Functional analysis of the glaucoma-causing TIGR/myocilin protein: Integrity of amino-terminal coiled-coil regions and olfactomedin homology domain is essential for extracellular adhesion and secretion

Gobeil, Stéphane; Letartre, Laurence; Raymond, Vincent

doi:10.1016/j.exer.2005.11.002

Cited by 82 publications

(112 citation statements)

References 79 publications

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“…Transfection of cultured trabecular meshwork cells with glaucoma-causing MYOC mutations leads to the increased death of these cells (28). Consistent with this, decreasing the temperature of cell culture increased the proportion of MYOC that was secreted, decreased the amount of protein that accumulated within the cells, and led to an overall improvement of cellular morphology and viability (10,28,55). Furthermore, at a secretion-permissive temperature, the secretion efficiency for disease-causing alleles of MYOC is inversely proportional to the severity (age at onset and magnitude of IOP elevation) of the disease in patients with the mutations (55).…”

supporting

confidence: 51%

Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma

Gould

Reedy

Wilson

et al. 2006

Molecular and Cellular Biology

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Glaucoma is a leading cause of blindness, affecting over 70 million people worldwide. Vision loss is the result of death of the retinal ganglion cells. The best-known risk factor for glaucoma is an elevated intraocular pressure (IOP); however, factors leading to IOP elevation are poorly understood. Mutations in the MYOC gene are an important cause of open-angle glaucoma. Over 70 MYOC mutations have been identified, and they lead to approximately 5% of all primary open-angle glaucoma cases. Nevertheless, the pathogenic mechanisms by which these mutations elevate IOP are presently unclear. Data suggest that a dominant interfering effect of misfolded mutant MYOC molecules may be pathogenic. To test this hypothesis, we have generated mice carrying a mutant allele of Myoc that is analogous to a human mutation that leads to aggressive glaucoma in patients. We show that mutant MYOC is not secreted into the aqueous humor. Instead of being secreted, mutant MYOC accumulates within the iridocorneal angle of the eye, consistent with the behavior of abnormally folded protein. Surprisingly, the accumulated mutant protein does not activate the unfolded protein response and lead to elevated intraocular pressure or glaucoma in aged mice of different strains. These data suggest that production, apparent misfolding, and nonsecretion of mutant MYOC are not, by themselves, sufficient to cause glaucoma in vivo.Glaucoma is a progressive neurodegenerative disease and a leading cause of blindness, especially in the elderly (27). There are approximately 70 million people with glaucoma worldwide, and this number is expected to increase as the population ages (39). Vision loss in patients with glaucoma results from the demise of the retinal ganglion cells (RGC). Development of an elevated intraocular pressure (IOP) is an important risk factor for glaucoma (14,26,45). IOP elevation most often appears to be caused by an increased resistance to outflow of aqueous humor through the drainage structures in the iridocorneal angle (the trabecular meshwork and Schlemm's canal). The molecular mechanisms that lead to IOP elevation remain poorly defined. Although current drug treatments that lower IOP are effective in decreasing visual loss in many patients, they are not effective in significant numbers of individuals.Understanding the pathological mechanisms that lead to IOP elevation will help to suggest new treatment targets, with the goal of more effective care for more patients. Deciphering the pathogenic mechanisms of mutations in specific glaucoma genes promises more targeted and tailored treatments based on genotype. A number of genes and loci have been associated with primary open-angle glaucoma (POAG), a common glaucoma subtype (27). Mutations in the myocilin gene (MYOC) are an important cause of POAG (46). Mutations in MYOC underlie glaucoma in up to 5% of patients with POAG and up to 30% of patients with juvenile open-angle glaucoma, an earlier-onset and more severe form of POAG (9). Of the approximately 70 MYOC mutations so far identified...

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supporting

confidence: 51%

Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma

Gould

Reedy

Wilson

et al. 2006

Molecular and Cellular Biology

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“…In assigning pathogenic status to a given variant, the following issues are taken into consideration: the predicted disruption of protein translation (e.g., frameshift mutations and premature stop codons), the frequency of the sequence variant in the control (unaffected) populations, the location of the variant in the MYOC gene (i.e., cross-species conservation of coding sequence), evidence for partial segregation with the phenotype within a family, and when available, results of solubility studies [Gobeil et al, 2006;Zhou and Vollrath, 1999]. Nonetheless, as further work is conducted the pathogenic status ascribed to rare variants may change.…”

Section: Data Integritymentioning

confidence: 99%

Myocilinallele-specific glaucoma phenotype database

2008

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Communicated by Daniel F. SchorderetGlaucoma, a complex heterogenous disease, is the leading cause for optic nerve-related blindness worldwide.Since 1997, when mutations in the myocilin (MYOC) gene were identified as causing juvenile onset as well as a proportion of primary open-angle glaucoma (POAG), more than 180 variants have been documented. Approximately one in 30 unselected patients with POAG have a disease-causing myocilin mutation and it has been shown that firm genotype-phenotype correlations exist. We have compiled an online catalog of myocilin variants and their associated phenotypes. This locus-specific resource, to which future submissions can be made, is available online (www.myocilin.com; last accessed 28 August 2007). The database, constructed using MySQL, contains three related sheets that contain data pertaining to the information source, variant identified, and relevant study data, respectively. The website contains a list of all identified variants and summary statistics as well as background genomic information, such as the annotated sequence and cross-protein/species homology. Phenotypic data such as the mean7standard deviation (SD) age at POAG diagnosis, mean7SD maximum recorded intraocular pressure, proportion of patients requiring surgical intervention, and age-related penetrance can be viewed by selecting a particular mutation. Approximately 40% of the identified sequence variants have been characterized as disease causing, with the majority (85%) of these being missense mutations. Preliminary data generated from this online resource highlight the strong genotype-phenotype correlations associated with specific myocilin mutations. The large-scale assimilation of relevant data allows for accurate comprehensive genetic counseling and the translation of genomic information into the clinic. Hum Mutat 29(2), [207][208][209][210][211] 2008.

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“…However, many glaucoma-causing mutant MYOCs have been found to be misfolded and to form detergent-resistant, secretion-incompetent aggregates. 19,[23][24][25][26][27] The secretion block of POAG-causing mutant MYOCs could be overcome by lowering the cell culture temperature from 37 to 30°C, a condition known to improve protein folding. 17,19 Increasing evidence suggests that mutant MYOC acts by a pathological gain-of-function mechanism.…”

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confidence: 99%

“…19,[23][24][25][26][27] The secretion block of POAG-causing mutant MYOCs could be overcome by lowering the cell culture temperature from 37 to 30°C, a condition known to improve protein folding. 17,19 Increasing evidence suggests that mutant MYOC acts by a pathological gain-of-function mechanism. 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.…”

mentioning

confidence: 99%

“…17,18 A recent functional analysis has shown the importance of the olfactomedin-homology domain of MYOC for its secretion and that of the amino-terminal coiled-coil regions for the interactions of MYOC with extracellular matrix components. 19 The molecular pathogenesis of MYOC-caused POAG is still poorly defined. 20 Absence 21 or overexpression 22 of wild-type (WT) MYOC in transgenic mice has been shown not to be critical for the development of POAG.…”

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confidence: 99%

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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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Functional analysis of the glaucoma-causing TIGR/myocilin protein: Integrity of amino-terminal coiled-coil regions and olfactomedin homology domain is essential for extracellular adhesion and secretion

Cited by 82 publications

References 79 publications

Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma

Mutant Myocilin Nonsecretion In Vivo Is Not Sufficient To Cause Glaucoma

Myocilinallele-specific glaucoma phenotype database

Aggregated Myocilin Induces Russell Bodies and Causes Apoptosis

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