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Genetics and Epigenetics of Eye Diseases
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Genetics and Epigenetics of Eye Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 17256

Special Issue Editors

Prof. Dr. Janusz Blasiak

E-Mail Website
Guest Editor
Faculty of Biology and Environmental Sciences, Department of Molecular Genetics, University of Lodz, 90-136 Lodz, Poland
Interests: DNA and RNA structure; DNA damage and repair; DNA damage response; mutagenesis; cancer transformation; age-related macular degeneration; autophagy; mitochondrial quality control; mitophagy; miRNA-lncRNA regulation; gene regulation; epigenetics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Kai Kaarniranta

E-Mail Website
Guest Editor
Department of Ophthalmology, University of Eastern Finland, 70211 Kuopio, Finland
Interests: autophagy; oxidative stress; inflammation; lysosome; retinal pigment epithelium; reactive oxygen species; lipid peroxidation; age-related macular degeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Everything lies in genes or rather their expression, which is regulated genetically (transcription factors and other functional and structural proteins) and epigenetically (DNA methylation, histone modifications, non-coding RNAs). Deregulated gene expression is at the very heart of many human pathologies. Most human eye diseases are complex disorders, whose pathogenesis is underlined by an interplay between genetic/epigenetic, environmental, and life-style factors. The aim of this Special Issue is to shed some light on molecular aspects on this interplay. Therefore, all manuscripts, including clinical reports, experimental works and reviews as well as meta-analyses, reporting associations between eye disease phenotype and changes in the genome and epigenome are welcome. Because eye diseases in humans can be hardly studied in the target tissue, reports on experimental modeling of the involvement of genetic/epigenetic factors in their pathogenesis are also welcome.

Prof. Dr. Janusz Blasiak
Prof. Dr. Kai Kaarniranta
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Gene/genome expression
  • DNA damage/repair
  • DNA mutation/polymorphism
  • DNA methylation
  • Histone modifications
  • Non-coding RNAs

Related Special Issue

Published Papers (7 papers)

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Research

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16 pages, 4092 KiB  
Article
TGF-β/Smad Signalling Activation by HTRA1 Regulates the Function of Human Lens Epithelial Cells and Its Mechanism in Posterior Subcapsular Congenital Cataract
by Xiaolei Lin, Tianke Yang, Xin Liu, Fan Fan, Xiyue Zhou, Hongzhe Li and Yi Luo
Int. J. Mol. Sci. 2022, 23(22), 14431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214431 - 20 Nov 2022
Cited by 2 | Viewed by 1603
Abstract
Congenital cataract is the leading cause of blindness among children worldwide. Patients with posterior subcapsular congenital cataract (PSC) in the central visual axis can result in worsening vision and stimulus deprivation amblyopia. However, the pathogenesis of PSC remains unclear. This study aims to [...] Read more.
Congenital cataract is the leading cause of blindness among children worldwide. Patients with posterior subcapsular congenital cataract (PSC) in the central visual axis can result in worsening vision and stimulus deprivation amblyopia. However, the pathogenesis of PSC remains unclear. This study aims to explore the functional regulation and mechanism of HTRA1 in human lens epithelial cells (HLECs). HTRA1 was significantly downregulated in the lens capsules of children with PSC compared to normal controls. HTRA1 is a suppression factor of transforming growth factor-β (TGF-β) signalling pathway, which plays a key role in cataract formation. The results showed that the TGF-β/Smad signalling pathway was activated in the lens tissue of PSC. The effect of HTRA1 on cell proliferation, migration and apoptosis was measured in HLECs. In primary HLECs, the downregulation of HTRA1 can promote the proliferation and migration of HLECs by activating the TGF-β/Smad signalling pathway and can significantly upregulate the TGF-β/Smad downstream target genes FN1 and α-SMA. HTRA1 was also knocked out in the eyes of C57BL/6J mice via adeno-associated virus-mediated RNA interference. The results showed that HTRA1 knockout can significantly upregulate p-Smad2/3 and activate the TGF-β/Smad signalling pathway, resulting in abnormal proliferation and irregular arrangement of lens epithelial cells and leading to the occurrence of subcapsular cataract. To conclude, HTRA1 was significantly downregulated in children with PSC, and the downregulation of HTRA1 enhanced the proliferation and migration of HLECs by activating the TGF-β/Smad signalling pathway, which led to the occurrence of PSC. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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16 pages, 2513 KiB  
Article
Deglycosylation Increases the Aggregation and Angiogenic Properties of Mutant Tissue Inhibitor of Metalloproteinase 3 Protein: Implications for Sorsby Fundus Dystrophy
by Jian Hua Qi and Bela Anand-Apte
Int. J. Mol. Sci. 2022, 23(22), 14231; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214231 - 17 Nov 2022
Cited by 2 | Viewed by 1261
Abstract
Sorsby fundus dystrophy (SFD) is an autosomal dominant macular disorder caused by mutations in tissue Inhibitor of the metalloproteinase-3 (TIMP3) gene with the onset of symptoms including choroidal neovascularization as early as the second decade of life. We have previously reported that [...] Read more.
Sorsby fundus dystrophy (SFD) is an autosomal dominant macular disorder caused by mutations in tissue Inhibitor of the metalloproteinase-3 (TIMP3) gene with the onset of symptoms including choroidal neovascularization as early as the second decade of life. We have previously reported that wild-type TIMP3 is an endogenous angiogenesis inhibitor that inhibits Vascular Endothelial Growth Factor (VEGF)-mediated signaling in endothelial cells. In contrast, SFD-related S179C-TIMP3 when expressed in endothelial cells, does not have angiogenesis-inhibitory properties. To evaluate if this is a common feature of TIMP3 mutants associated with SFD, we examined and compared endothelial cells expressing S179C, Y191C and S204C TIMP3 mutants for their angiogenesis-inhibitory function. Western blot analysis, zymography and reverse zymography and migration assays were utilized to evaluate TIMP3 protein, Matrix Metalloproteinase (MMP) and MMP inhibitory activity, VEGF signaling and in vitro migration in endothelial cells expressing (VEGF receptor-2 (VEGFR-2) and wild-type TIMP3 or mutant-TIMP3. We demonstrate that mutant S179C, Y191C- and S204C-TIMP3 all show increased glycosylation and multimerization/aggregation of the TIMP3 protein. In addition, endothelial cells expressing TIMP3 mutations show increased angiogenic activities and elevated VEGFR-2. Removal of N-glycosylation by mutation of Asn184, the only potential N-glycosylation site in mutant TIMP3, resulted in increased aggregation of TIMP3, further upregulation of VEGFR-2, VEGF-induced phosphorylation of VEGFR2 and VEGF-mediated migration concomitant with reduced MMP inhibitory activity. These results suggest that even though mutant TIMP3 proteins are more glycosylated, post-translational deglycosylation may play a critical role in the aggregation of mutant TIMP3 and contribute to the pathogenesis of SFD. The identification of factors that might contribute to changes in the glycome of patients with SFD will be useful. Future studies will evaluate whether variations in the glycosylation of mutant TIMP3 proteins are contributing to the severity of the disease. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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15 pages, 1916 KiB  
Article
Evaluation of Orbital Lymphoproliferative and Inflammatory Disorders by Gene Expression Analysis
by Karim Al-Ghazzawi, Sven Holger Baum, Roman Pförtner, Svenja Philipp, Nikolaos Bechrakis, Gina Görtz, Anja Eckstein, Fabian D. Mairinger and Michael Oeverhaus
Int. J. Mol. Sci. 2022, 23(15), 8609; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158609 - 03 Aug 2022
Cited by 3 | Viewed by 1883
Abstract
Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are often challenging to differentiate. Furthermore, it is still uncertain how chronic inflammation, such as IgG4-ROD, can lead to mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we aimed to evaluate the diagnostic value of gene [...] Read more.
Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are often challenging to differentiate. Furthermore, it is still uncertain how chronic inflammation, such as IgG4-ROD, can lead to mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we aimed to evaluate the diagnostic value of gene expression analysis to differentiate orbital autoimmune diseases and elucidate genetic overlaps. First, we established a database of NSOI, relapsing NSOI, IgG4-ROD and MALT lymphoma patients of our orbital center (2000–2019). In a consensus process, three typical patients of the above mentioned three groups (mean age 56.4 ± 17 years) at similar locations were selected. Afterwards, RNA was isolated using the RNeasy FFPE kit (Qiagen) from archived paraffin-embedded tissues. The RNA of these 12 patients were then subjected to gene expression analysis (NanoString nCounter®), including a total of 1364 target genes. The most significantly upregulated and downregulated genes were used for a machine learning algorithm to distinguish entities. This was possible with a high probability (p < 0.0001). Interestingly, gene expression patterns showed a characteristic overlap of lymphoma with IgG4-ROD and NSOI. In contrast, IgG4-ROD shared only altered expression of one gene regarding NSOI. To validate our potential biomarker genes, we isolated the RNA of a further 48 patients (24 NSOI, 11 IgG4-ROD, 13 lymphoma patients). Then, gene expression pattern analysis of the 35 identified target genes was performed using a custom-designed CodeSet to assess the prediction accuracy of the multi-parameter scoring algorithms. They showed high accuracy and good performance (AUC ROC: IgG4-ROD 0.81, MALT 0.82, NSOI 0.67). To conclude, genetic expression analysis has the potential for faster and more secure differentiation between NSOI and IgG4-ROD. MALT-lymphoma and IgG4-ROD showed more genetic similarities, which points towards progression to lymphoma. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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14 pages, 4058 KiB  
Article
Applying Protein–Protein Interactions and Complex Networks to Identify Novel Genes in Retinitis Pigmentosa Pathogenesis
by Su-Bin Yoon, Yu-Chien (Calvin) Ma, Akaash Venkat, Chun-Yu (Audi) Liu and Jie J. Zheng
Int. J. Mol. Sci. 2022, 23(7), 3962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073962 - 02 Apr 2022
Viewed by 2634
Abstract
Retinitis Pigmentosa (RP) is a hereditary retinal disorder that causes the atrophy of photoreceptor rod cells. Since individual defective genes converge on the same disease, we hypothesized that all causal genes of RP belong in a complex network. To explore this hypothesis, we [...] Read more.
Retinitis Pigmentosa (RP) is a hereditary retinal disorder that causes the atrophy of photoreceptor rod cells. Since individual defective genes converge on the same disease, we hypothesized that all causal genes of RP belong in a complex network. To explore this hypothesis, we conducted a gene connection analysis using 161 genes attributed to RP, compiled from the Retinal Information Network, RetNet. We then examined the protein interaction network (PIN) of these genes. In line with our hypothesis, using STRING, we directly connected 149 genes out of the recognized 159 genes. To uncover the association between the PIN and the ten unrecalled genes, we developed an algorithm to pinpoint the best candidate genes to connect the uncalled genes to the PIN and identified ten such genes. We propose that mutations within these ten genes may also cause RP; this notion is supported by analyzing and categorizing the known causal genes based on cellular locations and related functions. The successful establishment of the PIN among all documented genes and the discovery of novel genes for RP strongly suggest an interconnectedness that causes the disease on the molecular level. In addition, our computational gene search protocol can help identify the genes and loci responsible for genetic diseases, not limited to RP. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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15 pages, 3225 KiB  
Article
Regulation of Opsin Gene Expression by DNA Methylation and Histone Acetylation
by Jin Song, Julia A. VanBuskirk and Shannath L. Merbs
Int. J. Mol. Sci. 2022, 23(3), 1408; https://doi.org/10.3390/ijms23031408 - 26 Jan 2022
Cited by 7 | Viewed by 2664
Abstract
One important role of epigenetic regulation is controlling gene expression in development and homeostasis. However, little is known about epigenetics’ role in regulating opsin expression. Cell cultures (HEK 293, Y79, and WERI) producing different levels of opsins were treated with 5-aza-2’-deoxycytidine (5-Aza-dc) and/or [...] Read more.
One important role of epigenetic regulation is controlling gene expression in development and homeostasis. However, little is known about epigenetics’ role in regulating opsin expression. Cell cultures (HEK 293, Y79, and WERI) producing different levels of opsins were treated with 5-aza-2’-deoxycytidine (5-Aza-dc) and/or sodium butyrate (SB) or suberoylanilide hydroxamic acid (SAHA) for 72 h. Global DNA methylation, site-specific methylation, and expressions of opsins were measured by LUMA assay, bisulfite pyrosequencing, and qPCR, respectively. Mouse retinal explants from wild-type P0/P1 pups were ex vivo cultured with/without 5-Aza-dc or SAHA for 6 days. The morphology of explants, DNA methylation, and expressions of opsins was examined. The drugs induced global DNA hypomethylation or increased histone acetylation in cells, including DNA hypomethylation of rhodopsin (RHO) and L-opsin (OPN1LW) and a concomitant increase in their expression. Further upregulation of RHO and/or OPN1LW in HEK 293 or WERI cells was observed with 5-Aza-dc and either SB or SAHA combination treatment. Mouse retinal explants developed normally but had drug-dependent differential DNA methylation and expression patterns of opsins. DNA methylation and histone acetylation directly regulate opsin expression both in vitro and ex vivo. The ability to manipulate opsin expression using epigenetic modifiers enables further study into the role of epigenetics in eye development and disease. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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16 pages, 1751 KiB  
Article
Epigenetic Age Acceleration Is Not Associated with Age-Related Macular Degeneration
by Neil Saptarshi, Daniel Green, Angela Cree, Andrew Lotery, Luminita Paraoan and Louise F. Porter
Int. J. Mol. Sci. 2021, 22(24), 13457; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413457 - 15 Dec 2021
Cited by 6 | Viewed by 2950
Abstract
DNA methylation age (DNAm age) estimation is a powerful biomarker of human ageing. To date, epigenetic clocks have not been evaluated in age-related macular degeneration (AMD). Here, we perform genome-wide DNA methylation analyses in blood of AMD patients with a documented smoking history [...] Read more.
DNA methylation age (DNAm age) estimation is a powerful biomarker of human ageing. To date, epigenetic clocks have not been evaluated in age-related macular degeneration (AMD). Here, we perform genome-wide DNA methylation analyses in blood of AMD patients with a documented smoking history (14 AMD, 16 Normal), identifying loci of differential methylation (DML) with a relaxed p-value criterion (p ≤ 10−4). We conduct DNAm age analyses using the Horvath-multi tissue, Hannum and Skin & Blood epigenetic clocks in both blood and retinal pigment epithelium (RPE). We perform Ingenuity Pathway Analysis Causal Network Analysis (IPA CNA) on the topmost significantly differentially methylated CpG probes in blood and RPE. Results show poor performance of epigenetic clocks in RPE. Epigenetic age acceleration (EAA) was not observed in AMD. However, we observe positive EAA in blood of smokers, and in smokers with AMD. DML analysis revealed hypomethylation at cg04953735 within RPTOR (p = 6.51 × 10−5; Δβ = −11.95%). IPA CNA in the RPE also identified RPTOR as the putative master regulator, predicted to be inhibited in AMD. In conclusion, this is the first study evaluating an association of epigenetic ageing in AMD. We posit a role for RPTOR as a common master regulator of methylation changes in the RPE in AMD. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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Review

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18 pages, 13886 KiB  
Review
Potential of Long Non-Coding RNAs in Age-Related Macular Degeneration
by Janusz Blasiak, Juha M. T. Hyttinen, Joanna Szczepanska, Elzbieta Pawlowska and Kai Kaarniranta
Int. J. Mol. Sci. 2021, 22(17), 9178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179178 - 25 Aug 2021
Cited by 9 | Viewed by 2747
Abstract
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with poorly known pathogenesis and lack of effective treatment. Age and family history are the strongest AMD risk factors, and several loci were identified to contribute to AMD. [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with poorly known pathogenesis and lack of effective treatment. Age and family history are the strongest AMD risk factors, and several loci were identified to contribute to AMD. Recently, also the epigenetic profile was associated with AMD, and some long non-coding RNAs (lncRNAs) were shown to involve in AMD pathogenesis. The Vax2os1/2 (ventral anterior homeobox 2 opposite strand isoform 1) lncRNAs may modulate the balance between pro- and anti-angiogenic factors in the eye contributing to wet AMD. The stress-induced dedifferentiation of retinal pigment epithelium cells can be inhibited by the ZNF503-AS1 (zinc finger protein 503 antisense RNA 2) and LINC00167 lncRNAs. Overexpression of the PWRN2 (Prader-Willi region non-protein-coding RNA 2) lncRNA aggravated RPE cells apoptosis and mitochondrial impairment induced by oxidative stress. Several other lncRNAs were reported to exert protective or detrimental effects in AMD. However, many studies are limited to an association between lncRNA and AMD in patients or model systems with bioinformatics. Therefore, further works on lncRNAs in AMD are rational, and they should be enriched with mechanistic and clinical studies to validate conclusions obtained in high-throughput in vitro research. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases)
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