Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Abstract

Objective: To identify the interaction between the MYOC Y437H mutation and TGF-β2 in a family with primary open-angle glaucoma (POAG). Methods: The MYOC Y437H mutation was identified in a family with POAG; the family was a fourth-generation family with 27 members, of which 6 members were affected. Analysis focused on the secreted myocilin protein and TGF-β2 found in the aqueous humor. Samples were taken both from normal controls and MYOC mutant carriers and cross-talk between MYOC Y437H and TGF-β2 were evaluated in the trabecular meshwork (TM) cells. Results: Aqueous humor secreted myocilin protein levels were reduced while TGF-β2 levels were increased in patients with the MYOC (c.1309T>C) mutation. This inverse relationship indicated that elevated TGF-β2 may be an important pathogenic mechanism in the progression of myocilin-related POAG. In TM cells expressing the MYOC Y437H mutant, exogenous TGF-β2 also significantly increased myocilin expression as well as the endoplasmic reticulum (ER) stress markers GRP94 and CHOP. This increase in TGF-β2 was also associated with increased cell death in cells carrying the MYOC Y437H mutation. Conclusion: These data collectively suggest that the mutual interaction between glaucomatous MYOC mutation and TGF-β2 contributed to the cell death of TM cells. This relationship also provides a new, therapeutic targets for the treatment of glaucoma.

Mesenchymal stromal cells from human Wharton’s jelly modulate the intraocular immune response in a glucocorticoid hypertension model: an exploratory analysis

“…We observed that GC-induced OH could also increase the concentrations of IL-6, IL-8, TNF-α, IL-10, and IFN-γ in both the aqueous and vitreous humors, as described in other forms of glaucoma [47][48][49]. We corroborated the findings of Yang et al [50] by observing an increase in TGF-β levels in the OH group, suggesting that the increase in this cytokine may be the triggering factor for the imbalance of certain cytokines in the ocular microenvironment.…”

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

“…Diagnosis JOAG (W. L. Alward et al, 2002; Lei, Li, Liu, & Zhang, 2019; Wiggs et al, 1998; Yang et al, 2020) POAG (W. L. Alward et al, 1998; W. L. Alward et al, 2002; Fingert et al, 1999; Lei et al, 2019; E. M. Stone et al, 1997) OHT (Lei et al, 2019) …”

“…Family History of POAG/JOAG? Yes (W. L. Alward et al, 1998; Lei et al, 2019; E. M. Stone et al, 1997; Wiggs et al, 1998; Yang et al, 2020) …”

Myocilin Mutation N480K Leads to Early Onset Juvenile and Adult-onset Primary Open Angle Glaucoma in a Six Generation Family

“…In addition, early detection will allow better therapeutic interventions. 15,18,19 In this study, we have screened a large family from Kadaladi, Tamil Nadu, India, for MYOC mutations based on the initial findings, in which the proband was diagnosed as JOAG. We examined the exons as well as whole-exome sequences of the selected patients.…”

“…Thus, screening MYOC mutations among JOAG patients of the family helps detect the disease early. In addition, early detection will allow better therapeutic interventions 15,18,19 …”