Explore the vast range of titles available.

Purpose Bilateral pediatric cataract (BPC) is one of the most common causes of childhood visual impairment and blindness worldwide. A significant percentage of pediatric cataracts are caused by genetic alterations. We aim to characterize the set of genes and variants that cause BPC in the Israeli and Palestinian populations and to assess genotype-phenotype correlation. Methods Retrospective study in a multidisciplinary center for visual impairment, located in a tertiary medical center. Medical charts of families who underwent genetic counseling because of BPC in a family member were reviewed. Clinical characteristics and genetic tests results were obtained from medical records of affected subjects. Results Twenty-two families (47 patients) underwent genetic counseling and completed genetic testing. Causative variants were identified in 18/22 (81.8%) of the families, including 3 novel variants. Genetic testing used included mainly panel for congenital cataracts and whole exome sequencing. Eleven families performed genetic testing with the intention of future pregnancy planning. Main causative genes identified were crystalline genes followed by transcription factor genes. BCOR gene variants were associated with persistent fetal vasculature (PFV) cataract in two of three families. Conclusions Combined molecular techniques are useful in identifying variants causing pediatric cataracts and showed a high detection rate in our population. BCOR gene variants might be associated with PFV type of cataracts. The study of pathogenic variants may aid in family planning and prevention of pediatric cataracts in future pregnancies. Additionally, in certain cases, it assists in diagnosing non-suspected syndromic types of pediatric cataracts. Key message What is known • Bilateral pediatric cataracts are often inherited. • Detection rate of causative variants is high. • Correlation between genes and phenotype is still scarce. What is new • First evidence of possible correlation between BCOR gene and persistent fetal vasculature cataract. • Additional data supporting recently published relationship between GJA3 gene variant (c.199G > T) and glaucoma. • Importance of genetic testing in diagnosing “non-suspected syndromic types of pediatric cataracts”. • Three novel causative variants identified.

BackgroundCataract is a major health burden in many countries and a significant problem in India. While observational studies show lower cataract risk with increasing dietary or plasma vitamin C, randomised controlled trials of supplements have been negative. Genetic variants in vitamin C transporter proteins (SLC23A1), especially rs33972313, may provide evidence on a causal association of vitamin C with cataract.MethodsWe used data from a randomly selected population-based study in people aged 60 years and above in north and south India. Of 7518 sampled, 5428 (72%) were interviewed for socioeconomic and lifestyle factors, attended hospital for lens imaging and blood collection and were subsequently genotyped for rs33972313 and rs6596473. Mixed or pure types of cataract were graded by the Lens Opacity Classification System III as nuclear (2404), cortical (494) or posterior subcapsular cataract (PSC) (1026); 1462 had no significant cataract and no history of cataract surgery and 775 had bilateral aphakia/pseudophakia.Resultsrs33972313 was associated with cortical (OR 2.16; 95% CI 1.34 to 3.49, p=0.002) and PSC (OR 1.68; 95% CI 1.06 to 2.65, p=0.03) but not with nuclear cataract. In analyses of pure cataracts, associations were found only between rs33972313 and pure cortical cataracts (OR 2.29; 95% CI 1.12 to 4.65, p=0.03) and with a standardised cortical opacity score. There was no association with rs6596473 and any cataract outcomes.ConclusionsUsing an established genetic variant as a proxy for lifetime ascorbate concentrations, our results support a causal association of vitamin C with cataract.

Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype–phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.

Exploring the genetic basis of congenital cataracts in two families identifies a molecule, lanosterol, which prevents intracellular protein aggregation of various cataract-causing mutant crystallins, and which can reduce cataract severity and increase lens transparency in vivo in dogs. Lanosterol counters cataract formation In a study of the genetic basis of congenital cataract formation in two families, Kang Zhang and colleagues demonstrate that lanosterol, a sterol present naturally in the lens, can prevent intracellular aggregation of various cataract-causing mutant crystallin proteins. The mutations identified in the genetic study impair the function of lanosterol synthase, an enzyme for synthesizing lanosterol. In dogs with naturally occurring cataracts, the application of eye drops containing lanosterol for six weeks reduced cataract severity and increased lens transparency, suggesting that lanosterol or molecules with similar activity might provide an alternative to surgery for the management of cataracts. The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people 1 , and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

Background Genetic variants are the leading cause of congenital cataract (CC). To date, numerous genes have been implicated in the development of CC. The objective of the present study was to report two previously unrecognized gene variants associated with CC in two unrelated Chinese families, identified through whole exome sequencing (WES). Methods Two unrelated Chinese families affected by CC were recruited. Cytogenetic and molecular genetic analyses were performed using karyotyping, chromosomal microarray analysis (CMA), and WES. In addition, RNA sequencing was conducted to assess differentially expressed genes in affected individuals compared with healthy controls. Results Karyotype and CMA elicited none of chromosome abnormalities in both of the families. However, WES revealed a novel missense variant NM_006891.4:c.154 T > C(p.S52P) in the CRYGD gene in the proband of Family 1, which was inherited from her mother with CC. In Family 2, a novel frameshift variant NM_000276.4:c.1046dup(p.M349Ifs∗36) in the OCRL gene was identified in the fetus via WES, which was inherited from the mother who had CC. RNA sequencing further demonstrated significantly reduced OCRL mRNA expression in the fetus compared with age‐matched controls. Conclusion The present study reports, for the first time, two novel variants in CRYGD and OCRL that were identified in the Chinese families with CC. These findings may expand the mutational spectrum of CC and highlight the utility of WES for the genetic diagnosis of patients with CC.

Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial-mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.

A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). Two hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

Age‐related cataract (ARC) is caused by the exposure of the lens to UVB which promotes oxidative damage and cell death. This study aimed to explore the role of lncRNA H19 in oxidative damage repair in early ARC. lncRNAs sequencing technique was used to identify different lncRNAs in the lens of early ARC patients. Human lens epithelial cells (HLECs) were exposed to ultraviolet irradiation; and 8‐OHdG ELISA, Cell counting kit 8 (CCK8), EDU, flow cytometry and TUNEL assays were used to detect DNA damage, cell viability, proliferation and apoptosis. Luciferase assay was used to examine the interaction among H19, miR‐29a and thymine DNA glycosylase (TDG) 3'UTR. We found that lncRNA H19 and TDG were highly expressed while miR‐29a was down‐regulated in the three types of early ARC and HLECs exposed to ultraviolet irradiation, compared to respective controls. lncRNA H19 knockdown aggravated oxidative damage, reduced cell viability and proliferation, and promoted apoptosis in HLECs, while lncRNA H19 overexpression led to opposite effects in HLECs. Mechanistically, miR‐29a bound TDG 3'UTR to repress TDG expression. lncRNA H19 up‐regulated the expression of TDG by repressing miR‐29a because it acted as ceRNA through sponging miR‐29a. In conclusion, the interaction among lncRNA H19, miR‐29a and TDG is involved in early ARC. lncRNA H19 could be a useful marker of early ARC and oxidative damage repair pathway of lncRNA H19/miR‐29a/TDG may be a promising target for the treatment of ARC.

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.

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.