 3,4 However, the underlying molecular and cellular mechanisms through which mutant MYOC protein exerts its effect on the outflow drainage are mainly unknown.…”

Section: Discussionmentioning

confidence: 99%

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Yam

Gaplovská-Kyselá

Zuber

et al. 2007

The American Journal of Pathology

123

View full text Add to dashboard Cite

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

show abstract

“…The second theory claims that mutations in the coding-region produce an amino-acid change, the result being a different protein with nonfunctional conformation. This protein shows a solubility different from that shown by the wild type, 18,19 and it will accumulate as defective conformation aggregates. This accumulation would be interfering in the normal aqueous flow, and it would produce an increase in IOP, which would cause …”

Section: Discussionmentioning

confidence: 86%

Mutations including the promoter region of myocilin/TIGR gene

et al. 2004

View full text Add to dashboard Cite

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.

show abstract

Inefficient Processing of an Olfactomedin-Deficient Myocilin Mutant: Potential Physiological Relevance to Glaucoma

Cited by 72 publications

References 38 publications

Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227

Myocilin Mutations Causing Glaucoma Inhibit the Intracellular Endoproteolytic Cleavage of Myocilin between Amino Acids Arg226 and Ile227

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

Mutations including the promoter region of myocilin/TIGR gene

Contact Info

Product

Resources

About