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      Case Report: Reversal and subsequent return of optic disc cupping in a myocilin (MYOC) gene-associated severe Juvenile Open-Angle Glaucoma (JOAG) patient

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          Abstract

          To our knowledge, this case report describes the first instance of reversal of glaucomatous optic nerve cupping in a young adult with a rare form of juvenile open-angle glaucoma (JOAG) associated with a novel variant of the myocilin gene (MYOC). This 25-year-old woman with severe-stage MYOC-associated JOAG presented with blurry vision and intermittent pain in her left eye. She had a strong family history of glaucoma in multiple first-degree relatives with an identified novel variant of MYOC. Examination revealed intraocular pressures (IOPs) of 10 mmHg OD and 46 mmHg OS, with cup-to-disc ratios of 0.90 and 0.80. The patient experienced substantial reversal of optic disc cupping OS following dramatic IOP reduction with trabeculectomy, and subsequently experienced a return of cupping after an IOP spike 15 months postoperatively. The reversal of cupping did not correspond to any changes in the patient’s visual field. After an initial decrease in retinal nerve fiber layer (RNFL) thickness, RNFL remained stable for over 2 years after trabeculectomy as seen on Optical Coherence Tomography (OCT). This case suggests reversal of cupping can occur well into adulthood in a MYOC-associated JOAG patient, and it demonstrates the potential bidirectionality of this phenomenon. Moreover, it suggests that these structural changes may not correspond to any functional changes in visual fields or RNFL thickness.

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          Most cited references28

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          Identification of a gene that causes primary open angle glaucoma.

          Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.
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            Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells.

            MYOC encoding a 55kDa secretory glycoprotein named myocilin is closely linked to primary open-angle glaucoma (POAG). To understand a role played by MYOC in glaucoma, we examined the cellular fate of various mutant myocilins that were adenovirally expressed in human trabecular meshwork cells. Most myocilins with mutations such as G364V, Q368X, K423E, Y437H, and I477N were intrinsically stable, and appeared to have interactions with wild-type myocilin but not with stromelysin and thereby selectively inhibited the secretion of the former protein. The myocilins expressed were identified to be concentrated into fine punctate aggregates in endoplasmic reticulum, but never developed into the formation of aggresomes. In endoplasmic reticulum, the accumulation of the myocilins resulted in the upregulation of 78kDa glucose-regulated protein and protein disulfide isomerase. In addition, the expression of the myocilins led to deformed cellular morphology and diminished cell proliferation, an effect postulated to result in the dysfunction of trabecular cells that could be a cause of glaucoma. Therefore, our results support the statement that gain of function rather than haploinsufficiency is a critical mechanism for POAG in individuals with mutations on MYOC.
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              Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma.

              Glaucoma is a progressive blinding disease characterized by gradual loss of vision due to optic neuropathy and retinal ganglion cell death. Increased intraocular pressure is a common feature of glaucoma that is thought to arise from an increased resistance to outflow of aqueous humor through the trabecular meshwork. Mutations of the myocilin gene are one cause of autosomal dominant juvenile- and adult-onset primary open angle glaucoma, but the mechanism by which mutant myocilins cause disease is poorly understood. We have found that disease-causing myocilin mutants are misfolded, are highly aggregation-prone and accumulate in large aggregates in the endoplasmic reticulum (ER) of human embryonic kidney cells and differentiated primary human trabecular meshwork (HTM) cells. In HTM cells, Pro370Leu mutant myocilin is not secreted under normal culture conditions and prolonged expression results in abnormal cell morphology and cell killing. Culturing HTM cells at 30 degrees C, a condition known to facilitate protein folding, promotes secretion of mutant myocilin, normalizes cell morphology and reverses cell lethality. Our results indicate that myocilin-associated glaucoma is an ER storage disease and suggest a progression of events in which chronic expression of misfolded, non-secreted myocilin leads to HTM cell death, trabecular meshwork dysfunction and, ultimately, a dominant glaucoma phenotype. The beneficial effects of facilitating folding and secretion of mutant myocilin suggest a new type of treatment for this form of glaucoma.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: InvestigationRole: VisualizationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: InvestigationRole: VisualizationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Data CurationRole: Formal AnalysisRole: InvestigationRole: VisualizationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Data CurationRole: InvestigationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Data CurationRole: InvestigationRole: Writing – Original Draft Preparation
                Role: ConceptualizationRole: Funding AcquisitionRole: Project AdministrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – Review & Editing
                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000 Research Limited (London, UK )
                2046-1402
                22 November 2022
                2022
                : 11
                : 1361
                Affiliations
                [1 ]Glaucoma Service, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 02114, USA
                [2 ]Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, 02115, USA
                [1 ]Alexandria University, Alexandria, Alexandria Governorate, Egypt
                [1 ]Tan Tock Seng Hospital, Singapore, Singapore
                Author notes

                Competing interests: Dr. David Solá-Del Valle receives Allergan (an AbbVie company) XEN Gel Stent lecture fees.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Author information
                https://orcid.org/0000-0002-2558-7675
                https://orcid.org/0000-0001-5636-6720
                Article
                10.12688/f1000research.127871.1
                11167334
                38868171
                9317a019-580a-488b-998b-58b332844e7d
                Copyright: © 2022 El Helwe H et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 November 2022
                Funding
                The author(s) declared that no grants were involved in supporting this work.
                Categories
                Case Report
                Articles

                reversal of optic nerve head cupping,juvenile open-angle glaucoma,myocilin gene,glaucoma filtration surgery

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