Mechanism Of Cataract Formation Research Articles

Comprehensive landscape of RNA N6-methyladenosine modification in lens epithelial cells from normal and diabetic cataract

To gain more insight into the mechanism of cataract formation from the perspective of epigenetics in the diabetic population, lens epithelium from diabetic cataract patients and healthy donors were collected separately and analyzed for N6-methyladenosine (m6A)-modified RNA using methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Subsequently, differential expression analysis was performed on m6A-regulated messenger RNA (mRNA), circular RNA (circRNA), and long non-coding RNA (lncRNA), followed by functional annotation using the Gene Ontology (GO) database. Furthermore, analysis of single-cell data of lens complemented the intrinsic association and cellular heterogeneity of cataract and m6A regulators. In this study, both the global expression levels and peak intensity of m6A-tagged RNAs were increased in patients with diabetic cataract. And we noted multiple core enzymes were upregulated in the diabetic cataract (DC) samples. Besides, single-cell RNA sequencing analysis of the lens revealed the heterogeneous expression of RNA m6A regulators across different cell types, and we noted that the early fiber cell cluster was also closely associated with the onset of cataract and m6A modification. The results comprehensively revealed the dynamic modification landscape of m6A on mRNA, circRNA, and lncRNA, which might provide valuable resources for future studies of the pathogenesis of DCs.

Cataract-causing mutations S78F and S78P of γD-crystallin decrease protein conformational stability and drive aggregation

Congenital cataract is the leading cause of childhood blindness, which primarily results from genetic factors. γD-crystallin is the most abundant γ-crystallin and is essential for maintaining lens transparency and refractivity. Numerous mutations in γD-crystallin have been reported with unclear pathogenic mechanism. Two different cataract-causing mutations Ser78Phe and Ser78Pro in γD-crystallin were previously identified at the same conserved Ser78 residue. In this work, firstly, we purified the mutants and characterized for the structural change using fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and size-exclusion chromatography (SEC). Both mutants were prone to form insoluble precipitates when expressed in Escherichia coli strain BL21 (DE3) cells. Compared with wild-type (WT), both mutations caused structural disruption, increased hydrophobic exposure, decreased solubility, and reduced thermal stability. Next, we investigated the aggregation of the mutants at the cellular level. Overexpression the mutants in HLE-B3 and HEK 293T cells could induce aggresome formations. The environmental stresses (including heat, ultraviolet irradiation and oxidative stress) promoted the formation of aggregates. Moreover, the intracellular S78F and S78P aggregates could be reversed by lanosterol. Molecular dynamic simulation indicated that both mutations disrupted the structural integrity of Greek-key motif 2. Hence, our results reveal the vital role of conserved Ser78 in maintaining the structural stability, which can offer new insights into the mechanism of cataract formation.

Analysis of Age and Gender Factors on the Incidence Rate of Cataracts in the Ophthalmology Clinic

Cataracts are a cause of blindness which accounts for approximately half of all blindness in the world, especially in developing countries. The mechanism of cataract formation is highly multifactorial. Loss of transparency in the nucleus and cortex of the lens of the eye can occur as a result of oxidation of membrane lipids, structural or enzymatic proteins by peroxides or free radicals induced by UV light. Other factors that can cause cataract formation are degenerative processes and diabetes mellitus). Cataract therapy is a surgical procedure by removing the cloudy lens, because no medical therapy has been proven to remove cataracts in adults. There are many methods that can be done with surgery for cataract patients. One of them is phacoemulsification, which is a cataract surgery using a small incision method. In this technique, liquefaction of the lens is made using an ultrasound probe that is inserted through an incision in the cornea or anterior sclera. This study aims to determine the relationship between age and gender with the incidence of cataracts at the Eye Polyclinic Outpatient Installation in 2022. This is a retrospective analytic study by examining data in the Recamedics Department. The data is grouped by age, sex and type of cataracts. There were 197 patients who came to the eye polyclinic in July 2022. From the results of the study, 197 people suffered from cataracts with a percentage of 88 men (45%) and 109 women (55%) and the age group that suffered the most from cataracts was the age group 53-68 years and the most common cataracts were senile cataract. Analysis of the relationship between age and gender with the incidence of cataracts in the Outpatient Installation (Poly Eyes) for the period of July 2022 obtained a value for the relationship between age and the incidence of cataracts P = 0.846 and the relationship between sex and the incidence of cataracts P = 0.01. Conclusion: In this study there is a significant relationship between gender and the incidence of cataracts and there is no relationship between age and the incidence of cataracts.

The role of oxidative damage in cataract etiopathogenesis.

Cataract usually occurs due to age and diabetes, but the mechanisms of cataract formation have not yet been fully elucidated. In this study, the relationship between cataract and oxidative stress was evaluated by examining the aqueous humor reflecting lens metabolism. In this study, the effect of oxidative stress on the etiopathogenesis of cataract was investigated through the total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and arylesterase (ARE) levels in aqueous humor samples of patients with cataract. A prospective cohort study. This study was conducted on patients who were scheduled for cataract surgery between June 2020 and March 2021. The patients were divided into four groups according to their cataract density as grades 1, 2, 3, and 4. TOS, TAS, and ARE levels of aqueous humor samples were measured spectrophotometrically, and comparisons were made between groups. A total of 100 eyes of 100 patients were included in this study. TAS levels were found significantly higher in the grade 2 group compared with the grade 4 group (p = 0.006). In addition, a significant negative correlation was present between cataract grade and TAS level (r = -0.237; p = 0.018). There was no significant difference between diabetic and nondiabetic patients in terms of TAS, TOS, OSI, and ARE levels. The aqueous humor of patients with a high degree of cataract is characterized by low antioxidant capacity. Decreased antioxidant capacity has a role in cataract formation and progression.

Mutations of CX46/CX50 and Cataract Development.

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

EFFECT OF AMINOGUANIDINE ON CATARACTOGENESIS IN EXPERIMENTAL DIABETES MELLITUS

Nonenzymatic glycosylation of lens proteins in diabetes mellitus is one of the pathogenetic mechanisms of cataract formation. According to the results of this study, aminoguanidine, which has anti-glycation activity, inhibits cataractogenesis in experimental diabetes. Laboratory animals with streptozotocin-induced diabetes mellitus treated with aminoguanidine showed less clouding in the lenses, and the content of advanced glycation end products, in particular, carboxymethyllysine, in the lenses was found to be reduced compared to the same parameters in animals from the control diabetic group.

Steroid cataract in patients with hemoblastosis

Modern technologies of treatment of children with oncohaematological diseases allowed to noticebly increase the survival indexes in this group of patients, enhancing the value of maintenance of their life quality. More than half of those who received long-term steriod and radiation treatment develop cataract that causes decrease in vision. In this review we represent data concerning mechanisms of cataract formation in patients after steriod and radiation treatment, results of anatomical, physiological and biochemical studies of the lens as well as metabolic changes in aqueous humor leading to cataract formation.

Structural and functional characterization of a missense mutant of human γS-crystallin associated with dominant infantile cataracts

Infantile cataracts constitute one of the most important causes of childhood blindness worldwide. Human γS-crystallin is the most abundant protein in the eye lens cortex. A missense mutant of human γS-crystallin, Y67N (abbreviated hereafter as γS-Y67N) is recently reported to be associated with dominant infantile cataracts. To understand the structural basis for γS-Y67N to cause lens opacification, we constructed, expressed and purified γS-Y67N and its wild-type (abbreviated hereafter as γS-WT) and studied the structural and functional differences between them in solution using circular dichroism (CD), differential scanning calorimetry (DSC), fluorescence spectroscopy and extrinsic spectral probes. Extensive equilibrium characterization indicate that replacement of the highly conserved Tyr at 67th position by Asn distorts the conserved Tyr corner at the second Greek key motif in the N-terminal domain (NTD) and leads to substantial loss of structural stability. Our intrinsic fluorescence quenching results reveal differential in-vitro refolding kinetics identifying partially folded kinetic intermediates for both proteins. Extrinsic fluorescence studies further reveal loosening up of the compact structure of γS-crystallin upon mutation associated with enhanced aggregation. As Ca2+ homeostasis is a crucial regulator of lens transparency, we further investigated the Ca2+-binding properties of γS-WT and γS-Y67N by isothermal titration calorimetry (ITC) to identify lens Ca2+ distribution in health and in disease. Overall, our results highlight the vital role of conserved Tyr corners in stabilizing Greek key motifs and provide useful structural and functional insights into the mechanism of cataract formation in humans.

The impact of GJA8 SNPs on susceptibility to age-related cataract

The gap junction protein alpha 8 (GJA8) gene has been widely studied in human congenital cataracts. However, little is known about its relationship with age-related cataract (ARC). In this study, three GJA8-tagged single nucleotide polymorphisms related to an increased ARC risk were identified: rs2132397 for general ARC under both dominant and additive models; rs7541950 for general ARC under both recessive and additive models; and rs6657114 for cortical cataract under the recessive model. To uncover the underlying mechanisms, this study also sought to explore whether GJA8 is involved in the autophagy process in human lens epithelial cells. The results showed that GJA8 may participate in autophagy to maintain the intracellular environment, which may be a novel mechanism for cataract formation induced by GJA8. In conclusion, this study identified the genetic susceptibility of GJA8 polymorphisms on ARC and provides new clues for fully understanding the pathological mechanism of GJA8 variants in affecting lens opacity.

Ultrastructure of the lens anterior capsule in secondary cataract associated with uveitis under an electron microscope

Objective: To observe the ultrastructure of lens epithelium cells in cataract associated with uveitis. Methods: A cross-sectional study. Seven patients(7 eyes) received phacoemulsification in Peking University First Hospital from August 2016 to March 2017 due to complicated cataract associated with uveitis[2 males and 5 females,with an average age of (49±20) years] and 3 patients of age-related cataract (3 eyes, females, aged 54, 71, 74 years) were enrolled. Anterior capsule samples were collected during surgery. Transmission electron microscopy was performed. The cell morphology, the proportion of cell nuclear and organelle changes and the proportion of apoptosis in cataract associated with uveitis were described statistically by x±s or median (range). Results: Spindle-shaped epithelial cells were observed in cataract associated with uveitis (100%), while 28.00%,16.67%,16.67% of spindle-shaped epithelial cells were observed in age-related cataract. The organelle changes included mitochondria swelling and damage to the tight cell junction in cataract associated with uveitis. The tight junction between two cells was damaged in different degrees, only 8.33% (0-16.67%)of the cell nuclei appeared normal, and increased chromatin density(47.07%±22.28%), nuclear pyknosis(38.02%±19.61%) and nuclear fragmentation (9.96%±8.10%) were observed in cataract secondary to uveitis. The apoptosis rate was (48.16%±26.66%) in cataract associated with uveitis and correlated to the duration of intraocular inflammation. While the apoptosis rate were 0, 8.33%, 0 in age-related cataract patients. No autophagosome was observed in cataract associated with uveitis. Conclusions: Ultrastructure changes existed in lens epithelium cells in cataract associated with uveitis. The increased rate of apoptosis and inhibition of autophagy could be the possible mechanism of cataract formation in uveitic eyes. (Chin J Ophthalmol, 2018, 54: 357-362).

Activation of Caspase‐8/BID Pathway in Dexamethasone‐Induced Apoptosis in a Human Lens Epithelial Cell Line

BackgroundProlonged glucocorticoid steroid usage is capable of inducing changes to the transcription of genes in lens epithelial cells and is associated with the development of several ocular diseases, including cataract formation. Mechanisms of cataract formation, however, are not well known, although apoptosis has been implicated. We therefore investigated glucocorticoid dexamethasone‐induced apoptosis in a human lensepithelial cell line.MethodsHuman lens epithelial cells were exposed to dexamethasone and apoptosis was evaluated using flow cytometry for AnnexinV expression, chromogenic substrates for Caspase activity measurements, Western blotting for Bax andBCL‐2 expression as well as PARP cleavage, and agarose gel electrophoresis for detection of DNA fragmentation. Mitochondrial pathway activity was determined by measuring the levels of Cytochrome C release, Bax translocation to the mitochondria, and BID cleavage.ResultsA significant induction of early apoptosis was observed by the AnnexinV/PI dual staining flow cytometric analyses. Increased expression ratios of pro‐apoptotic protein Bax toanti‐apoptotic protein BCL‐2 following dexamethasone exposure demonstrated apro‐apoptotic tendency. Sequential activation of caspase‐8 and caspase‐3, and BID cleavage with Cytochrome C extrusion from mitochondria, indicated an extrinsic apoptotic pathway. Nuclear changes of DNA fragmentation and PARP cleavage, both indicative of late stage apoptosis, were detected by electrophoresis only after dexamethasone exposure, despite lack of increased late stage apoptotic detection using Flow cytometry.ConclusionResults suggest that Dexamethasone exposure induces an extrinsic apoptotic pathway in a human lensepithelial cell line which follows along the activation of caspase‐8/BIDpathway and supports the hypothesis that apoptosis may be an important mechanism involved in steroid‐induced cataract formation.Support or Funding InformationIntramural Funding from the Department of Defense

Characterization of cholesterol crystalline domains in model and biological membranes using X-ray diffraction.

In this review, we discuss the use of small-angle X-ray diffraction approaches in studying the formation of cholesterol crystalline domains in membranes derived from model and biological sources. Numerous studies have shown that monomeric cholesterol can self-associate and form immiscible, membrane-restricted domains as a result of increased membrane concentration or systematic oxidation of membrane phospholipids. These domains are observed, in an X-ray diffraction pattern, as reflections describing a unit cell periodicity of 34 Å, which is consistent with cholesterol molecules arranged in a tail-to-tail, bilayer conformation. In vascular smooth muscle cells isolated from animal models of atherosclerosis, plasmalemmal cholesterol domain formation is associated with cellular dysfunction, including the disruption of calcium transport mechanisms. Cholesterol domains are also observed in macrophages and precede the deposition of extracellular cholesterol crystals in the atheroma. We have also shown that cholesterol domains can be produced in model membranes following exposure to oxidative stress and other disease-like conditions such as hyperglycemia. By contrast, cholesterol domains appear to be essential to the normal physiology of certain cell groups such as those of the human ocular lens. Cholesterol domains are a prominent structural feature of the lens fiber cell plasma membrane where they are believed to facilitate lens tissue transparency and interfere with various mechanisms of cataract formation. These contrasting biologic effects highlight the complex role that cholesterol domains play in cell plasma membrane structure-function relationships in both health and disease.KeywordsCholesterol DomainsFiber Cell Plasma MembraneFiber CellsCalcium Transport MechanismsTulenkoThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Osmotic stress induced oxidative damage: Possible mechanism of cataract formation in diabetes

Chronic hyperglycemia causes increased level of reactive oxygen species which is thought to be involved in the pathogenesis of diabetes associated complications including cataract. In diabetic cataractous lens, over production of free radicals and decreased capacity of antioxidant defense system are the major contributors to oxidative damage by polyol pathway and advanced glycation end products. The current study focused on analysis of factors associated with osmotic imbalance and oxidative stress in aging and diabetic human cataractous lenses. We examined activities of polyol pathway enzymes, G6PD and glutathione system in lenses from subjects suffering from cataract due to aging and diabetes. We observed elevated activities of aldose reductase and sorbitol dehydrogenase while G6PD and glutathione system enzyme activities were found to be lower in cataractous subjects suffering from diabetes. The findings from the current study support the premise that osmotic imbalance, AGEs formation and oxidative stress contribute synergistically to the development of lens opacity in hyperglycemia.

Mechanism of Cataract Formation in αA-crystallin Y118D Mutation

The aim of this study was to elucidate the molecular mechanisms that lead to a dominant nuclear cataract in a mouse harboring the Y118D mutation in the alphaA-crystallin gene. The physicochemical properties of alpha-crystallin obtained from mouse lenses with the Y118D mutation as well as a recombinant Y118D alphaA-crystallin were studied using gel filtration, two-dimensional (2D) gel electrophoresis, multi-angle light scattering, circular dichroism, fluorescence, and chaperone activities. Both native alpha-crystallin from mutant lens and recombinant alphaA-Y118D displayed higher molecular mass distribution than the wild-type. Circular dichroism spectra indicated changes in the secondary structures of alphaA-Y118D. The alphaA-Y118D protein prevented nonspecific protein aggregation more effectively than wild-type alphaA-crystallin. The gel filtration and 2D gel electrophoresis analysis showed a significant reduction of Y118D mutant protein in comparison with wild-type alphaA protein of heterozygous mutant lenses. Quantitative RT-PCR results confirmed a decrease in alphaA and alphaB transcripts in the homozygous mutant alpha A(Y118D/Y118D) lenses. The alphaA-Y118D mutant protein itself displays an increased chaperone-like activity. However, the dominant nuclear cataract is associated with a significant decrease in the amount of alphaA-crystallin, leading to a reduction in total chaperone capacity needed for maintaining lens transparency.

Heat in Workplaces Such as a Neighborhood Bakery or a Glass Factory Can Promote Aging of the Eye Lens

Abstract: Aging can be described as accumulation of damage with time. The eye lens is a good model for study the aging process because of limited repair mechanisms. The function of the eye lens is to help the cornea focus light on the retina and consequently the lens must remain transparent throughout life. Cataracts (loss of lens transparency) are a major cause of blindness in the aging population. Despite the amount of research done, the mechanisms of cataract formation are not completely understood. One of the major insults that can promote cataract is exposure to heat. Many workers are exposed to high temperatures in bakeries and glass factories. We investigated the mechanisms involved in heat damage in such work-places on the eye lens using a unique lens organ culture system. Bovine lenses were placed in specially designed culture containers for incubation of 11 to 15 days. Lenses were exposed to 39.5oC or 37.8oC by simulating the heat reach-ing the eye lens in a neighborhood bakery (39.5oC) and a glass factory (37.8oC). Lens optical quality was followed and lens epithelial samples were analyzed for ATPase activities. Lenses exposed to both temperatures show changes in lens optical quality and damage to lens epithelial cells. Lenses exposed to 37.8oC show an increase in lens epithelial ATPase activities. Lenses exposed to 39.5oC show a reduction in ATPase activities.

Noninvasive Measurement of Protein Aggregation by Mutant Huntingtin Fragments or α-Synuclein in the Lens

Many diverse human diseases are associated with protein aggregation in ordered fibrillar structures called amyloid. Amyloid formation may mediate aberrant protein interactions that culminate in neurodegeneration in Alzheimer, Huntington, and Parkinson diseases and in prion encephalopathies. Studies of protein aggregation in the brain are hampered by limitations in imaging techniques and often require invasive methods that can only be performed postmortem. Here we describe transgenic mice in which aggregation-prone proteins that cause Huntington and Parkinson disease are expressed in the ocular lens. Expression of a mutant huntingtin fragment or alpha-synuclein in the lens leads to protein aggregation and cataract formation, which can be monitored in real time by noninvasive, highly sensitive optical techniques. Expression of a mutant huntingtin fragment in mice lacking the major lens chaperone, alphaB-crystallin, markedly accelerated the onset and severity of aggregation, demonstrating that the endogenous chaperone activity of alphaB-crystallin suppresses aggregation in vivo. These novel mouse models will facilitate the characterization of protein aggregation in vivo and are being used in efficient and economical screens for chemical and genetic modifiers of disease-relevant protein aggregation.

Lens Epithelium-derived Growth Factor Relieves Transforming Growth Factor-β1-induced Transcription Repression of Heat Shock Proteins in Human Lens Epithelial Cells

Lens epithelium-cell derived growth factor (LEDGF) is a transcriptional activator. It protects the cells by binding to cis-stress response ((A/T)GGGG(T/A)), and heat shock (HSE; nGAAn) elements in the stress genes and activating their transcription. Transforming growth factor-beta (TGF-beta) has been implicated in the control of tissue homeostasis, terminal differentiation, and apoptosis. Here we provide evidence that TGF-beta1 down-regulates LEDGF expression and diminishes its affinity for DNA during TGF-beta1-induced phenotypic changes and apoptosis in human lens epithelial cells. Surprisingly, TGF-beta1 treatment for 48 h markedly decreased the LEDGF, Hsp27, and alphaB-crystallin promoter activities with the decrease of abundance of LEDGF mRNA and protein. Deletion mutants of the LEDGF promoter showed that one TGF-beta1 inhibitory element (TIE) like sequence nnnTTGGnnn (-444 to -433) contributed to this negative regulation. Mutation of TIE (TTGG to TATT) abolished the down-regulation of the LEDGF promoter. Gel mobility and supershift assays showed that LEDGF in the nuclear extracts of TGF-beta1-treated human lens epithelial cells did not bind to stress-response elements and HSE. The TGF-beta1-induced down-regulation of LEDGF, Hsp27, and alphaB-crystallin promoters activity was reversed by cotransfection with a plasmid expressing LEDGF. Because overexpression of LEDGF was able to relieve TGF-beta1 and/or stress-induced changes, it would be a candidate molecule to postpone age-related degenerating disorders.

New Light on Cataracts

Add another ailment to the mischief caused by waning estrogen concentrations. A new study in mice suggests that cataracts are members of the club that already includes osteoporosis, heart disease, cognitive declines, mood swings, and hot flashes (see "More Than a Hot Flash" ). The findings might prod exploration of estrogen as a cataract therapy. The discovery of estrogen receptors in the lens and retina in the late 1990s suggested that the hormone might act in the eye, and epidemiological studies reinforce this notion. After menopause, when estrogen concentrations sink, the incidence of cataracts in women overtakes that in men. Moreover, women taking tamoxifen, a strong estrogen inhibitor, are particularly prone to cataracts. Vicki Davis, an endocrinologist at Cedars-Sinai Medical Center in Los Angeles, was investigating the role of estrogen in bone when she glimpsed its effects on vision. Davis engineered two types of mice by adding mutant estrogen receptor genes and control switches designed to disrupt estrogen's function only in bone. The extra DNA landed in different spots in the two genomes. The control switch Davis employed--a shortened version of one that flicks on a bone-specific gene--misbehaved, and the mice produced the mutant estrogen receptor in many tissues, including the eye. When the females from one strain hit puberty and began producing estrogen, their eyes turned white, indicating that they had cataracts. Littermates without the mutant gene had clear eyes. Intrigued, Davis shifted her focus from bone to eye. Although females of the second strain and males of both strains didn't develop cataracts from naturally occurring estrogen, their eyes turned cloudy after treatment with a potent synthetic version of the hormone diethylstilbestrol (DES). Perhaps individuals of the first strain make more of the mutant receptor than those of the second strain do because the DNA snippet lies in a more active part of the genome, Davis speculates. This situation might explain why females in the second strain require a more robust hormone jolt to provoke cataract formation. Together, the results suggest that estrogen depletion usually encourages cataracts, Davis proposes--even though that model is counterintuitive at first glance. In the animals carrying the altered receptor, estrogen is used to block estrogen signaling, whereas under normal circumstances the hormone activates it. Estrogen receptors pair up when the hormone is present, and the receptor duo then binds to DNA, turning genes on and off. Davis suggests that the mutant receptor can hook up with another receptor, but the team cannot bind its DNA targets, some of which are required to keep the lens clear. Age-related drops in estrogen production also thwart receptor coupling and might have a similar effect. Earlier studies hinted that estrogen is important for lens clarity, says Deborah Carper, who studies mechanisms of cataract formation in the aging eye at the U.S. National Eye Institute in Bethesda, Maryland. But Davis's work provides evidence that blocking estrogen signaling in a live animal can cause cataracts, she says. Already known for its multiple roles, estrogen keeps dazzling onlookers with its versatility. --Bijal P. Trivedi V. L. Davis, C.-C. Chan, T. J. Schoen, J. F. Couse, G. J. Chader, K. S. Korach, An estrogen receptor repressor induces cataract formation in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. , 24 June 2002 [e-pub ahead of print]. [Abstract] [Full Text]

Lens changes in hereditary hyperferritinemia-cataract syndrome

PURPOSE: To provide detailed description and illustration of the lens changes found in hereditary hyperferritinemia-cataract syndrome, a newly reported autosomal dominant condition. METHODS: Observational case reports. A 19-year-old man was referred for evaluation of possible hereditary hyperferritinemia-cataract syndrome. His serum ferritin level was increased at 1291 μg/L during a routine screening examination. Genetic analysis revealed mutation G51C on chromosome 19, predicting an altered iron response element in L-ferritin mRNA. Subsequent evaluation of his 46-year-old father revealed similar findings. RESULTS: Multiple breadcrumb-like nuclear and cortical lens opacities were seen in this father-son pair. These cases represent the first detailed description and illustration of hereditary hyperferritinemia-cataract syndrome cataracts in the ophthalmic literature. CONCLUSION: Hereditary hyperferritinemia-cataract syndrome can be associated with distinct breadcrumb-like lens opacities. Recognition of these characteristic cataracts may aid identification and study of patients with this unusual disorder and provide insight into mechanisms of cataract formation.

A 76-bp Deletion in the Mip Gene Causes Autosomal Dominant Cataract in Hfi Mice

Hfi is a dominant cataract mutation where heterozygotes show hydropic lens fibers and homozygotes show total lens opacity. The Hfi locus was mapped to the distal part of mouse chromosome 10 close to the major intrinsic protein (Mip), which is expressed only in cell membranes of lens fibers. Molecular analysis of Mip revealed a 76-bp deletion that resulted in exon 2 skipping in Mip mRNA. In Hfi/Hfi this deletion resulted in a complete absence of the wildtype Mip. In contrast, Hfi/+ animals had the same amount of wildtype Mip as +/+. Results from pulse–chase expression studies excluded hetero-oligomerization of wildtype and mutant Mip as a possible mechanism for cataract formation in the Hfi/+. We propose that the cataract phenotype in the Hfi heterozygote mutant is due to a detrimental gain of function by the mutant Mip resulting in either cytotoxicity or disruption in processing of other proteins important for the lens. Cataract formation in the Hfi/Hfi mouse is probably a combined result of both the complete loss of wildtype Mip and a gain of function of the mutant Mip.