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Genetics and Epigenetics of Eye Diseases: 2nd Edition

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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: 20 April 2025 | Viewed by 16404

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Prof. Dr. Janusz Blasiak

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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
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Prof. Dr. Kai Kaarniranta

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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

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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

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Keywords

gene/genome expression
DNA damage/repair
DNA mutation/polymorphism
DNA methylation
histone modifications
non-coding RNAs

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Genetics and Epigenetics of Eye Diseases in International Journal of Molecular Sciences (7 articles)

Published Papers (9 papers)

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Research

Jump to: Review, Other

14 pages, 1256 KiB

Open AccessArticle

Novel and Recurrent Copy Number Variants in ABCA4-Associated Retinopathy

by Zelia Corradi, Claire-Marie Dhaenens, Olivier Grunewald, Ipek Selen Kocabaş, Isabelle Meunier, Sandro Banfi, Marianthi Karali, Frans P. M. Cremers and Rebekkah J. Hitti-Malin

Int. J. Mol. Sci. 2024, 25(11), 5940; https://doi.org/10.3390/ijms25115940 - 29 May 2024

Viewed by 1106

Abstract

ABCA4 is the most frequently mutated gene leading to inherited retinal disease (IRD) with over 2200 pathogenic variants reported to date. Of these, ~1% are copy number variants (CNVs) involving the deletion or duplication of genomic regions, typically >50 nucleotides in length. An in-depth assessment of the current literature based on the public database LOVD, regarding the presence of known CNVs and structural variants in ABCA4, and additional sequencing analysis of ABCA4 using single-molecule Molecular Inversion Probes (smMIPs) for 148 probands highlighted recurrent and novel CNVs associated with ABCA4-associated retinopathies. An analysis of the coverage depth in the sequencing data led to the identification of eleven deletions (six novel and five recurrent), three duplications (one novel and two recurrent) and one complex CNV. Of particular interest was the identification of a complex defect, i.e., a 15.3 kb duplicated segment encompassing exon 31 through intron 41 that was inserted at the junction of a downstream 2.7 kb deletion encompassing intron 44 through intron 47. In addition, we identified a 7.0 kb tandem duplication of intron 1 in three cases. The identification of CNVs in ABCA4 can provide patients and their families with a genetic diagnosis whilst expanding our understanding of the complexity of diseases caused by ABCA4 variants. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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32 pages, 3685 KiB

Open AccessArticle

Association of Alpha-Crystallin with Human Cortical and Nuclear Lens Lipid Membrane Increases with the Grade of Cortical and Nuclear Cataract

by Preston Hazen, Geraline Trossi-Torres, Raju Timsina, Nawal K. Khadka and Laxman Mainali

Int. J. Mol. Sci. 2024, 25(3), 1936; https://doi.org/10.3390/ijms25031936 - 5 Feb 2024

Cited by 1 | Viewed by 1636

Abstract

Eye lens α-crystallin has been shown to become increasingly membrane-bound with age and cataract formation; however, to our knowledge, no studies have investigated the membrane interactions of α-crystallin throughout the development of cataracts in separated cortical membrane (CM) and nuclear membrane (NM) from single human lenses. In this study, four pairs of human lenses from age-matched male and female donors and one pair of male lenses ranging in age from 64 to 73 years old (yo) were obtained to investigate the interactions of α-crystallin with the NM and CM throughout the progression of cortical cataract (CC) and nuclear cataract (NC) using the electron paramagnetic resonance spin-labeling method. Donor health history information (diabetes, smoker, hypertension, radiation treatment), sex, and race were included in the data analysis. The right eye lenses CM and NM investigated were 64 yo male (CC: 0), 68 yo male (CC: 3, NC: 2), 73 yo male (CC: 1, NC: 2), 68 yo female (CC: 3, NC: 2), and 73 yo female (CC: 1, NC: 3). Similarly, left eye lenses CM and NM investigated were 64 yo male (CC: 0), 68 yo male (CC: 3, NC: 2), 73 yo male (CC: 2, NC: 3), 68 yo female (CC: 3, NC: 2), and 73 yo female (CC: 1, NC: 3). Analysis of α-crystallin binding to male and female eye lens CM and NM revealed that the percentage of membrane surface occupied (MSO) by α-crystallin increases with increasing grade of CC and NC. The binding of α-crystallin resulted in decreased mobility, increased order, and increased hydrophobicity on the membrane surface in male and female eye lens CM and NM. CM mobility decreased with an increase in cataracts for both males and females, whereas the male lens NM mobility showed no significant change, while female lens NM showed increased mobility with an increase in cataract grade. Our data shows that a 68 yo female donor (long-term smoker, pre-diabetic, and hypertension; grade 3 CC) showed the largest MSO by α-crystallin in CM from both the left and right lens and had the most pronounced mobility changes relative to all other analyzed samples. The variation in cholesterol (Chol) content, size and amount of cholesterol bilayer domains (CBDs), and lipid composition in the CM and NM with age and cataract might result in a variation of membrane surface mobility, membrane surface hydrophobicity, and the interactions of α-crystallin at the surface of each CM and NM. These findings provide insight into the effect of decreased Chol content and the reduced size and amount of CBDs in the cataractous CM and NM with an increased binding of α-crystallin with increased CC and NC grade, which suggests that Chol and CBDs might be a key component in maintaining lens transparency. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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14 pages, 968 KiB

Open AccessCommunication

DNAJC30 Gene Variants Are a Frequent Cause of a Rare Disease: Leber Hereditary Optic Neuropathy in Polish Patients

by Anna Skorczyk-Werner, Katarzyna Tońska, Aleksandra Maciejczuk, Katarzyna Nowomiejska, Magdalena Korwin, Monika Ołdak, Anna Wawrocka and Maciej R. Krawczyński

Int. J. Mol. Sci. 2023, 24(24), 17496; https://doi.org/10.3390/ijms242417496 - 15 Dec 2023

Cited by 3 | Viewed by 1904

Abstract

Leber hereditary optic neuropathy (LHON) is a rare disorder causing a sudden painless loss of visual acuity in one or both eyes, affecting young males in their second to third decade of life. The molecular background of the LHON is up to 90%, genetically defined by a point mutation in mitochondrial DNA. Recently, an autosomal recessive form of LHON (LHONAR1, arLHON) has been discovered, caused by biallelic variants in the DNAJC30 gene. This study provides the results of the DNAJC30 gene analysis in a large group of 46 Polish patients diagnosed with LHON, together with the clinical characterization of the disease. The c.152A>G (p.Tyr51Cys) substitution in the DNAJC30 gene was detected in all the patients as homozygote or compound heterozygote. Moreover, we identified one novel variant, c.293A>G, p.(Tyr98Cys), as well as two ultra-rare DNAJC30 variants: c.293A>C, p.(Tyr98Ser), identified to date only in one individual affected with LHONAR1, and c.130_131delTC (p.Ser44ValfsTer8), previously described only in two patients with Leigh syndrome. The patients presented here represent the largest group of subjects with DNAJC30 gene mutations described to date. Based on our data, the autosomal recessive form of LHON caused by DNAJC30 gene mutations is more frequent than the mitochondrial form in Polish patients. The results of our study suggest that Sanger sequencing of the single-exon DNAJC30 gene should be a method of choice applied to identify a molecular background of clinically confirmed LHON in Polish patients. This approach will help to reduce the costs of molecular testing. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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9 pages, 2517 KiB

Open AccessCommunication

Complex Chromosomal Rearrangement Involving Chromosomes 10 and 11, Accompanied by Two Adjacent 11p14.1p13 and 11p13p12 Deletions, Identified in a Patient with WAGR Syndrome

by Andrey V. Marakhonov, Tatyana A. Vasilyeva, Marina E. Minzhenkova, Natella V. Sukhanova, Peter A. Sparber, Natalya A. Andreeva, Margarita V. Teleshova, Fatima K.-M. Baybagisova, Nadezhda V. Shilova, Sergey I. Kutsev and Rena A. Zinchenko

Int. J. Mol. Sci. 2023, 24(23), 16923; https://doi.org/10.3390/ijms242316923 - 29 Nov 2023

Viewed by 1369

Abstract

Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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22 pages, 679 KiB

Open AccessArticle

Genetic Modulation of the Erythrocyte Phenotype Associated with Retinopathy of Prematurity—A Multicenter Portuguese Cohort Study

by Mariza Fevereiro-Martins, Ana Carolina Santos, Carlos Marques-Neves, Hercília Guimarães, Manuel Bicho and on behalf of the GenE-ROP Study Group

Int. J. Mol. Sci. 2023, 24(14), 11817; https://doi.org/10.3390/ijms241411817 - 23 Jul 2023

Cited by 2 | Viewed by 1508

Abstract

The development of retinopathy of prematurity (ROP) may be influenced by anemia or a low fetal/adult hemoglobin ratio. We aimed to analyze the association between DNA methyltransferase 3 β (DNMT3B) (rs2424913), methylenetetrahydrofolate reductase (MTHFR) (rs1801133), and lysine-specific histone demethylase 1A (KDM1A) (rs7548692) polymorphisms, erythrocyte parameters during the first week of life, and ROP. In total, 396 infants (gestational age < 32 weeks or birth weight < 1500 g) were evaluated clinically and hematologically. Genotyping was performed using a MicroChip DNA on a platform employing iPlex MassARRAY^®. Multivariate regression was performed after determining risk factors for ROP using univariate regression. In the group of infants who developed ROP red blood cell distribution width (RDW), erythroblasts, and mean corpuscular volume (MCV) were higher, while mean hemoglobin and mean corpuscular hemoglobin concentration (MCHC) were lower; higher RDW was associated with KDM1A (AA), MTHFR (CC and CC + TT), KDM1A (AA) + MTHFR (CC), and KDM1A (AA) + DNMT3B (allele C); KDM1A (AA) + MTHFR (CC) were associated with higher RDW, erythroblasts, MCV, and mean corpuscular hemoglobin (MCH); higher MCV and MCH were also associated with KDM1A (AA) + MTHFR (CC) + DNMT3B (allele C). We concluded that the polymorphisms studied may influence susceptibility to ROP by modulating erythropoiesis and gene expression of the fetal/adult hemoglobin ratio. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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Review

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16 pages, 1991 KiB

Open AccessReview

Epigenetic Switches in Retinal Homeostasis and Target for Drug Development

by Kalpana Rajanala and Arun Upadhyay

Int. J. Mol. Sci. 2024, 25(5), 2840; https://doi.org/10.3390/ijms25052840 - 29 Feb 2024

Cited by 1 | Viewed by 1952

Abstract

Retinal homeostasis, a tightly regulated process maintaining the functional integrity of the retina, is vital for visual function. Emerging research has unveiled the critical role of epigenetic regulation in controlling gene expression patterns during retinal development, maintenance, and response to mutational loads and injuries. Epigenetic switches, including DNA methylation, histone modifications, and non-coding RNAs, play pivotal roles in orchestrating retinal gene expression and cellular responses through various intracellular, extracellular, and environmental modulators. This review compiles the current knowledge on epigenetic switches in retinal homeostasis, providing a deeper understanding of their impact on retinal structural integrity and function and using them as potential targets for therapeutic interventions. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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15 pages, 10626 KiB

Open AccessReview

A New Generation of Gene Therapies as the Future of Wet AMD Treatment

by Janusz Blasiak, Elzbieta Pawlowska, Justyna Ciupińska, Marcin Derwich, Joanna Szczepanska and Kai Kaarniranta

Int. J. Mol. Sci. 2024, 25(4), 2386; https://doi.org/10.3390/ijms25042386 - 17 Feb 2024

Cited by 5 | Viewed by 2822

Abstract

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of “one and done” therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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9 pages, 1850 KiB

Open AccessCase Report

Aland Island Eye Disease with Retinoschisis in the Clinical Spectrum of CACNA1F-Associated Retinopathy—A Case Report

by Dorota Wyględowska-Promieńska, Marta Świerczyńska, Dorota Śpiewak, Dorota Pojda-Wilczek, Agnieszka Tronina, Mariola Dorecka and Adrian Smędowski

Int. J. Mol. Sci. 2024, 25(5), 2928; https://doi.org/10.3390/ijms25052928 - 2 Mar 2024

Viewed by 1423

Abstract

Aland island eye disease (AIED), an incomplete form of X-linked congenital stationary night blindness (CSNB2A), and X-linked cone-rod dystrophy type 3 (CORDX3) display many overlapping clinical findings. They result from mutations in the CACNA1F gene encoding the α_1F subunit of the Cav1.4 channel, which plays a key role in neurotransmission from rod and cone photoreceptors to bipolar cells. Case report: A 57-year-old Caucasian man who had suffered since his early childhood from nystagmus, nyctalopia, low visual acuity and high myopia in both eyes (OU) presented to expand the diagnostic process, because similar symptoms had occurred in his 2-month-old grandson. Additionally, the patient was diagnosed with protanomalous color vision deficiency, diffuse thinning, and moderate hypopigmentation of the retina. Optical coherence tomography of the macula revealed retinoschisis in the right eye and foveal hypoplasia in the left eye. Dark-adapted (DA) 3.0 flash full-field electroretinography (ffERG) amplitudes of a-waves were attenuated, and the amplitudes of b-waves were abolished, which resulted in a negative pattern of the ERG. Moreover, the light-adapted 3.0 and 3.0 flicker ffERG as well as the DA 0.01 ffERG were consistent with severely reduced responses OU. Genetic testing revealed a hemizygous form of a stop-gained mutation (c.4051C>T) in exon 35 of the CACNA1F gene. This pathogenic variant has so far been described in combination with a phenotype corresponding to CSNB2A and CORDX3. This report contributes to expanding the knowledge of the clinical spectrum of CACNA1F-related disease. Wide variability and the overlapping clinical manifestations observed within AIED and its allelic disorders may not be explained solely by the consequences of different mutations on proteins. The lack of distinct genotype–phenotype correlations indicates the presence of additional, not yet identified, disease-modifying factors. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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13 pages, 1660 KiB

Open AccessCase Report

Genotypic–Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families

by Olivia A. Zin, Luiza M. Neves, Daniela P. Cunha, Fabiana L. Motta, Bruna N. S. Agonigi, Dafne D. G. Horovitz, Daltro C. Almeida, Jr., Jocieli Malacarne, Ana Paula S. Rodrigues, Adriana B. Carvalho, Cinthia A. Rivello, Rita Espariz, Andrea A. Zin, Juliana M. F. Sallum and Zilton F. M. Vasconcelos

Int. J. Mol. Sci. 2023, 24(15), 11876; https://doi.org/10.3390/ijms241511876 - 25 Jul 2023

Cited by 1 | Viewed by 1587

Abstract

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis—a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Eye Diseases: 2nd Edition)

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