Inherited cataracts: Genetic mechanisms and pathways new and old

Shiels, Alan; Hejtmancik, J. Fielding

doi:10.1016/j.exer.2021.108662

Cited by 47 publications

(45 citation statements)

References 177 publications

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“… 24 , 35 What's more, prolonged UPR-induced apoptosis in the lens leads to cell death, structural disruption, and vacuolization in some severe situations. 14 , 23 , 24 , 35 Similar phenotypes were also found in Jamc knockout lenses, accompanied by UPR activation. We presume that activation of the UPR induces global attenuation of translation, decreases protein synthesis, and results in subsequent initiation of apoptosis, which may disrupt lens homeostasis and finally lead to lens opacity.…”

Section: Discussionsupporting

confidence: 66%

“…Binding immunoglobulin protein (BiP), also known as heat shock protein family A member 5 (HSPA5) or 78-kDa glucose-regulated protein (GRP78), is usually located in the endoplasmic reticulum (ER) membrane and binds to three main UPR sensors (IRE1α, PERK, and ATF6) to keep them inactive. 14 When the accumulation of unfolded, misfolded, or denatured proteins induces ER stress, BiP dissociates from the three sensors and subsequently activates downstream signaling pathways to increase chaperone expression, reduce protein synthesis, and accelerate misfolded protein degradation. 15 Thus, BiP is usually considered to be an ER stress hallmark; however, prolonged ER stress induces cell death when the UPR is insufficient to cope with the stress.…”

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confidence: 99%

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Deficiency of Jamc Leads to Congenital Nuclear Cataract and Activates the Unfolded Protein Response in Mouse Lenses

Tan

Sun

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose The malfunction of junctional adhesion molecule C (JAM-C) has been reported to induce congenital cataract in humans and mice; however, specific characters and the mechanism of this cataract are still unclear. This study aimed to characterize abnormal lens development in Jamc knockout mice and clarify the underlying mechanism. Methods Jamc knockout mice backcrossed onto the C57BL/6 genetic background were used for this research. Slit-lamp and darkfield images showed the cataract phenotype of Jamc − / − mice. Hematoxylin and eosin staining was performed to visualize the morphological and histological features. RNA sequencing was applied to detect differentially expressed genes. Quantitative RT-PCR, western blot, and immunofluorescence were used to determine the level of unfolded protein response (UPR)-related genes. TUNEL staining was utilized to label cell death. Results Jamc knockout mice exhibited nuclear cataract with abnormal lens morphology and defective degradation of nuclei and organelles in lens fiber cells. Compared with wild-type control mice, the expression level of BiP, CHOP, TRIB3, and CHAC1, genes involved in endoplasmic reticulum stress and the UPR, were highly upregulated in Jamc − / − lenses, suggesting that abnormal lens development was accompanied by UPR activation. Moreover, increased cell death was also found in Jamc −/− lenses. Conclusions Congenital nuclear cataract caused by Jamc deficiency is accompanied by defective degradation of nuclei and organelles in lens fiber cells, lens structure disorder, and UPR activation, suggesting that JAM-C is required for maintaining normal lens development and that UPR activation is involved in cataract formation in Jamc -deficient lenses.

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Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Deficiency of Jamc Leads to Congenital Nuclear Cataract and Activates the Unfolded Protein Response in Mouse Lenses

Tan

Sun

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…Collagens are located extracellularly between differentiating fiber cells during lens development, so it is reasonable to expect a congenital cataract phenotype including for COL11A1 ( 32–36 ). Intriguingly with collagen mutations, it can be observed that unilateral lens cataract develops ( 33 ) in the affected individual and can even be absent between generations ( 36 ) demonstrating that phenotypic variability is a known complication for congenital cataract ( 37 ). Why the highly damaging COL11A1 mutation in the Japanese resulted in an unaffected phenotype remains unknown; however, further study is needed to explore the pathogenic consequences of both of these variants in the lens to understand the underlying molecular and functional mechanisms, but this also applies to other collagen mutations associated with congenital cataract.…”

Section: Discussionmentioning

confidence: 99%

A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family

Berry

Fujinami

Mochizuki

et al. 2022

Ophthalmic Genetics

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Background Genetically determined cataract is both clinically and molecularly highly heterogeneous. Here, we have identified a heterozygous variant in the lens integral membrane protein LIM2, the second most abundant protein in the lens, responsible for congenital sutural/lamellar cataract in a three-generation Japanese family. Methods Whole exome sequencing (WES) was undertaken in one affected and one unaffected individual from a family with autosomal dominant congenital cataract to establish the underlying genetic basis. Results A recurrent missense variant LIM2: c.388C>T; p.R130C was identified and found to co-segregate with disease. In addition, one variant COL11A1:c.3788C>T of unknown significance (VUS) was also identified. Conclusions We report a variant in LIM2 causing an isolated autosomal-dominant congenital sutural/lamellar cataract in a Japanese family. This is the first report of a LIM2 variant in the Japanese population. Hence, we expand the mutation spectrum of LIM2 variants in different ethnic groups.

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“…In the layer of lens epithelial cells, abundant expression of Cx43 could be detected, whereas Cx46 is exclusively present in the lens fiber cell, where its expression corresponds with fiber cell differentiation, and Cx50 is widely expressed in both lens epithelial and fiber cells (Figure 1) (Paul et al, 1991;Delvaeye et al, 2018;Ceroni et al, 2019;Tong et al, 2021). Although the pathogenesis of cataracts is not yet fully clear (Davison, 2020;Hashemi et al, 2020;Shiels and Hejtmancik, 2021;Taylan Sekeroglu and Utine, 2021), a number of studies have shown that disruption of lens connexin hemichannels proteins Cx46 and Cx50 expression are associated with cataract formation (White et al, 1998;Chang et al, 2002;Addison et al, 2006;Xia et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

Mutations of CX46/CX50 and Cataract Development

Shi

Yang

2022

Front. Mol. Biosci.

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Cataract is a common disease in the aging population. Gap junction has been considered a central component in maintaining homeostasis for preventing cataract formation. Gap junction channels consist of connexin proteins with more than 20 members. Three genes including GJA1, GJA3, and GJA8, that encode protein Cx43 (connexin43), Cx46 (connexin46), and Cx50 (connexin50), respectively, have been identified in human and rodent lens. Cx46 together with Cx50 have been detected in lens fiber cells with high expression, whereas Cx43 is mainly expressed in lens epithelial cells. Disrupted expression of the two connexin proteins Cx46 and Cx50 is directly related to the development of severe cataract in human and mice. In this review article, we describe the main role of Cx46 and Cx50 connexin proteins in the lens and the relationship between mutations of Cx46 or Cx50 and hereditary cataracts. Furthermore, the latest progress in the fundamental research of lens connexin and the mechanism of cataract formation caused by lens connexin dysfunction are summarized. Overall, targeting connexin could be a novel approach for the treatment of cataract.

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Inherited cataracts: Genetic mechanisms and pathways new and old

Cited by 47 publications

References 177 publications

Deficiency of Jamc Leads to Congenital Nuclear Cataract and Activates the Unfolded Protein Response in Mouse Lenses

Deficiency of Jamc Leads to Congenital Nuclear Cataract and Activates the Unfolded Protein Response in Mouse Lenses

A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family

Mutations of CX46/CX50 and Cataract Development

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