Age at Glaucoma Diagnosis in Germline Myocilin Mutation Patients: Associations with Polymorphisms in Protein Stabilities

Tanji, Tarin T.; Cohen, Emily; Shen, Darrick; Zhang, Chi; Yu, Fei; Coleman, Anne L.; Zheng, Jie

doi:10.3390/genes12111802

Cited by 8 publications

(5 citation statements)

References 82 publications

(81 reference statements)

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“…In addition, there is an age at diagnosis for variants now considered benign because individuals harboring myocilin polymorphisms can still develop glaucoma even if the relationship is not causal. Nevertheless, in our early biophysical study of the OLF domain ( Burns et al, 2011 ), a weak positive linear correlation between OLF variant T m and age at diagnosis was suggested, and this apparent relationship was repeated in a recent literature review by others ( Tanji et al, 2021 ). Upon plotting the new variants characterized here alongside all variants for which clinical and experimental stability data are available, no convincing trendline was observed, however ( Fig.…”

Section: Resultsmentioning

confidence: 65%

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability

Scelsi

Hill

Barlow

et al. 2023

Disease Models &Amp; Mechanisms

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Accurate predictions of pathogenicity for mutations associated with genetic disease are key to the success of precision medicine. Inherited, missense coding mutations in the myocilin gene (MYOC), within its olfactomedin (OLF) domain, comprise the strongest genetic link to primary open angle glaucoma via a toxic gain of function, and MYOC is an attractive precision medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The gnomAD database lists ∼100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To disambiguate disease from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identify two variants with features of aggregation-prone familial disease variants. Next, we consider all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric, thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless, and irreversible age-onset disease.

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Section: Resultsmentioning

confidence: 65%

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability

Scelsi

Hill

Barlow

et al. 2023

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…For example, the first pathogenic mutation for primary open-angle glaucoma has been identified in the myocilin gene [ 36 ]. The aggregation of mutant myocilin can lead to a severe decline in TM cellularity due to endoplasmic reticulum stress [ 37 , 38 ]. To this end, it is very important to investigate how damage occurs in different TM subpopulations.…”

Section: Discussionmentioning

confidence: 99%

Application of a Magnetic Platform in α6 Integrin-Positive iPSC-TM Purification

Feng

Wang

et al. 2023

Bioengineering

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The emergence of induced pluripotent stem cell (iPSC) technology has provided a new approach to regenerating decellularized trabecular meshwork (TM) in glaucoma. We have previously generated iPSC-derived TM (iPSC-TM) using a medium conditioned by TM cells and verified its function in tissue regeneration. Because of the heterogeneity of iPSCs and the isolated TM cells, iPSC-TM cells appear to be heterogeneous, which impedes our understanding of how the decellularized TM may be regenerated. Herein, we developed a protocol based on a magnetic-activated cell sorting (MACS) system or an immunopanning (IP) method for sorting integrin subunit alpha 6 (ITGA6)-positive iPSC-TM, an example of the iPSC-TM subpopulation. We first analyzed the purification efficiency of these two approaches by flow cytometry. In addition, we also determined cell viability by analyzing the morphologies of the purified cells. To conclude, the MACS-based purification could yield a higher ratio of ITGA6-positive iPSC-TM and maintain a relatively higher cell viability than the IP-based method, allowing for the preparation of any iPSC-TM subpopulation of interest and facilitating a better understanding of the regenerative mechanism of iPSC-based therapy.

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“…Myocilin is mainly expressed in TM cell, and excessively accumulated in ER when MYOC is mutated or overexpressed, which may trigger or disrupt protein clearance mechanisms including ER-associated degradation (ERAD) and autophagy ( Kasetti et al, 2021 ; Tanji et al, 2021 ). However, previous studies only reported the difference between WT-MYOC and mutated-MYOC (Y437H, G364V, Q368X, etc ), ignoring the alteration induced by MYOC neutral polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Structure‒function‒pathogenicity analysis of C-terminal myocilin missense variants based on experiments and 3D models

Zhou

Lin

et al. 2022

Front. Genet.

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MYOC is a common pathogenic gene for primary open-angle glaucoma and encodes the protein named myocilin. Multiple MYOC variations have been found, with different clinical significance. However, the pathogenesis of glaucoma induced by MYOC mutations has not been fully clarified. Here, we analyze the molecular and cellular biological differences caused by multiple variant myocilins, including protein secretion characteristics, structural changes, subcellular localization, cellular autophagic activity and oxidative stress. Denaturing and nondenaturing electrophoresis showed myocilin to be a secreted protein with the tendency to self-oligomerize. The full-length myocilin and its C-terminal cleavage fragment are secreted. Secretion analysis of 23 variant myocilins indicated that secretion defects are closely related to the pathogenicity of MYOC variants. Structural analysis showed that the alteration of steric clash is associated with the secretion characteristics and pathogenicity of myocilin variants. Immunocytochemistry results demonstrated that mutated myocilins are retained in the endoplasmic reticulum and disrupt autophagy. MTT assay, MitoTracker staining, and DCFH-DA staining showed increased oxidative injury in cells expressing MYOC mutants. Taken together, MYOC mutations are able to induce cell dysfunction via secretion defects and intracellular accumulation resulting from steric clash alterations.

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Age at Glaucoma Diagnosis in Germline Myocilin Mutation Patients: Associations with Polymorphisms in Protein Stabilities

Cited by 8 publications

References 82 publications

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability

Quantitative differentiation of benign and misfolded glaucoma-causing myocilin variants on the basis of protein thermal stability

Application of a Magnetic Platform in α6 Integrin-Positive iPSC-TM Purification

Structure‒function‒pathogenicity analysis of C-terminal myocilin missense variants based on experiments and 3D models

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