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Human γD-crystallin, a monomeric protein abundant in the eye lens nucleus, must remain stably folded for an individual's entire lifetime to avoid aggregation and protein deposition-associated cataract formation. γD-crystallin contains two homologous domains, an N-terminal domain (NTD) and a C-terminal domain (CTD), which interact via a hydrophobic interface. Several familial mutations in the gamma crystallin gene are linked to congenital early-onset cataract, most of which affect the NTD. Some of these, including V75D and W42R, are known to populate intermediates under partially denaturing conditions possessing a natively folded CTD and a completely unfolded NTD. We employed hydrogen-deuterium exchange mass spectrometry to probe the structural and energetic features of variants of γD-crystallin under both native and partially denaturing conditions. For V75D and W42R, we identify a species under native conditions that retains partial structure in the NTD and is structurally and energetically distinct from the intermediate populated under partially denaturing conditions. Residues at the NTD-CTD interface play crucial roles in stabilizing this intermediate, and disruption of interface contacts either by amino acid substitution or partial denaturation permits direct observation of two intermediates simultaneously. These data suggest that the intermediate identified under native conditions is accessed from the native state and not on the folding pathway. The intermediate we have identified here exposes hydrophobic amino acids that are buried in both the folded full-length protein and in the protein's stable isolated domains. Such nonnative exposure of a hydrophobic patch may play an important role in cataract formation., Competing Interests: Competing interests statement:The authors declare no competing interest.

Highly myopic cataract (HMC) is a leading cause of blindness among the working-age individuals, with its pathogenesis poorly understood. This study aimed to elucidate the role of ferroptosis in HMC development as well as the underlying mechanisms. In HMC lens epithelia, levels of Fe 2+ and lipid peroxidation were found elevated, with increased vulnerability towards ferroptosis as revealed by transmission electron microscopy. Mechanistically, RNA sequencing of HMC lens epithelial samples identified up-regulated expression of discoidin domain receptor tyrosine kinase 2 (DDR2) as a key factor, which could enhance ferroptosis sensitivity via the Src-Hippo pathway. Specifically, DDR2 interacted with Src kinase, leading to the nuclear translocation of homologous transcriptional regulators (yes-associated protein 1 [YAP1] and WW domain containing transcription regulator 1 [WWTR1]) of the Hippo pathway, which altered the expression level of ferroptosis-related genes. Notably, highly myopic eyes of mice exhibited higher sensitivity to RSL3, a ferroptosis inducer, manifested as more severe nuclear lens opacities both in vitro and in vivo compared with the contralateral control eyes, which could be alleviated by inhibitors of either ferroptosis or DDR2. Altogether, these findings highlighted the role of DDR2 in mediating ferroptosis in HMC formation, providing a novel insight for therapeutic interventions., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: This study received ethical approval from the Ethics Committee of the Eye, Ear, Nose, and Throat (Eye & ENT) Hospital of Fudan University (approval number: 81470613, date of approval: 2020-06-01). All procedures adhered to the tenets of the Declaration of Helsinki. Prior to surgery, written informed consents were obtained from all participants for the utilization of their clinical data and biological samples (lens epithelium). Animal experiments were approved by the Animal Research Committee of the Eye & ENT Hospital of Fudan University and were aligned with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, USA)., (© 2025. The Author(s).)

Phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE) was recently identified as a causative gene for cataract. Pikfyve phosphatidylinositol phosphate kinase domain-deficient (pikfyve Δ8 ) zebrafish lens and PIKFYVE-inhibited human lens epithelial cells developed vacuoles, colocalized with late endosome marker RAB7. In this study, the pikfyve Δ8 zebrafish with vacuole-like cataract underwent transcriptomic and proteomic analyses to explore the underlying mechanisms of vacuole formation. PIKFYVE-knockout and PIKFYVE-inhibited human lens epithelial cells with vacuoles further verified these omics results and rescued with Bafilomycin A1(Baf-A1) and U18666A. We discovered no significant differences in lysosomal fusion, but upregulation in acid hydrolase. The composition of late endosomal membrane was changed, and vacuolar ATPase and endosomal sorting complexes required for transport (ESCRT) at late endosome were upregulated. These changes are related with the late endosome homeostasis. Strikingly, vacuoles in human lens epithelial cells could be partially rescued by Baf-A1 and almost completely rescued by U18666A. Collectively, these findings suggest that vacuoles in pikfyve Δ8 zebrafish lens and PIKFYVE-inhibited cells were colocalized with swollen late endosomes, and generated by perturbing late endosome homeostasis due to enhanced ESCRT mechanisms and decreased stability in late endosomal membrane. This study expands our understanding of the mechanisms underlying cataract development and reveals potentially effective therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Many studies have identified disease-causing variants of PIKFYVE in ocular tissues; however, a comprehensive review of these variants and their ocular phenotypes is lacking. The phosphoinositide kinase PIKFYVE plays crucial roles in the endolysosomal pathway in autophagy and phagocytosis, both essential for cellular homeostasis. In this review, we evaluate the reported disease-causing PIKFYVE variants and their associated phenotypes in humans to identify potential genotype-phenotype correlations. Variants in PIKFYVE have been associated with corneal fleck dystrophy, congenital cataracts and possibly keratoconus. There are unvalidated associations of variants in PIKFYVE with autism spectrum disorder and congenital heart disease. We show that variants causing corneal fleck dystrophy exist in the chaperonin-like domain of PIKFYVE as well as the region between the chaperonin-like and the kinase domains. Similarly, congenital cataract variants appear to be specific to the kinase domain of the protein. This review consolidates existing knowledge on PIKFYVE variants in ocular disease and bridges fundamental science and clinical manifestations, potentially informing future diagnostic and treatment strategies for PIKFYVE-associated ocular disorders., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: PHARC syndrome, a rare autosomal recessive neurodegenerative disorder caused by mutations in the ABHD12 gene, is characterized by demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP), and early-onset cataracts. If patients are first diagnosed in the ophthalmology department, they are easily misdiagnosed as having RP or Usher syndrome. This study aimed to identify the genetic etiology and determine the clinical diagnosis of a Chinese family with suspected PHARC syndrome., Method: Comprehensive ophthalmic examinations and systemic evaluations were conducted to confirm the phenotype. The genotype was identified through Whole Exome Sequencing (WES), and the current literature was reviewed understand better manifestations of PHARC syndrome related to pathogenic variants., Results: The principal symptoms of the proband comprised profound sensorineural hearing loss since childhood, severe visual impairment, congenital cataracts, cone-rod dystrophy, and ataxia. WES revealed that the proband carried a compound heterozygous variant in the ABHD12 gene: M1, a known nonsense variation c.477G > A (p.Trp159Ter); and M2, a novel copy number variant with a deletion of approximately 18.10 Kbp in chromosome 20p11.21 (seq[GRCh38]del(20) (p11.21)chr20:g. 25302218_25320318del), covering exons 4-12 of the ABHD12 gene. The literature review indicated that there were 65 patients with PHARC from 30 different families. All clinical information of the described patients with PHARC syndrome and all known mutations associated with the disease to date were compiled., Conclusion: This study expands the spectrum of pathogenic variants and phenotype for PHARC syndrome and suggests genetic testing is necessary for a definitive diagnosis of PHARC syndrome., (© 2025 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 ( EPG5 ) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions. Abbreviations : AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5 : ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC : TSC complex; VS: Vici syndrome.

High myopia and age‑related cataracts are prevalent ocular disorders that compromise visual acuity. The molecular mechanisms underlying these conditions remain largely unclear. Here, microRNA (miRNA or miR) sequencing was performed on aqueous humor samples obtained from individuals with age‑related cataracts and high myopia (AH, n=9), young patients with high myopia (YH, n=9) and a control group of elderly patients with age‑related cataracts, matched in terms of sex and age (AN, n=9). miRNA sequencing and differential expression were performed. Intersecting miRNAs were identified, as well as metabolism‑related genes from MsigDB were intersected with miRNA target genes. Functional enrichment was performed and disease targets predicted using DisGeNET. A protein‑protein interaction network was built with STRING, and hub genes were identified via Cytoscape. GeneMANIA analyzed hub genes, while drug predictions were made using Comparative Toxicogenomics Database. Long non‑coding RNAs and transcription factors were predicted via mirNet and ChEA3. Results were validated by RT‑qPCR. A total of 18 miRNAs were significantly differential expressed between AH and AN group, of which eight were up‑ and 10 were downregulated. A total of 23 miRNAs were significantly differential expressed between the YH and AN group, of which six were up‑ and 17 were downregulated. hsa‑miR‑490‑3p, hsa‑miR‑4423‑3p and hsa‑miR‑4485‑3p may serve as characteristic miRNAs. A total of 289 target genes were predicted. Functional enrichment analysis yielded 169 terms, with 'herpes simplex virus 1 infection' the most significantly enriched. There were 19 metabolism‑associated target genes linked with these miRNAs, suggesting a potential role of metabolic processes in pathogenesis of these conditions. The biosynthetic process of carbohydrate derivatives may serve a key role during the development of high myopia. There were 10 hub genes and Propionyl‑CoA Carboxylase Subunit β could potentially serve as a biomarker. Drugs that could modulate their function were predicted; cyclosporine, tretinoin and acetaminophen may exert a broad influence on these hub genes. Hub gene networks based on the miRNAs were constructed to predict 44 associated long non‑coding RNAs and 98 transcription factors. The present findings offer novel insights into the molecular mechanisms of age‑related cataracts and high myopia and propose potential therapeutic targets.

Prcis: Alterations in the PTEN-induced kinase 1 (PINK)-mediated mitophagy pathway play an important role in pseudoexfoliation syndrome (PEX) disease., Purpose: PEX is a condition in which aberrant fibrillary protein builds up in various components of the eye and other extraocular tissues. In this study, we aim to investigate the functionality of intracellular auto-degradative machinery-especially mitophagy-and related genes and proteins in PEX., Materials and Methods: Anterior lens capsules were obtained from cataract patients with and without PEX to constitute the PEX group and age-matched controls during microincision cataract surgery. PINK1-mediated mitophagy markers were evaluated on the transcriptional and translational level via reverse transcriptionquantitative polymerase chain reaction and immunohistochemistry analysis, respectively., Results: The lens epithelial cells of PEX patients were characterized by significantly higher PINK1 gene expression compared with that of the controls ( P <0.05). In terms of intensity of staining of expressed proteins, PINK1 ( P <0.05), Parkin ( P <0.01), and microtubule-associated protein 1A/1B-light chain 3 B ( P <0.01) were all statistically higher in PEX, compared with the controls., Conclusion: Altered auto-degradative response-specifically mitophagy-is a component of increased oxidative stress in PEX patients. The role of this mechanism in emerging complications warrants further research., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pediatric neurological disorders include neurodegenerative diseases causing cognitive impairment and vision loss. They are one of the important causes of morbidity and mortality in children with diverse etiologies. Diagnosis is difficult despite genetic work, and a final diagnosis can be achieved in only 60% of cases., Case Presentation: We explore three Indian cases of pediatric neurological diseases (with age presented at the clinic), viz. arthrogryposis (8 years), autism (18 months), and congenital bilateral cataract (3 years), by analyzing clinical exomes. In this work, we attempt to understand rare neurological disorders in an Indian pediatric cohort using exome studies., Conclusion: We used our benchmarked CONVEX pipeline for screening consensus variants, wherein EIF2B2 was found to be inherently pathogenic. We map the association of variants and genes and disease correlation to neuroleptic malignant syndrome, which matches the phenotype to the cases., Competing Interests: Declarations. Ethics approval and consent to participate: The individuals were recruited from an outpatient clinic of Lifecare Hospitals, Amravati, Maharashtra, India. Before taking the patients’ DNA samples and subjecting them to clinical exome sequencing, informed consent was duly obtained from their parents. Consent for publication: Written informed consent was obtained from the patients’ legal guardians for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: The authors declare no conflicts of interest., (© 2025. The Author(s).)

DNA methylation is known to be associated with cataracts. In this study, we used a mouse model and performed DNA methylation and transcriptome sequencing analyses to find epigenetic indicators for age-related cataracts (ARC). Anterior lens capsule membrane tissues from young and aged mice were analyzed by MethylRAD-seq to detect the genome-wide methylation of extracted DNA. The young and aged mice had 76,524 and 15,608 differentially methylated CCGG and CCWGG sites, respectively. The Pearson correlation analysis detected 109 and 33 differentially expressed genes (DEGs) with negative methylation at CCGG and CCWGG sites, respectively, in their promoter regions. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses showed that DEGs with abnormal methylation at CCGG sites were primarily associated with protein kinase C signaling (Akap12, Capzb), protein threonine kinase activity (Dmpk, Mapkapk3), and calcium signaling pathway (Slc25a4, Cacna1f), whereas DEGs with abnormal methylation at CCWGG sites were associated with ribosomal protein S6 kinase activity (Rps6ka3). These genes were validated by pyrosequencing methylation analysis. The results showed that the ARC group (aged mice) had lower Dmpk and Slc25a4 methylation levels and a higher Rps6ka3 methylation than the control group (young mice), which is consistent with the results of the joint analysis of differentially methylated and differentially expressed genes. In conclusion, we confirmed the genome-wide DNA methylation pattern and gene expression profile of ARC based on the mouse cataract model with aged mice. The identified methylation molecular markers have great potential for application in the future diagnosis and treatment of ARC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Nance-Horan syndrome (NHS) is a rare, frequently underdiagnosed, X-linked disease caused by mutations in the NHS gene. In males, it causes bilateral dense pediatric cataracts, dental anomalies, and facial dysmorphisms. Females traditionally have a more subtle phenotype with discrete lens opacities as an isolated feature. The objective of this case report is to describe a novel variant in NHS, as well as to discuss genotype-phenotype correlations., Methods: Whole-exome sequencing was performed in 3 affected individuals (2 males and 1 female) with pediatric cataracts from the same family, as well as in 2 unaffected members from the same family. Ophthalmological and clinical genetic evaluations were conducted., Results: The likely pathogenic variant c.3333del (p.Phe1111Leufs*9) was found in all affected individuals, as well as in one unaffected female family member. Our family was initially diagnosed with isolated hereditary cataracts, but only after the sequencing results was the phenotype revealed, with the systemic features being identified., Conclusions: This reinforces the importance of genetic testing of bilateral familial pediatric cataracts, especially since systemic features such as dental anomalies and intellectual disability may take years before they develop. Not only did genetic testing help to identify extraocular features, but it also made possible accurate family counseling essential in all pediatric cataract cases.

Objective: We compared the protein structure and pathogenicity of clinically relevant variants of the COG4 gene with AlphaFold2 (AF2), Alpha Missense (AM), and ThermoMPNN for the first time., Methods and Analysis: The sequences of clinically relevant Cog4 missense variants (one novel identified p.Y714F and three pre-existing p.G512R, p.R729W and p.L769R from Uniprot Q9H9E3) were imported into AF2 for protein structural prediction, and the pathogenicity was estimated using AM and ThermoMPNN. Different pathogenicity metrics were aggregated with principal component analysis (PCA) and further analysed at three levels (amino acid position, substitution and post-translation) based on all possible Cog4 missense variants (n=14 915)., Results: Localised protein structural impact including change of conformation and amino acid polarity, breakage of hydrogen bond and salt-bridge, and formation of alpha-helix were identified among clinically relevant Cog4 variants. The global structural comparison with multidimensional scaling demonstrated variants with similar protein structures (AF2) tended to exhibit similar clinical and biological phenotypes. The Cog4 p.Y714F variant exhibited greater protein structural similarity to mutated Cog4 found in Saul‒Wilson syndrome (p.G512R) and shared similar clinical phenotype (congenital cataract and psychomotor retardation). PCA of included pathogenic metrics demonstrated p.Y714F occurred at a critical position in Cog4 amino acid sequence with disrupted post-translational phosphorylation., Conclusion: Deep learning algorithms, including AF2, AM and ThermoMPNN, can be useful for evaluating variant of uncertain significance (VUS) by structural and pathogenicity prediction. Despite classified as VUS (American College of Medical Genetics and Genomics criteria: PM1, PP4), the pathogenicity in this Cog4 variant cannot be ruled out and warrants further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objectives: Exploration of medical histories and medications associated with Alzheimer disease neuropathologic change (ADNC) absence and potential resistance may identify protective factors against ADNC. This was a retrospective examination of data from participants age ≥90 years who enrolled in The 90+ Study , a longitudinal study based in California. Participants underwent neuropathologic analysis for the presence of neuritic amyloid plaques (NPs) (any), beta amyloid plaques (Thal phase > 0), and neurofibrillary tangles (>2). Odds ratios (ORs) for the presence of pathologic changes to APOE genotype, self-reported medical histories, and medication use were estimated by logistic regression and (a)djusted for sex, age at death (continuous), and education., Results: We examined 267 participants; 75% were female, with a mean age at death of 98 (± 3.5) years. Variables associated with ADNC absence/presence were for NPs: heart disease (adjusted OR [aOR] = 0.46), APOE -ε4 (aOR = 3.48), angiotensin-converting enzyme (ACE) inhibitors (aOR = 0.46), cataracts (aOR = 0.26), and beta-blockers (aOR = 0.51); for Aβ: heart disease (aOR = 0.33) and APOE -ε4 (aOR = 8.10); and for neurofibrillary tangles: ACE inhibitors (aOR = 0.46), glaucoma (aOR = 0.29), HTN (aOR = 0.44), seizures (aOR = 0.16), APOE -ε2 presence (aOR = 0.39), and vasodilators (aOR = 0.36). These observations would not survive multiple comparison corrections., Discussion: Cataract formation, APOE status, ACE inhibitors, and beta-blockers may be associated with ADNC absence because of differential lipid trafficking. Survival bias and type 1 errors warrant consideration.

Several protocols have been established for the generation of lens organoids from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and other cells with regenerative potential in humans or various animal models. It is important to examine how well the regenerated lens organoids reflect lens biology, in terms of its development, homeostasis, and aging. Toward this goal, the iSyTE database (integrated Systems Tool for Eye gene discovery; https://research.bioinformatics.udel.edu/iSyTE/ ), a bioinformatics resource tool that contains meta-analyzed gene expression data in wild-type lens across different embryonic, postnatal, and adult stages, can serve as a resource for comparative analysis. This article outlines the approaches toward effective use of iSyTE to gain insights into normal gene expression in the mouse lens, enriched expression in the lens, and differential gene expression in select mouse gene-perturbation cataract/lens defects models, which in turn can be used to evaluate expression of key lens-relevant genes in lens organoids by transcriptomics (e.g., RNA-sequencing (RNA-seq), microarrays, etc.) or other downstream methods (e.g., RT-qPCR, etc.)., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To analyze the role of Slit2 in lens epithelial cell oxidative damage and its underlying mechanism., Methods: Human lens epithelial cells (SRA01/04 cells) and rat transparent lens were cultured with H 2 O 2 to establish cell oxidative stress models and rat cataract models. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot assays were employed to detect Slit2 levels within age-related cataracts(ARC) lens anterior capsule samples, rat cataract models, and cell oxidative stress models. In this study, qRT-PCR and Western blot assays were performed to derermine E-cadherin, N-cadherin, occludens1(ZO-1), α-SMA(α‑smooth muscle actin), Bcl-2, Bax, p-AKT, and AKT levels. In addition, Flow cytometry were performed to examine reactive oxygen species (ROS) and cell apoptosis. Cell viability, invasion, and migration were detected by CCK8, Transwell, and Wound healing., Results: Increased expression of Slit2 was found in ARC lens anterior capsule samples, H 2 O 2 -induced rat cataract models, and Human lens epithelial cells (HLECs) oxidative stress models. H 2 O 2 significantly increased cell apoptosis and ROS generation, also accelerating cell migration, invasion, and epithelial-mesenchymal transition (EMT). In addition, H 2 O 2 treatment repressed AKT phosphorylation and cell viability. Knock-down of Slit2 promoted cell viability and AKT phosphorylation levels, as well as repressed cell invasion, migration, apoptosis, ROS production and EMT., Conclusion: Slit2 promoted lens epithelial cells oxidative stress damage via the AKT signalling pathways, providing a novel insight in ARC treatment.

Background: Sengers syndrome is an autosomal recessive mitochondrial DNA depletion syndrome characterized by hypertrophic cardiomyopathy, congenital cataracts, skeletal myopathy, exercise intolerance, and lactic acidosis. Dysfunction of acylglycerol kinase (AGK) is responsible for the disease, and several AGK gene variants have been reported., Methods: We employed a comprehensive genomic analysis approach, including whole-genome sequencing and RNA sequencing, combined with various bioinformatics tools., Results: Our analysis successfully diagnosed Sengers syndrome in a patient by detecting a known pathogenic variant and a previously unreported large deletion involving the AGK gene in a segmental duplication., Conclusion: This study demonstrates the effectiveness of combining multiple genomic analysis approaches for the accurate diagnosis of Sengers syndrome, particularly in cases involving complex genetic variations such as large deletions in segmental duplications., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Heterozygous mutations in the OPA3 gene are associated with autosomal dominant optic atrophy-3 (OPA3), whereas biallelic mutations cause autosomal recessive 3-methylglutaconic aciduria type III. To date, all cases with pathogenic variants in the gene OPA3 have presented with optic atrophy. We report a large family with congenital cataracts, hearing loss and neuropathy, with a likely pathogenic novel missense variant in OPA3, c.30G>C; p.(Lys10Asn) that segregates with disease in the family pedigree. The family's clinical presentation has significant phenotypic overlap with previously reported cases of OPA3, except for a notable lack of optic atrophy. The analysis of all known disease-associated variants in OPA3 revealed an enrichment in missense variants in patients with OPA3 phenotype compared with loss-of-function variants, which are more likely to be observed in individuals with 3-methylglutaconic aciduria type III, supporting different mechanisms of disease. This case broadens the clinical and genetic spectrum associated with OPA3 mutations and highlights that optic atrophy is not an obligate feature of OPA3-related disorders., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Cataracts remain the leading cause of visual impairment worldwide, yet the underlying molecular mechanisms, particularly in age-related cataracts (ARCs), are not fully understood. The Notch signaling pathway, known for its critical role in various degenerative diseases, may also contribute to ARC pathogenesis, although its specific involvement is unclear. This study investigates the role of Notch signaling in regulating ferroptosis in lens epithelial cells (LECs) and its impact on ARC progression. RNA sequencing of anterior lens capsule samples from ARC patients revealed a significant downregulation of Notch signaling, coupled with an upregulation of ferroptosis-related genes. Notch1 expression decreased, while ferroptosis markers increased in an age-dependent manner. In vitro, upregulation of Notch signaling alleviated ferroptosis by decreasing ferritin heavy chain 1 (FTH1) and p53 levels while enhancing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). Conversely, inhibition of Notch signaling exacerbated ferroptosis, as evidenced by reduced Nrf2, GPX4, and SLC7A11 expression. These findings suggest that downregulation of Notch signaling promotes ferroptosis in LECs by impairing the Nrf2/GPX4 antioxidant pathway, thereby contributing to ARC development. This study offers new insights into ARC pathogenesis and highlights the Notch signaling pathway as a potential therapeutic target for preventing or mitigating ARC progression.

Fine-Lubinsky syndrome is a rare clinically defined syndrome sometimes referred to as brachycephaly, deafness, cataract, microstomia, and impaired intellectual development syndrome. Here we provide a clinical and molecular update for a sibling pair diagnosed with Fine-Lubinsky syndrome. An extensive genetic work-up, including chromosomal microarray analysis and quad exome sequencing, was nondiagnostic. However, a research reanalysis of their exome sequencing data revealed that both were homozygous for an intronic c.749+39G>A [NM&#95;001383.6] variant in DPH1. RNAseq analysis performed on RNA from fibroblasts revealed significantly reduced expression of DPH1 transcripts suggestive of abnormal splicing followed by nonsense mediated mRNA decay. Since the phenotypes of this sibling pair were consistent with those associated with the inheritance of biallelic pathogenic variants in DPH1, they were given a diagnosis of developmental delay with short stature, dysmorphic facial features, and sparse hair 1 (DEDSSH1). This leads us to recommend that all individuals with a clinical diagnosis of Fine-Lubinsky syndrome be screened for variants in DPH1. The clinical histories of this sibling pair emphasize that hearing loss associated with DEDSSH1 may remit over time and that individuals with DEDSSH1 should be monitored for the development of cardiomyopathy. This case also demonstrates the clinical utility of RNAseq as a means of functionally validating the effects of intronic variants that may affect splicing., (© 2024 Wiley Periodicals LLC.)

Epithelial mesenchymal transition (EMT) of lens epithelial cells (LECs) is one of the most important pathogenic mechanisms in lens fibrotic disorders, and the regulatory mechanisms of EMT have not been fully understood. Here, we demonstrate that the cAMP-response element binding protein (CREB) can regulate lens EMT in a phosphorylation-dependent and phosphorylation-independent manners with dual mechanisms. First, CREB-S133 phosphorylation is implicated in TGFβ-induced EMT of mouse LECs and also in injury-induced mouse anterior subcapsular cataract model. The interaction between CREB and p300 is necessary for CREB regulation of TGFβ-induced EMT, since inhibition of CREB-p300 interaction and p300 knockdown led to attenuated expression of mesenchymal genes. Second, S133A-CREB, a mutant mimicking constant dephosphorylation at S133, exhibits notable occupancy in the enhancers of mesenchymal genes and confers robust transcription activity on EMT genes. Introduction of R314A mutation in S133A-CREB, which abolishes the interaction between S133A-CREB and its co-activator, cAMP-regulated transcriptional co-activators led to substantial suppression of mesenchymal gene expression in mouse LECs. Taken together, our results showed that CREB regulates lens EMT in dual mechanisms and that the S133A-CREB acts as a novel transcription factor. Mechanistically, CREB interacts with p300 in a S133 phosphorylation-dependent manner to positively regulate lens EMT genes. In contrast, S133A-CREB interacts with cAMP-regulated transcriptional co-activators to confer a robust activation of lens EMT genes., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Congenital cataract is one of the most common causes of childhood blindness, typically resulting from genetic mutations. Over a hundred gene mutations associated with congenital cataract have been identified, with approximately half occurring in the Crystallin genes. In this study, we identified a novel γA-crystallin pathogenic mutation (c. 29G > C, p. Arg10Pro (R10P)), from a four-generation Chinese family with congenital cataract, and investigated its potential molecular mechanisms underlying congenital cataracts. We compared the protein structure and stability of purified the wild type (WT) and R10P under physiological conditions and environmental stresses (UV irradiation, pH imbalance, heat shock, and chemical denaturation) using spectroscopic experiments, SEC analysis, and the UNcle protein analysis system. The results demonstrate that γA-R10P has no significant impact on the structure of γA-crystallin on normal condition. However, it is more sensitive to UV irradiation at high concentrations and prone to aggregation at high temperatures. Therefore, our study reveals the crucial role of the conserved site mutation R10P in maintaining protein structure and stability, providing new insights into the mechanisms of cataract formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Oculocutaneous albinism is a rare autosomal recessive disorder caused by congenital melanin deficiency, resulting in hypopigmentation of the eyes, hair, and skin. This study included a Chinese family with an oculocutaneous albinism pedigree, in which the proband presented with oculocutaneous albinismcombined with secondary angle closure, which has been rarely reported in previous literature. This article primarily focused on the clinical and genetic examination results of this patient and provided recommendations for ophthalmologist to treat patients with oculocutaneous albinism in clinical practice., Case Presentation: The proband in this case study is a 53-year-old Chinese male who showed depigmentation of the skin, hair, iris, and fundus, accompanied by photophobia, decreased vision, high intraocular pressure, nystagmus, macular fovea hypoplasia, and cataracts. Owing to the opacity and expansion of the lens, the volume ratio of lens to eyeball was increased, causing crowded anterior segment, bombed iris, and narrowed chamber angle and, ultimately, leading to secondary angle closure. Whole-exome sequencing suggested that the two patients in the pedigree harbored the compound heterozygous variants c.230G > A (p. Arg77Gln) and c.832G > A (p. Arg278*) in the TYR gene, while the healthy member carried the TYR c.230G > A (p. Arg77Gln) variant, which was consistent with the autosomal recessive inheritance pattern and further confirmed the diagnosis was oculocutaneous albinism. On the basis of the above results, the patient was diagnosed with oculocutaneous albinism, senile mature cataract, and secondary angle closure in the right eye and ocular hypertension in the left eye, as well as bilateral nystagmus. Then, the patient was prescribed carteolol eye drops to control intraocular pressure and underwent phacoemulsification and intraocular lens implantation surgery for the right eye. Postoperatively, the patient's intraocular pressure was effectively controlled, and visual acuity improved., Conclusion: We report a patient with oculocutaneous albinism combined with cataract and secondary angle closure, and whole-exome sequencing suggested that he harbored TYR gene variants. Comprehensive examinations were important for identifying the causes of angle closure and making proper treatment strategies. Genetic testing enabled precise diagnosis and genetic counseling., Competing Interests: Declarations. Ethics approval and consent to participate: Ethical approval was not applicable. This study had no novel intervention and all treatments were standard treatments of an oculocutaneous albinism combined with angle closure. All patients gave written, informed consent to publish these cases and any accompanying images. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Purpose: To explore the expressions and functions of lncRNAs in the pathogenesis of pathologic myopia complicated with cataract (PMC)., Methods: The anterior capsular tissues were collected from patients with age-related cataract (ARC) and PMC. One group of the samples was used to detected by whole-transcriptome sequencing (LC-Bio, Hangzhou, China) and investigated by GO and KEGG enrichment analysis. We selected the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), predicted the miRNAs with gene binding sites to it and the downstream mRNAs with gene binding sites to miRNAs through the Starbase and Targetscan websites. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the other group to further preliminarily validate the prediction., Results: A total of 471 lncRNAs were significantly differential expressed in PMC group compared with ARC group, in which 231 lncRNAs were up-regulated, including MALAT1, and 240 lncRNAs were down-regulated. GO and KEGG enrichment analysis showed that lncRNAs targeted differential mRNAs were involved in various biological functions, cell components, molecular functions and signaling pathways. Taking MALAT1 as an example, we predicted that it had binding sites with 113 miRNAs such as hsa-miR-20a-5p, has-miR-20b-5p, hsa-miR-26a-5p, has-miR-106-5p and hsa-miR-204-5p, which were lower in PMC group than these in ARC group. Inversely, the downstream mRNAs of the above miRNAs, such as MMP9, TNF-α, TGF-β2, NF-KB, IL6 and Smad4 were higher., Conclusion: The differentially expressed lncRNAs, especially MALAT1, may act as ceRNA via sponging miRNAs and to regulate the targeting downstream mRNAs in development of PMC and participate in numerous biological processes through interconnected signaling pathways., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethics approval: This study was approved by the Ethics Review Committee of the First Affiliated Hospital of Bengbu Medical University. Consent to participate: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The transparent ocular lens is essential for vision because it focuses light onto the retina. Despite recognition of the importance of its unique cellular architecture and mechanical properties, the molecular mechanisms governing these attributes remain elusive. This study aims to elucidate the role of ankyrin-B (AnkB, encoded by ANK2), a membrane scaffolding protein, in lens cytoarchitecture, growth and function using a conditional knockout (cKO) mouse model. The AnkB cKO mouse has no defects in lens morphogenesis but exhibited changes that supported a global role for AnkB in maintenance of lens clarity, size, cytoarchitecture, membrane organization and stiffness. Notably, absence of AnkB led to nuclear cataract formation, which was evident from postnatal day 16. AnkB cKO lens fibers exhibit progressive disruption in membrane organization of the spectrin-actin cytoskeleton, cell adhesion proteins and channel proteins; loss and degradation of several membrane proteins [such as NrCAM. N-cadherin (CDH2) and aquaporin-0 (also known as MIP)]; along with a disorganized plasma membrane and impaired membrane interdigitations. Furthermore, absence of AnkB led to decreased lens stiffness. Collectively, these results illustrate the essential role for AnkB in lens architecture, growth and function through its involvement in membrane skeletal and protein organization and stability., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: WFS1 -spectrum disorders are caused by a mutation in the WFS1 gene. The term includes a wide range of rare disorders, from the most severe Wolfram syndrome with autosomal recessive inheritance to milder clinical manifestations with a single causative variant in the WFS1 gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. Methods: The aim of this study was to evaluate genotype-phenotype correlations in Polish patients with WFS1 -spectrum disorders. The study group constituted 22 patients (10 F; 12 M), including 10 patients (3 F; 7 M) referred to the Outpatient Clinic for Rare Diseases in Children and Adolescents and Diabetogenetics between 2019 and 2024 with clinical symptoms suggestive of WFS1 -spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS ( Targeted Next Generation Sequencing ; Illumina) and analyzed for variants in the WFS1 gene. Results : Thirteen different variants in the WFS1 gene were found in 22 individuals (10 patients and family members), including the identification of two new variants (c.1535T>C and c.2485C>G). All patients had hyperglycemia or DM, hearing impairment, OA, or a combination of these symptoms. Four patients in the study group were diagnosed with Wolfram syndrome and all were compound heterozygotes for variants in the WFS1 gene. Conclusions: The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of WFS1 -spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis.

Objective: To determine the causal relationship between cataracts and type 2 diabetes mellitus (T2D) by the Mendelian randomization (MR) analysis using the genome-wide association study (GWAS) data. Methods: Data on T2D and cataracts in the European population were obtained from the OpenGWAS database. The single nucleotide polymorphisms (SNPs) that met the genome-wide significance criteria ( P <5×10⁻⁸) of T2D (48 286 cases, 250 671 controls) and cataracts (5 045 cases, 356 096 controls) were selected. The main method was random effects inverse variance weighting (IVW), and four other two-sample MR methods were also used, including MR Egger, Simple median, Weighted median, and Weighted mode, to assess the causal relationship using odds ratios ( OR ). Sensitivity analyses were conducted using the leave-one-out approach to evaluate the robustness of the results. Results: The MR Egger analysis showed a significant risk association between T2D and cataracts ( OR= 1.003, 95% CI =1.001-1.006; P =0.013). Using the methods of Weighted median ( OR =1.002, 95% CI =1.000-1.004; P =0.029) and Weighted mode ( OR =1.002, 95% CI =1.000-1.005; P =0.046), similar results were obtained. However, the IVW test failed to confirm the causality ( P =0.149). The sensitivity analyses using the MR Egger and IVW tests did not show significant heterogeneity between T2D and cataracts (all P >0.05). With the leave-one-out analysis, the SNPs with significant effects were not identified, indicating the robustness of the MR results in this study. The MR Egger interception of the SNPs showed significant directional pleiotropy ( P =0.038), suggesting a directional pleiotropy between T2D and cataracts. Conclusions: The results of the MR analysis suggest there is a causal relationship between T2D and cataracts, and T2D increases the risk of cataracts.

Purpose: To identify the role of lipocalin-2 (LCN2) in diabetic cataract (DC) and diabetic retinopathy (DR), diabetes models were established in wild-type (WT) and LCN2 gene knockout (LCN2-/-) mice by streptozotocin (STZ), this study aimed to investigate the metabolic alterations and underlying pathways in the lens and retina., Methods: Untargeted metabolomic analysis was performed on the lenses and retinas of WT and LCN2-/- diabetic mice, and relevant pathways were predicted through bioinformatics analysis., Results: LCN2 was notably elevated in the anterior capsules of DC and the vitreous humor of DR. Metabolic profiling of the lenses and retinas of diabetic mice indicated that the differential metabolites were mostly amino acids, fatty acids, carbohydrates, and their derivatives. In the lenses of STZ-induced WT mice, the differential abundance score (DA-score) revealed an increase in metabolites associated with the citrate (or TCA) cycle and glucagon signaling pathway, whereas a decrease was observed in metabolites related to cholesterol metabolism. After the knockout of LCN2, the DA-score indicated that the majority of metabolites involved in cholesterol metabolism, cysteine and methionine metabolism, and tryptophan metabolism were diminished. In the STZ-induced retina, there was an increase in metabolites associated with the mTOR signaling pathway, and this increase was inhibited by the knockout of LCN2., Conclusions: Numerous metabolites exhibited substantial alterations in the lenses and retinas of diabetic mice. Untargeted metabolomics has provided insights into the function of LCN2 in DC and DR. These changes in metabolites, along with their related pathways, could be the mechanisms by which LCN2 modulated DC and DR.

Background: BCL6 co-repressor ( BCOR ) gene variants are involved in oculofaciocardiodental (OFCD) syndrome, acute myeloid leukaemia, renal tumours, and photoreceptor degenerative diseases. Here, we describe a British family with a pathogenic heterozygous variant in the BCOR gene causing congenital nuclear cataract., Methods: Whole-exome sequencing was conducted on an individual affected by X-linked dominant congenital cataract in a three-generation family to establish the underlying genetic basis. Bioinformatics analysis confirmed the variants with damaging pathogenicity scores., Results: A novel likely pathogenic frameshift variant BCOR NM&#95;001123385.1: c.3621del; p.Lys1207AsnfsTer31, was identified and found to co-segregate with the disease in this family., Conclusions: This is apparently the first report of a variant in BCOR causing X-linked dominant congenital cataract which is potentially isolated or presenting with a remarkably mild systemic phenotype. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of BCOR variants.

Background: Diabetic cataract (DC) is a major cause of blindness, with its pathogenesis involving oxidative stress and ferroptosis, according to recent studies., Methods: We performed a Mendelian Randomization (MR) study using GWAS data to select SNPs and assess the causal link between diabetes and cataracts. DC datasets were analyzed for differential gene expression, WGCNA, and protein-protein interactions to identify key oxidative stress and ferroptosis genes. An SVM-RFE algorithm developed a diagnostic model, and ImmuCellAI analyzed immune infiltration patterns., Results: MR analysis confirmed diabetes as a cataract risk factor and identified core genes related to oxidative stress and ferroptosis in DC. Four key genes (Hspa5/Nfe2l2/Atf3/Stat3) linked to both processes were discovered. Immune infiltration analysis revealed an imbalance associated with these genes., Conclusions: A functional interaction between oxidative stress and ferroptosis genes in DC is suggested, with a 4-gene model, indicating their potential as a 'bridge' in DC pathogenesis.

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations., (© 2024 The Author(s). American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Exosomes are membranous structures measuring between 40-120 nm that are secreted by various cells of the human body into the body fluid system. Exosomes contain proteins, mRNA, miRNA, and signaling molecules, and physiologically they assist in the intercellular transport of proteins and RNA molecules. In this study, we used an immunoaffinity filter paper platform combined with scanning electron microscopy and microfluidic systems to detect the size of exosomes within the aqueous humor. Eight aqueous humor samples showed three distinct sizes of exosomes that were significantly different on scanning electron microscopy( P  < 0.01). We further used nanoparticle tracking analysis to assess the size distribution of exosomes within the aqueous humor. We found significantly different distributions of exosomes between patients with three different ocular diseases and patients with normal cataracts as controls. An obvious peak of exomeres(size around 35 nm)was found in the patients with central retinal vein occlusion and vitreous hemorrhage. Flare-ups of large exosomes(size 90-120 nm)were found in the patients with the inflammatory ocular disease pars planitis. No obvious peaks in exomeres or large exosomes were found in the control group. There was a high association between the distribution of exosomes and the pathogenesis of ocular diseases. After intravitreal anti-vascular endothelial growth factor treatment, the aqueous humor from the patients with neovascular diseases showed a significant reduction in exosomes in nanoparticle tracking analysis. These findings suggest that at least three distinct sizes of exosomes exist in the aqueous humor:(1)exomeres:<35 nm;(2)small exosomes:60-80 nm; and (3)large exosomes:90-120 nm. Different sizes of exosomes may have different implications in normal or diseased eyes.

Purpose: To investigate visual development and long-term complications after cataract surgery in childhood., Methods: This cross-sectional study included patients from a family with Marner's hereditary cataracts who had cataract surgery before 18 years of age. The study was conducted from 1 January 2022 until 31 December 2022. The patients contributed to their medical files and participated in an updated ophthalmologic examination., Results: We included 52 patients (101 eyes, 34 females). The median age at cataract surgery was 7 years (IQR: 5-10) and the age at examination was 40 years (IQR: 21-54). Primary and secondary intraocular lens implantation had been performed in 47.5% (25 patients, 48 eyes) and 16.8% (10 patients, 17 eyes). Visual acuity was ≤0.3 logMAR in 77% (78 eyes), and <0.5 logMAR in 8% (8 eyes). Glaucoma was present in 17% (9 patients, 12 eyes), ocular hypertension in 6% (3 patients, 4 eyes), and 10% (5 patients, 5 eyes) had prior retinal detachment. Mild visual field loss (2 < mean defect (MD) ≤ 6 dB) was found in 62% (63 eyes) and moderate to advanced visual field loss (MD > 6 dB) in 24% (24 eyes). Thirty-five patients (67%) held a driver's licence, and three were not allowed to drive due to low visual function. All patients were employed., Conclusion: After cataract surgery in childhood, many patients achieve normal visual acuity, but mild visual field loss is common. Long-term follow-up is important due to the high risk of glaucoma., (© 2024 The Author(s). Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

The αA-crystallin protein plays a vital role in maintaining the refractive index and transparency of the eye lens. Significant clinical studies have emerged as the αA-crystallin is prone to aggregation, resulting in the formation of cataracts with varied etiologies due to mutations. This work aims to comprehend the structural and functional role of cataract-causing mutations in αA-crystallin, particularly at N-Terminal and α-Crystallin Domains, using in-silico approaches including molecular dynamics simulation. About 19 mutants of αA-crystallin along with native structure were simulated for 100 ns and the post-simulations analyses reveal pronounced dynamics of αA-crystallin due to the enhanced structure flexibility as its native compactness was lost and is witnessed mainly by the mutants R12L, R21L, R21Q, R54L, R65Q, R116C and R116H. It is observed that αA-crystallin discloses the NTD motions as the dominant one and the same was endorsed by the linear variation between Rg and the center-of-mass of αA-crystallin. Interestingly, such enhanced dynamics of αA-crystallin mutants associated with the structure flexibility is internally modulated by the dynamic exchange of secondary structure elements β-sheets and coils (R 2  = 0.619) during simulation. Besides, the observed pronounced dynamics of dimer interface region (β3-L6-β4 segment) of ACD along with CTD dynamics also gains importance. Particularly, the highly dynamic mutants are also characterized by enhanced non-covalent and hydrophobic interactions which renders detrimental effects towards its stability, and favours possible protein unfolding mechanisms. Overall, this study highlights the mutation-mediated structural distortions in αA-crystallin and demands the need for further potential development of inhibitors against cataract formation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

There are few cerebrotendineous xanthomatosis (CTX) case series and observational studies including a significant number of Latin American patients. We describe a multicenter Brazilian cohort of patients with CTX highlighting their clinical phenotype, recurrent variants and assessing possible genotype-phenotype correlations. We analyzed data from all patients with clinical and molecular or biochemical diagnosis of CTX regularly followed at six genetics reference centers in Brazil between March 2020 and August 2023. We evaluated 38 CTX patients from 26 families, originating from 4 different geographical regions in Brazil. Genetic analysis identified 13 variants in the CYP27A1 gene within our population, including 3 variants that had not been previously described. The most frequent initial symptom of CTX in Brazil was cataract (27%), followed by xanthomas (24%), chronic diarrhea (13.5%), and developmental delay (13.5%). We observed that the median age at loss of ambulation correlates with the age of onset of neurological symptoms, with an average interval of 10 years (interquartile range 6.9 to 11 years). This study represents the largest CTX case series ever reported in South America. We describe phenotypic characteristics and report three new pathogenic or likely pathogenic variants., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Congenital cataract is one of the leading causes of vision loss in children, and a large proportion of cases are related to genetics. In a Chinese family, we reported a new missense mutation in CRYBA2 (c.223T>C: p.Tyr75His), which can cause autosomal dominant congenital bilateral cataract. We collected blood samples from family members (mother and two sons) and extracted DNA. Through whole-exome sequencing, we discovered a novel unreported mutation. According to relevant ACMG guidelines, this mutation was determined to be a variant of unknown clinical significance. This article further expands the site information on the CRYBA2 mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

PHARC, polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa and cataracts, or PHARC is a very rare progressive neurodegenerative autosomal recessive disease caused by biallelic mutations in the ABHD12 (a/b-hydrolase domain containing 12) gene, which encodes a lyso-phosphatidylserine (lyso-PS) lipase. The Orpha number for PHARC is ORPHA171848. The clinical picture of PHARC syndrome is very heterogeneous with a wide range of age at onset for each symptom, making a clinical diagnosis very challenging. Differential diagnoses of the disease include Refsum disease, Charcot-Marie-Tooth disease, and Usher syndrome. Many aspects of the disease, such as the biochemistry and pathophysiology, are still not fully understood. We generated a clinical overview of all PHARC patients, including their mutations, described in literature so far. Furthermore, we give an outline of the most recent developments in research on the pathophysiology of PHARC syndrome in an attempt to gain more insight into and increase awareness of the heterogeneity of the disease. We included 58 patients with PHARC from 37 different families with 27 known ABHD12 mutations. The age at onset (from early childhood to late thirties) and the severity of each feature of PHARC varied widely among patients. Demyelinating polyneuropathy was reported in 91% of the patients. In 86% of patients, hearing loss was present and 74% had cerebellar ataxia, the most variable symptom of PHARC. Retinitis pigmentosa and cataracts occurred in 82% and 86% of patients, respectively. Due to the rareness of the disease and the variable clinical phenotype, a diagnosis of PHARC is often delayed and mostly only made after an extensive genetic work-up. Therefore, we recommend adding the ABHD12 gene to diagnostic gene panels for polyneuropathy, cerebellar ataxia, hearing loss, retinal dystrophy, and cataracts. In addition, a full clinical work-up, neurological (with EMG and neuroimaging of the brain) and ophthalmological (with ERG) examination and audiological tests are indispensable to obtain a comprehensive overview of the clinical phenotype as some symptoms in PHARC may be very subtle and easily overlooked if not tested for. In conclusion, we strongly recommend that patients with (suspected) PHARC should be evaluated in a multidisciplinary setting involving ophthalmologists, audiologists, neurologists, and geneticists to ensure the best possible care. Furthermore, we discuss whether PHARC is a spectrum with various incomplete phenotypes even later in life, or whether it is a syndrome in which the clinical symptoms are variable in severity and age of onset., (© 2024. The Author(s).)

Age-related cataract (ARC) is regarded as the principal cause of vision impairment among the aged. The regulatory role of long noncoding RNAs (LncRNAs) in ARC remains unclear. The lncRNA maternally expressed gene 3 (MEG3) has been reported to promote ARC progression, and the underlying mechanism was further investigated in this study. Lens epithelium samples were collected to verify the expression of MEG3. Lens epithelial cells (LECs) were treated with H 2 O 2 to mimic microenvironment of ARC in vitro. Cell viability, reactive oxygen species, and ferroptosis were evaluated during the in viro experiments. In the present work, lncRNA MEG3 was highly expressed in ARC group, compared with normal group. MEG3 was induced, cell viability and glutathione peroxidase 4 (GPX4) level were inhibited, and ferroptosis was promoted in H 2 O 2 treated LECs. LncRNA MEG3 silence reversed the effects of H 2 O 2 on viability and ferroptosis in LECs. Thereafter, lncRNA MEG3 was found to bind to PTBP1 for GPX4 degradation. Silencing of GPX4 reversed the regulation of lncRNA MEG3 inhibition in H 2 O 2 -treated LECs. To sum up, lncRNA MEG3 exhibited high expression in ARC. In H 2 O 2 -induced LECs, inhibition of lncRNA MEG3 accelerated cell viability and repressed ferroptosis by interaction with PTBP1 for GPX4 messenger RNA decay. Targeting lncRNA MEG3 may be a novel treatment of ARC., (© 2024 Wiley Periodicals LLC.)

Purpose: Diabetic cataract (DC) is a major cause of blindness worldwide. Prion protein (PRNP) was proved to be up-regulated and hypomethylated in DC samples. Here, we investigated whether PRNP was involved in DC progression in N6-methyladenosine (m6A)-dependent manner, and its potential mechanisms., Methods: Levels of genes and proteins were assayed using qRT-PCR and western blotting. Cell proliferation and apoptosis were determined using Cell Counting Kit-8 assay, 5-thynyl-2'-deoxyuridine (EdU) assay, and flow cytometry, respectively. Oxidative stress was analyzed by measuring the production of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and malondialdehyde (MDA). The m6A modification was determined by RNA immunoprecipitation (Me-RIP) assay. The interaction between RBM15 (RNA binding motif protein 15) and PRNP was probed using RIP assay., Results: PRNP was highly expressed in DC patients and HG-induced HLECs. Functionally, PRNP deficiency reversed HG-induced apoptosis and oxidative stress in HLECs. Mechanistically, RBM15 induced PRNP m6A modification and directly bound to PRNP. Knockdown of RBM15 abolished HG-induced apoptotic and oxidative injury in HLECs, while these effects were rescued after PRNP overexpression., Conclusion: RBM15 silencing suppressed HG-induced lens epithelial cell injury by regulating PRNP in an m6A-mediated manner, hinting a novel therapeutic strategy for DC patients.

Various substances within the aqueous humor (AH) can directly or indirectly impact intraocular tissues associated with intraocular pressure (IOP), a critical factor in glaucoma development. This study aims to investigate individual changes in these AH substances and the interactions among altered components through a multi-omics approach. LC/MS analysis was conducted on AH samples from patients with exfoliation syndrome (XFS, n = 5), exfoliation glaucoma (XFG, n = 4), primary open-angle glaucoma (POAG, n = 11), and cataracts (control group, n = 7). Subsequently, differentially expressed proteins and metabolites among groups, alterations in their network interactions, and their biological functions were examined. Both data-independent acquisition and data-dependent acquisition methods were employed to analyze the AH proteome and metabolome, and the results were integrated for a comprehensive analysis. In the proteomics analysis, proteins upregulated in both the XFG and POAG groups were associated with lipid metabolism, complement activation, and extracellular matrix regulation. Metabolomic analysis highlighted significant changes in amino acids related to antioxidant processes in the glaucoma groups. Notably, VTN, APOA1, C6, and L-phenylalanine exhibited significant alterations in the glaucoma groups. Integration of individual omics analyses demonstrated that substances associated with inflammation and lipid metabolism, altered in the glaucoma groups, showed robust interactions within a complex network involving PLG, APOA1, and L-phenylalanine or C3, APOD, and L-valine. These findings offer valuable insights into the molecular mechanisms governing IOP regulation and may contribute to the development of new biomarkers for managing glaucoma., (© 2024 The Author(s). BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Stable isotope labeled standards of all major human lens crystallins were created to measure the abundance of lens endogenous crystallins from birth to adulthood. All major human crystallins (αA, αB, βA2, βA3/A1, βA4, βB1, βB2, βB3, γA, γB, γC, γD, γS) were cloned with N-terminal 6 x His tagged SUMO for ease of purification and the ability to generate natural N-termini by SUMO protease cleavage when producing crystallins for structure/function studies. They were then expressed in 15 N-enriched media, quantified by mass spectrometry, and mixed in proportions found in young human lens to act as an artificial lens standard. The absolute quantification method was tested using soluble protein from 5-day, 23-day, 18-month, and 18-year-old human lenses spiked with the 15 N artificial lens standard. Proteins were trypsinized, relative ratios of light and heavy labeled peptides determined using high-resolution precursor and data independent MS2 scans, and data analysis performed using Skyline software. Crystallin abundances were measured in both human donor lenses and in transgenic mouse αA N101D cataract lenses. Technical replicates of human crystallin abundance measurements were performed with average coefficients of variation of approximately 2% across all 13 crystallins. αA crystallin comprised 27% of the soluble protein of 5-day-old lens and decreased to 16% by 18-years of age. Over this time period αB increased from 6% to 9% and the αA/αB ratio decreased from 4.5/1 to 2/1. γS-crystallin also increased nearly 2-fold from 7% to 12%, becoming the 3rd most abundant protein in adult lens, while βB1 increased from 14% to 20%, becoming the most abundant crystallin of adult lens. Minor crystallins βA2, βB3, and γA comprised only about 1% each of the newborn lens soluble protein, and their abundance dropped precipitously by adulthood. While 9 of the SUMO tagged crystallins were useful for purification of crystallins for structural studies, γA, γB, γC, and γD were resistant to cleavage by SUMO protease. The abundance of WT and N101D human αA in transgenic mouse lenses was approximately 40-fold lower than endogenous mouse αA, but the deamidation mimic human αA N101D was less soluble than human WT αA. The high content of αA and the transient abundance of βA2, βB3, and γA in young lens suggest these crystallins play a role in early lens development and growth. βB1 becoming the most abundant crystallin may result from its role in promoting higher order β-crystallin oligomerization in mature lens. The full set of human crystallin expression vectors in the Addgene repository should be a useful resource for future crystallin studies. 15 N labeling of these crystallins will be useful to accurately quantify crystallins in lens anatomic regions, as well as measure the composition of insoluble light scattering crystallin aggregates. The standards will also be useful to measure the abundance of crystallins expressed in transgenic animal models., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ultraviolet (UV) radiation-triggered production of reactive oxygen species (ROS) is a primary contributor to apoptosis in human lens epithelial cells (HLECs), which can ultimately result in cataract formation. The nuclear factor erythroid-2-related factor 2 (Nrf2)-Kelch ECH associating protein 1 (Keap1) pathway, a fundamental oxidative stress regulation mechanism, plays a crucial role in the development of cataracts. Ferulic acid (FA), recognized for its potent antioxidant properties can activate the Nrf2 signaling pathway to mitigate oxidative damage and cell apoptosis. In this study, we have demonstrated the protective effects of FA in reducing UVA-induced oxidative damage and apoptosis in HLECs through the modulation of the Keap1/Nrf2 pathway, as evidenced by both cellular and animal experiments. HLECs and Lens were exposed to 10 J/cm 2 UVA radiation with or without prior treatment with FA. We found that UVA radiation increased oxidative damage and cell apoptosis in HLECs, ultimately leading to opacification of rat lenses, while FA was able to attenuate both oxidative damage and cell apoptosis in HLECs and reduce the degree of lens opacification. FA upregulated the expression of antioxidant response factors of the Keap1/Nrf2 pathway and downregulated the expression of apoptosis-related genes in HLECs, as demonstrated by Western blot and RT-qPCR analyses. We also found that UVA radiation increased the degree of demethylation of the Keap1 promoter in HLECs, whereas FA reduced the level of Keap1 promoter demethylation as determined by DNA sequencing. Additionally, UVA upregulated the expression of DNA active demethylase of the Keap1 promoter in HLECs, Dnmt1, Dnmt3a, and Dnmt3b, as shown by immunofluorescence, Western blot, and RT-qPCR, however, FA attenuated the activity of the passive demethylase TET1 in addition to the active demethylases. These results demonstrated that UVA radiation can cause oxidative damage, cell apoptosis, and rat lens opacification by increasing the demethylation of the Keap1 promoter in lens epithelial cells. Conversely, FA was shown to reduce oxidative damage, inhibit cell apoptosis, and decrease rat lens opacification by increasing the methylation of the Keap1 promoter. These findings suggest that FA could be therapeutically beneficial in preventing and mitigating cataracts induced by UVA radiation., (© 2024 Wiley Periodicals LLC.)

Background: CircRNA plays a regulatory role in multiple life processes. Circ&#95;0122396 could participate in the regulation of age-related cataract (ARC) progression. However, the precise molecular mechanisms of circ&#95;0122396 In ARC remain enigmatic., Methods: Circ&#95;0122396, microRNA (miR)-23a-3p, and matrix metalloprotease (MMP)-16 (MMP16) expression levels were detected via quantitative real-time polymerase chain reaction. Western blot was used to detect the levels of MMP16 and apoptosis-related proteins. Cell counting kit-8 analysis and 5-ethynyl-2'-deoxyuridine assay were used to assess human lens epithelial cells (HLECs) proliferation. Flow cytometry was performed to determine cell apoptosis. Levels of malondialdehyde (MDA) and glutathione peroxidase (GSH-PX) were measured using commercial kits. Luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA pull-down assay were used to examine the interaction among circ&#95;0122396, miR-23a-3p, and MMP16., Results: Circ&#95;0122396 and MMP16 were down-regulated while miR-23a-3p was up-regulated in ARC. H 2 O 2 constrained proliferation and GSH-PX level, promotes apoptosis and MDA level in HLECs, and overexpression of circ&#95;0122396 attenuated these effects. miR-23a-3p was a direct target of circ&#95;0122396, and MMP16 was a direct target of miR-23a-3p. The effect of circ&#95;0122396 overexpression on H 2 O 2 -induced HLECs was reversed by miR-23a-3p, and MMP16 elevation overturned the impacts of miR-23a-3p in H 2 O 2 -induced HLECs., Conclusions: Circ&#95;0122396 may regulate the progression of ARC via the miR-23a-3p/MMP16 pathway in H 2 O 2 -stimulated HLECs, which may serve as a potentially valuable biomarker and novel therapeutic target for ARC.

Purpose: The Stickler syndromes are a group of connective tissue disorders characterised by congenital myopia, giant retinal tear and retinal detachment, cleft palate, hearing loss and premature arthropathy. Patients with Stickler syndrome are also susceptible to abnormalities of the crystalline lens. Since neither type II or type XI collagen (those typically affected in the vast majority of Stickler patients) are highly expressed in the lens, this observational cohort study explores potential alternative mechanisms to explain why patients frequently exhibit such unusual but characteristic types of cataract., Methods: Author observations drawn from a cohort of over 1800 patients with genetically confirmed Stickler syndrome., Results: 3 distinct lens pathologies were identified. Firstly, a congenital quadrantic lamellar opacity. This can be present in both type 1 (COL2A1) and type 2 (COL11A1) Stickler syndrome. Secondly, early onset Pantone 557 C blue-green nuclear cataract. Thirdly, congenital lens coloboma associated with localised zonule deficiency., Conclusions: The characteristic quadrantic lamellar lens opacity can be helpful in alerting to the possible diagnosis, particularly in sub-groups with an ocular-only phenotype. Temporal and spatial signalling pathways shared embryologically by both the developing vitreous body and crystalline lens suggest an ancillary role of the fibrillar collagens in cell signalling beyond their basic structural function. A common pathway of TGFβ/BMP super-family dysregulation may be shared with allied disorders associated with both retinal detachment and cataract as well as the pathobiology linking retinal detachment and cataract in the population at large. Congenital lens coloboma associated with localised zonule deficiency can increase the difficulty and risks of cataract surgery. Strategies to mitigate such risks are presented., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. None., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Background: Previous Mendelian randomization (MR) studies showed an association between hypothyroidism and cataract and between high-normal free thyroxine (FT4) and late age-related macular degeneration (AMD), but not between FT4, thyroid stimulating hormone (TSH), or hyperthyroidism and diabetic retinopathy or cataract. These studies included a limited number of genetic variants for thyroid function and did not investigate autoimmune thyroid disease (AITD) or glaucoma, include bidirectional and multivariable MR (MVMR), and examine sex differences or potential mediation effects of diabetes. We aimed to address this knowledge gap. Methods: We examined the causality and directionality of the associations of AITD, and FT4 and TSH within the reference range with common age-related eye diseases (diabetic retinopathy, cataract, early and late AMD, and primary open-angle glaucoma). We conducted a bidirectional two-sample MR study utilizing publicly available genome-wide association study (GWAS) summary statistics from international consortia (ThyroidOmics, International AMD Genetics Consortium, deCODE, UK Biobank, FinnGen, and DIAGRAM). Bidirectional MR tested directionality, whereas MVMR estimated independent causal effects. Furthermore, we investigated type 1 diabetes (T1D) and type 2 diabetes (T2D) as potential mediators. Results: Genetic predisposition to AITD was associated with increased risk of diabetic retinopathy ( p = 3 × 10 -4 ), cataract ( p = 3 × 10 -3 ), and T1D ( p = 1 × 10 -3 ), but less likely T2D ( p = 0.01). MVMR showed attenuated estimates for diabetic retinopathy and cataract when adjusting for T1D, but not T2D. We found pairwise bidirectional associations between AITD, T1D, and diabetic retinopathy. Genetic predisposition to both T1D and T2D increased the risk of diabetic retinopathy and cataract ( p < 4 × 10 -4 ). Moreover, genetically predicted higher FT4 within the reference range was associated with an increased risk of late AMD ( p = 0.01), particularly in women ( p = 7 × 10 -3 ). However, we neither found any association between FT4 and early AMD nor between TSH and early and late AMD. No other associations were observed. Conclusions: Genetic predisposition to AITD is associated with risk of diabetic retinopathy and cataract, mostly mediated through increased T1D risk. Reciprocal associations between AITD, diabetic retinopathy, and T1D imply a shared autoimmune origin. The role of FT4 in AMD and potential sex discrepancies needs further investigation.

Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Disruption of Eph-ephrin bidirectional signaling leads to human congenital and age-related cataracts, but the mechanisms for these opacities in the eye lens remain unclear. Eph receptors bind to ephrin ligands on neighboring cells to induce canonical ligand-mediated signaling. The EphA2 receptor also signals non-canonically without ligand binding in cancerous cells, leading to epithelial-to-mesenchymal transition (EMT). We have previously shown that the receptor EphA2 and the ligand ephrin-A5 have diverse functions in maintaining lens transparency in mice. Loss of ephrin-A5 leads to anterior cataracts due to EMT. Surprisingly, both canonical and non-canonical EphA2 activation are present in normal wild-type lenses and in the ephrin-A5 knockout lenses. Canonical EphA2 signaling is localized exclusively to lens epithelial cells and does not change with age. Non-canonical EphA2 signaling is in both epithelial and fiber cells and increases significantly with age. We hypothesize that canonical ligand-dependent EphA2 signaling is required for the morphogenesis and organization of hexagonal equatorial epithelial cells while non-canonical ligand-independent EphA2 signaling is needed for complex membrane interdigitations that change during fiber cell differentiation and maturation. This is the first demonstration of non-canonical EphA2 activation in a non-cancerous tissue or cell and suggests a possible physiological function for ligand-independent EphA2 signaling.

Age-related cataracts is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation, and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Our study identified 101 independent genome-wide significant loci, 57 of which are novel. We identified multiple genes and biological pathways associated with the cataracts, including four drug-gene interactions. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults., (© 2024. The Author(s).)

Clinical studies and meta-analyses have suggested a link between thyroid dysfunction and lens opacification. The objective of this study is to investigate the causal relationship between hyperthyroidism and the development of cataracts using the Mendelian randomization approach, with the aim of filling the gap in knowledge about the systemic effects of hyperthyroidism on ocular health. Leveraging genetic variants as instrumental variables, the analysis used extensive datasets from the UK Biobank and the FinnGen Database and employed three common approaches for causal inference (the Inverse Variance Weighted method, a regression based method the Weighted Median estimator, and MR-Egger regression) and accompanying sensitivity analyses to ensure robustness. The results demonstrate that there is a strong likely causal relationship, with hyperthyroidism increasing the risk of developing senile cataracts (OR = 361.09, 95%CI 5.024 to 2.60 × 10 4 , P = 0.007). A sensitivity analysis provided no evidence of horizontal pleiotropy and no significant outliers, suggesting the results are robust. In conclusion, our study established a significant causal relationship between hyperthyroidism and increased risk of cataract development, underscoring the importance of considering the systemic effects of hyperthyroidism in clinical and public health interventions and policies. Future research should focus on elucidating the molecular mechanisms underlying this association, exploring the potential benefits of early intervention in hyperthyroidism to prevent cataract development, and investigating whether these findings translate across different ethnic populations. Additionally, further GWAS studies aimed at identifying genetic variants associated with both hyperthyroidism and cataracts are warranted to confirm and expand upon our results., (© 2024. The Author(s).)

Background: The oculo-facio-cardio-dental syndrome (OFCD) is an ultra-rare multiple congenital anomaly. This report describes clinical findings emphasising dental phenotype in five, molecularly confirmed, female cases from two Czech families., Case Presentation: Dental examinations were carried out. An orthopantomogram was taken in three patients, and all patients' intraoral cavities and teeth were photographed. Exome sequencing was performed in both probands. Results were validated by Sanger DNA sequencing which was also used to follow segregation of the variants in first-degree relatives. Dental abnormalities and congenital cataracts were present in all five cases, whilst other signs were variable and included facial dysmorphism, microphthalmia, and cardiac and skeletal abnormalities. Two individuals had cleft lip and/or cleft palate. Radiculomegaly occurred in three patients with permanent teeth and was diagnosed on orthopantomograms. Two patients had agenesis of permanent teeth. Malocclusion was also present in two patients due to crowding and a Class III malocclusion and mandibular overjet. De novo novel pathogenic variants in the BCOR gene were identified; c.2382del p.(Lys795Argfs*12) and c.3914dup p.(Gln1306Alafs*20) and co-segregated with the disease in each family., Conclusions: The OFCD syndrome has a unique dental phenotype and dentists should be aware of signs of this ultra-rare genetic disorder. All patients with congenital cataracts and dental abnormalities, including those without a family history, should be referred for genetic testing and indicated to specialised dental care., (© 2024. The Author(s).)

Objective: To analyse the characteristics of micronuclus and chromosomal aberrations and the lens opacity in different working years, ages and work type of radiation workers with lens opacity. Methods: In January 2022, we selected 400 radiation workers with lens opacity who had undergone occupational health examination in Hangzhou Hospital for the Prevention and Treatment of Occupational Disease from March 2014 to December 2021 as research objects. To analyze the differences of micronucleus, chromosome aberration and the lens opacification rates of different length of service, type of work, age radiologic workers. Results: The results showed that radiation the micronucleus abnormality (0.59‰) and chromosome aberration (2.67%) in peripheral blood in workers who served more than 20 years were significantly higher than that of micronucleus abnormality (0.18‰) and chromosome aberration (0.31%) in workers served less than 20 years, the differences were statistically significant ( P <0.05). The micronucleus abnormality (0.32‰) and chromosome aberration (0.57%) in the interventionist were higher than oral radiation workers (0.12‰ and 0.19%) and diagnostic radiologist (0.05‰ and 0.12%), the differences were statistically signcficant (χ(2)=23.98, 6.72, P <0.05) . Conclusion: The rates of micronucleus and chromosome aberration of the interventionaist are higher than oral radiation workers and the traditional radiologist. Workers engaged in radiation should improve personal protection and undertake regular occupational health examinations.