A de novo MYOC mutation detected in juvenile open angle glaucoma associated with reduced myocilin protein in aqueous humor

Kuchtey, John; Chowdhury, Uttio Roy; Uptegraft, Colby C.; Fautsch, Michael P.; Kuchtey, Rachel W.

doi:10.1016/j.ejmg.2013.03.002

Cited by 16 publications

(13 citation statements)

References 19 publications

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“… 49 Mutations that decrease the secretion of MYOC protein are associated with juvenile and adult-onset primary open angle glaucoma. 50 – 52 Although we have previously observed that RA regulates myoc expression in cranial neural crest cells in zebrafish embryos (unpublished data), in the present study, we found that treatment with exogenous RA or inhibition of RA synthesis did not significantly change myoc expression in the adult eye. However, in zebrafish, myoc is also expressed in the retina and optic nerve.…”

Section: Discussioncontrasting

confidence: 55%

Retinoic Acid Maintains Function of Neural Crest–Derived Ocular and Craniofacial Structures in Adult Zebrafish

Chawla

Swain

Williams

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeRetinoic acid (RA) is required for embryonic formation of the anterior segment of the eye and craniofacial structures. The present study further investigated the role of RA in maintaining the function of these neural crest–derived structures in adult zebrafish.MethodsMorphology and histology were analyzed by using live imaging, methylacrylate sections, and TUNEL assay. Functional analysis of vision and aqueous humor outflow were assayed with real-time imaging.ResultsBoth decreased and increased RA signaling altered craniofacial and ocular structures in adult zebrafish. Exogenous treatment with all-trans RA for 5 days resulted in a prognathic jaw, while inhibition of endogenous RA synthesis through treatment with 4-diethylaminobenzaldehyde (DEAB) decreased head height. In adult eyes, RA activity was localized to the retinal pigment epithelium, photoreceptors, outer plexiform layer, inner plexiform layer, iris stroma, and ventral canalicular network. Exogenous RA increased apoptosis in the iris stroma and canalicular network in the ventral iridocorneal angle, resulting in the loss of these structures and decreased aqueous outflow. DEAB, which decreased RA activity throughout the eye, induced widespread apoptosis, resulting in corneal edema, cataracts, retinal atrophy, and loss of iridocorneal angle structures. DEAB-treated fish were blind with no optokinetic response and no aqueous outflow from the anterior chamber.ConclusionsTight control of RA levels is required for normal structure and function of the adult anterior segment. These studies demonstrated that RA plays an important role in maintaining ocular and craniofacial structures in adult zebrafish.

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Section: Discussioncontrasting

confidence: 55%

Retinoic Acid Maintains Function of Neural Crest–Derived Ocular and Craniofacial Structures in Adult Zebrafish

Chawla

Swain

Williams

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…• n/a Secretion Assay Gobeil et al, 2006) • 30°C ○ - (Gobeil et al, 2006) Triton X-100 Solubility Assay et al, 2012) or 43.0°C (Burns et al, 2011) • Yes (Kuchtey et al, 2013;Lu et al, 2020;K. Michels-Rautenstrauss et al, 2002) gnomAD?…”

Section: Locationunclassified

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

et al. 2021

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Rare variants of the olfactomedin domain of myocilin are considered causative for inherited, early-onset open-angle glaucoma, with a misfolding toxic gain-of-function pathogenic mechanism detailed by 20 years of laboratory research. Myocilin variants are documented in the scientific literature and identified through large-scale genetic sequencing projects such as those curated in the Genome Aggregation Database (gnomAD). In the absence of key clinical and laboratory information, however, the pathogenicity of any given variant is not clear, because glaucoma is a heterogeneous and prevalent age-onset disease, and common variants are likely benign. In this review, we reevaluate the likelihood of pathogenicity for the~100 nonsynonymous missense, insertion-deletion, and premature termination of myocilin olfactomedin variants documented in the literature. We integrate available clinical, laboratory cellular, biochemical and biophysical data, the olfactomedin domain structure, and population genetics data from gnomAD. Of the variants inspected,~50% can be binned based on a preponderance of data, leaving many of uncertain pathogenicity that motivate additional studies. Ultimately, the approach of combining metrics from different disciplines will likely resolve outstanding complexities regarding the role of this misfolding-prone protein within the context of a multifactorial and prevalent ocular disease, and pave the way for new precision medicine therapeutics.

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“…Some studies have demonstrated that neither haploinsufficiency (16,19,67,76) nor the dominant negative effect (77) are involved in myocilin-associated pathogenicity. However, recent findings (42,78) have suggested that the dominant negative effect may be involved in the pathogenic role of myocilin in glaucoma. Notably, the majority of experimental evidence support gain-of-function as a pathogenic mechanism involved in myocilin mutation-associated glaucoma (21,23,36,37,41,42,67,73,76,79-84).…”

Section: Pathogenesis Of Mutant/misfolded Myocilinsmentioning

confidence: 99%

Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review)

Wang

Zhang

et al. 2018

Int J Mol Med

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Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure (IOP). Myocilin abnormalities may cause dysfunction of the TM, potentially leading to increased IOP. High IOP is a well-known primary risk factor for glaucoma. Myocilin mutations are common among glaucoma patients, and they are implicated in juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (POAG). Aggregation of aberrant mutant myocilins is closely associated with glaucoma pathogenesis. The aim of the present review was to discuss the recent findings regarding the major physiological functions of myocilin, such as intra- and extracellular proteolytic processes. We also aimed to discuss the risk factors associated with myocilin and the development of glaucoma, such as misfolded/mutant myocilin, imbalance of myocilin and extracellular proteins, and instability of mutant myocilin associated with temperature. Finally, we further outlined certain issues that are yet to be resolved, which may represent the basis for future studies on the role of myocilin in glaucoma.

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A de novo MYOC mutation detected in juvenile open angle glaucoma associated with reduced myocilin protein in aqueous humor

Cited by 16 publications

References 19 publications

Retinoic Acid Maintains Function of Neural Crest–Derived Ocular and Craniofacial Structures in Adult Zebrafish

Retinoic Acid Maintains Function of Neural Crest–Derived Ocular and Craniofacial Structures in Adult Zebrafish

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review)

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