Early-onset Cataracts Research Articles

Having an eye for myotonic dystrophy: A qualitative study on experiences and support needs in myotonic dystrophy type 1 patients with a diagnostic delay after early-onset cataract

Myotonic dystrophy type 1 is a neuromuscular disorder affecting multiple organ systems and is characterized by a variety of clinical presentations. Anticipation leads to an earlier and more severe phenotype in subsequent generations. Early-onset cataract is a common initial manifestation of the late or adult-onset type of myotonic dystrophy 1. Due to its multicausal nature, early-onset cataract is often not recognized as a feature of this disease, leading to diagnostic delay resulting in consequences for successive generations, treatment and counseling. A qualitative study with semi-structured interviews was performed with purposive sampling of eight participants with myotonic dystrophy type 1 and early-onset cataract to investigate the physical and psychosocial consequences experienced due to diagnostic delay. Prior to the early-onset cataract, all participants experienced other multisystem symptoms that could have been explained by myotonic dystrophy. The diagnostic delay had severe hereditary consequences: a subsequent generation with more severely affected (grand)children was born resulting in large emotional burden for the patients. To conclude, early-onset cataract is a warning sign and ophthalmologists play a crucial role in the early detection of myotonic dystrophy type 1 by recognizing this symptom and preventing the birth of severely affected children leading to emotional and psychosocial consequences.

Potential Risks of Corneal Refractive Surgery in Patients with Ectodermal Dysplasia.

Ectodermal dysplasia (ED) involves the aberrant development of at least two ectodermal derivatives, such as skin, teeth, hair, sweat glands, and ocular tissue. The group of over 200 conditions is commonly classified into two major types: hypohidrotic/anhidrotic ED, in which sweat glands are either absent or significantly reduced, and hidrotic ED, in which sweat glands are normal. Ocular manifestations pertinent to patients undergoing corneal vision correction surgery include multifaceted dry eye syndrome, corneal pathology, such as recurrent erosions, scars, neovascularization, and limbal stem cell deficiency, and early-onset cataracts and glaucoma. In this article we discuss the current understanding of ED and offer factors to consider when these patients are seeking corneal refractive surgery.

Abstract #1178239: Osteoporosis in Stickler syndrome

Stickler syndrome (hereditary progressive arthro-ophthalmopathy), an autosomal dominant disorder is characterized by severe myopia, early onset cataracts, glaucoma, retinal detachments, overly flexible joints, kyphosis, scoliosis, platyspondyly, precocious osteoarthritis, cleft palate, micrognathia, and hearing loss. First described in 1965, it is the most common cause of juvenile retinal detachment. Literature regarding osteoporosis in Stickler syndrome is sparse. We describe a case of Stickler syndrome presenting with multiple fractures.

Risk Factor Analysis of Early-Onset Cataracts in Taiwan.

Purpose: According to previous studies, the prevalence rate of cataracts has increased in recent years. This study aims to investigate and analyze the risk factors of early-onset cataracts in Taiwan. Methods: A total of 71 subjects aged between 20 and 55 were diagnosed with cataracts in a medical center. Participants were divided into three groups: control, early-onset cataract (EOC), and combined (EOC combined with dry eye) groups. Eye examinations including autorefraction, best-corrected visual acuity (BCVA), subjective refraction, axial length, fundus, slit lamp, and reactive oxygen species (ROS, including total antioxidative capacity, TAC; C-reactive protein, CRP; and glutathione peroxidase, GPx) were performed. In addition, a questionnaire on patient information, history, habits, family history, and Depression Anxiety Stress Scales (DASS) was completed before the examination. Results: 27 non-EOC (control group), 20 EOC, and 24 combined patients participated in the study. Compared with the control group, Body Mass Index (BMI), gender, educational level, hypertension, diabetes, hyperlipidemia, chronic pain, and body-related diseases were significantly different between the three groups. Family history was also significantly different: family heart disease, hypertension, asthma, allergies, stroke, and immune system were also significantly different. In addition, subjects who took hypertensive drugs, antihistamines, and other medications were also significantly different. Statistical analysis indicated that best corrective visual acuity and the spherical equivalent were significantly different between the three groups. Similar results were found in CRP blood analysis. Discussion and Conclusion: According to the results, EOC may result from systemic diseases. The risk corresponded to an increase in ROS blood analysis. Furthermore, eye drops and medicine intake significantly influenced EOC patients. To prevent or defer early-onset cataracts, monitoring physical health, CRP, and GPx analysis may be worth considering in the future.

Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2

Palmoplantar keratoderma-congenital alopecia syndrome type 2 is an autosomal recessive disorder with an unknown genetic basis. In this study, we identified biallelic variants in the LSS gene in two unrelated palmoplantar keratoderma-congenital alopecia syndrome type 2 cases (c.3G>A, p.Met1? and c.1025T>G, p.Ile342Ser in patient 1; c.1522G>T, p.Gly508Trp and c.428+42T>A in patient 2) presenting with additional clinical features, including early-onset cataracts, pseudoainhum, and agenesis of the corpus callosum. LSS encodes lanosterol synthase (LSS), which functions in the cholesterol biosynthesis pathway by converting (S)-2,3-oxidosqualene to lanosterol. The c.3G>A variant resulted in an alternative translation initiation at residue Met81, producing an N-terminal truncated protein (LSS-ΔN80), as shown by immunoblotting. The c.428+42T>A variant introduced a potential splicing site, leading to a premature stop codon. Exvivo studies revealed downregulation of LSS in both patients. Remarkably decreased lanosterol levels were found invitro in three LSS variants, LSS-ΔN80, p.Ile342Ser, and p.Gly508Trp, suggesting a loss of enzymatic activity. Transmission electron microscopy and immunofluorescence showed abnormal cornified envelope formation in the stratum corneum of the patients. Taken together, our findings indicate LSS as a causative gene for palmoplantar keratoderma-congenital alopecia syndrome type 2, which emphasizes the importance of the cholesterol synthesis pathway in human skin cornification.

OP005: AT-007 significantly reduces toxic galactitol in ACTION-galactosemia kids - the 1st therapeutic interventional clinical trial in children with classic galactosemia

Classic Galactosemia (CG) is a rare, autosomal recessive disease where galactose is not metabolized properly due to severe deficiency or absence of the GALT enzyme (galactose-1-phosphate uridyl transferase). At abnormally high levels, galactose becomes an aberrant substrate for the enzyme aldose reductase, resulting in conversion to an abnormal and toxic metabolite, galactitol. Newborn screening and implementation of a galactose-restricted diet has reduced newborn acute symptoms and significantly decreased fatalities. However, despite early dietary intervention, children continue to develop significant morbidities in speech, cognition, behavior, and motor function, which have been shown to progressively worsen with age, as well as cataracts and primary ovarian insufficiency in females. AT-007 is an oral CNS penetrant aldose reductase inhibitor, which prevents conversion of galactose to toxic galactitol, that is in development for the treatment of CG. Reduction in circulating galactitol by AT-007 has been shown to halt the progression of disease in a rat model of Galactosemia. ACTION-Galactosemia Kids is a sequential, two-part, randomized double-blind, placebo-controlled study evaluating the clinical benefit, safety, pharmacokinetics and pharmacodynamics of AT-007 in pediatric patients with CG. Patients were randomized 2:1 to AT-007 or placebo. Disease demographics, genetic variant, and patient history were assessed at baseline. Additionally, functional tests of speech, motor function, cognition and behavior were performed at baseline for all patients enrolled in the clinical study. The primary biomarker study endpoint was reduction in plasma galactitol over a minimum of 30 days of treatment with the target dose of AT-007 vs placebo. Baseline and 30-day plasma galactitol levels were drawn under fasted conditions and evaluated via a validated liquid chromatography-mass spectrometry assay. Baseline galactitol correlation with disease severity was evaluated via a linear model incorporating baseline speech, cognition, behavior and motor skills assessments. Forty-seven patients ranging in age from 2 to 17, were enrolled at 3 US clinical sites in ACTION-Galactosemia Kids across three predefined age groups (2-6 years old; 7-12 years old; 13-17 years old). The patients were predominantly White (98%), had a mean age of 9 and 51% were female/49% male. The most common baseline disease characteristics included learning disorders (∼50%), apraxia (∼40%), anxiety (∼35%), vitamin deficiency (∼30%), tremor (∼20%) and ataxia (∼20%). All the female patients older than 12 had primary ovarian insufficiency. Additionally, ∼10% of the patients suffered from seizures and ∼5% had early onset cataracts. Baseline disease and demographic characteristics were balanced across the placebo and AT-007 treatment groups. Galactitol levels at baseline correlated with total disease severity in this pediatric patient population (p=0.004). Treatment with AT-007 resulted in a 40.2% reduction in galactitol, which was significant when compared with patients on placebo (p<0.001). The reduction in toxic galactitol was consistent among age and dose groups and was not associated with changes in galactose or galacose-1-phosphate (Gal-1p). AT-007 was safe and well tolerated. The biomarker results from ACTION-Galactosemia Kids demonstrates that treatment with AT-007 resulted in a significant reduction of the toxic metabolite galactitol, a biomarker that correlated with disease severity, in pediatric patients with Classic Galactosemia. Treatment of pediatric Galactosemia patients age 2 to 17 with AT-007 was safe and well tolerated.

Retrospective Analysis of Cataract Formation and Nutritional Etiology in a Managed Collection of Parakeet Auklets (Aethia psittacula).

The parakeet auklet (Aethia psittacula) is a piscivorous seabird with a natural diet of various invertebrate and teleost species, which is challenging to replicate in a managed collection. A high prevalence of early onset cataracts was observed in a managed collection of parakeet auklets at the North Carolina Zoo (Asheboro, NC, USA), which was hypothesized to be related to inappropriate vitamin A and E levels. From 1994 to 2002, these parakeet auklets were offered dietary supplementation comprising Vita-Zu small bird tablets. In June 2002, the birds were transitioned to only Thiamin-E paste (vitamin E and thiamin only). Plasma samples were collected from birds with and without cataracts from 1998 to 2005 and submitted for vitamin A (retinol) and vitamin E (α-tocopherol) analysis. Food items comprising the birds' diet were also evaluated for vitamin content. This information was combined with clinical and necropsy data from medical records from 1994 to 2015. A total of 78% of birds (39/50) developed cataracts, with a median age of onset of 7 years (range, 2-12 years). Cataracts ranged from incipient to hypermature during both routine ophthalmic examinations and postmortem evaluations. The median (range) of plasma retinol and α-tocopherol values were 1.99 µg/mL (0.20-6.68 µg/mL) and 15.39 µg/mL (3.40-96.27 µg/mL), respectively. There were no significant differences in plasma concentrations of vitamins based on the animals' sex, origin, presence of cataracts, or administered vitamin supplementation product. No other etiologies for cataract development were identified in the population. Further research in free-ranging parakeet auklet nutrition and cataract occurrence is warranted for continued species collection management.

Gender effect on onset, prevalence and surgical treatment of cataract in patients with Myotonic Dystrophy type 1.

Myotonic Dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, affecting 1:8000 individuals. It is a multi-systemic disorder involving muscle, heart, endocrine and respiratory apparatus and eye. The eye symptoms can include ptosis, external ophthalmoplegia, epiphora, and early onset cataracts. Cataracts occur at a much earlier age (usually between 30 and 40) than the general population, where females are usually affected more than men. We studied gender differences in cataract prevalence and treatment age in 243 DM1 patients (134 M; 109 F), aged 18 to 70 years, who were subsequently screened at routine follow-up. For each patient, information was collected on age, sex, CTG expansion, age of cataract onset, and age at cataract surgery, when available. Seventy-three patients, 30 females and 43 males, had cataracts, at a mean age of onset of 41.14 ± 12.64 in females, and 40.36 ± 10.03 in males. Sixty-nine of them underwent cataract surgery, males at an earlier age than females (42.8 ± 9.8 years versus 47.3 ± 12.6 years) and in 52.5% of cases before the age of 40, compared to 17.2% of females. The difference was statistically significant. The assumption that females in general and those with DM1 in particular develop cataracts more frequently and earlier than males is not confirmed, at least in this study. A possible explanation for these results could be related to non-advanced age, the protective role of estrogen and the lower prevalence of smoking in the study population.

Rodzinne występowanie zespołu Marinesco – Sjögrena (opis przypadku występowania rzadkiego zespołu u rodzeństwa)

Marinesco-Sjögren syndrome (MSS) is a rare malformation syndrome inherited in an autosomal recessive manner. The most typical features are cerebellar ataxia with cerebellar atrophy, dysarthria, nystagmus, early-onset cataract, myopathy, hypotonia and muscle weakness. Additional symptoms often include psychomotor delay, hypergonadotropic hypogonadism and short stature. We present a case of a 6-year-old boy admitted to the Department due to psychomotor developmental retardation for completion of further diagnostics. Initial diagnostics led to a preliminary diagnosis of Marinesco-Sjögren syndrome, ultimately confirmed by genetic testing. When the patient’s younger brother was born, he presented with similar symptoms. Knowledge of his older sibling’s diagnosis aided in immediately using single- -gene testing to confirm the presence of two mutated copies of the SIL1 gene. This finding allowed to establish a proper diagnosis in the younger brother, leading to immediate multi-specialist intervention.

PI(3,4)P2-mediated cytokinetic abscission prevents early senescence and cataract formation.

Cytokinetic membrane abscission is a spatially and temporally regulated process that requires ESCRT (endosomal sorting complexes required for transport)–dependent control of membrane remodeling at the midbody, a subcellular organelle that defines the cleavage site. Alteration of ESCRT function can lead to cataract, but the underlying mechanism and its relation to cytokinesis are unclear. We found a lens-specific cytokinetic process that required PI3K-C2α (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2α), its lipid product PI(3,4)P2 (phosphatidylinositol 3,4-bisphosphate), and the PI(3,4)P2–binding ESCRT-II subunit VPS36 (vacuolar protein-sorting-associated protein 36). Loss of each of these components led to impaired cytokinesis, triggering premature senescence in the lens of fish, mice, and humans. Thus, an evolutionarily conserved pathway underlies the cell type–specific control of cytokinesis that helps to prevent early onset cataract by protecting from senescence.

Body mass index is not associated with early onset cataract in the 45 and Up cohort study.

BackgroundBody mass index (BMI) has been reported to be associated with age-related cataract, whereas its impact on early onset cataract (EOC) remains unknown.MethodsA total of 73,007 individuals aged 45–55 years who had no previous cataract surgeries at baseline were enrolled from the population-based 45 and Up Study. BMI was calculated based on self-reported height and weight from the baseline questionnaire. Data on cataract surgeries were obtained from the Medicare Benefits Schedule database. EOC was defined as cataract surgically treated prior to 65 years of age. A Cox proportional hazards regression was used to assess the association between BMI and the incidence of EOC during the follow-up.ResultsA total of 1,764 participants underwent cataract surgery over 643,717 person-years of follow-up. No significant association was observed between BMI and EOC (P for trend 0.35). Among participants who drank 5 to 7 alcoholic drinks per week, a 73% and 27% reduction in the risk of EOC was observed in participants with a BMI of 18.5–19.99 and 25.0–27.49 kg/m2, respectively, compared to those with a BMI of 20.0–22.49 kg/m2.ConclusionsNo association was identified between BMI and the incidence of EOC. Moderate alcohol intake may be protective against EOC.

Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract.

Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous. We investigated HCC that segregates in three inbred families (LUCC03, LUCC16, and LUCC24). Ophthalmological examinations revealed cataracts with variability related to the age of onset segregating in a recessive manner in these families. Exome sequencing of probands identified a novel homozygous c.2710delG;p.(Val904Cysfs*36) EPHA2 variant in LUCC03 and a known homozygous c.2353G>A;p.(Ala785Thr) EPHA2 variant in the other two recessive families. EPHA2 encodes a transmembrane tyrosine kinase receptor, which is primarily involved in membrane-transport, cell-cell adhesion, and repulsion signaling processes. Computational structural modeling predicts that substitution of a threonine for an alanine p.(Ala785Thr) results in the formation of three new hydrogen bonds with the neighboring residues, which causes misfolding of EPHA2 in both scenarios. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of EPHA2-related HCC.

The Phenotypic Spectrum of Patients with PHARC Syndrome Due to Variants in ABHD12: An Ophthalmic Perspective.

This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0; range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9; range from 0.1 to 2.8; equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity.

Findings from the 45 and Up Study: smoking is not associated with the risk of early-onset cataract.

BackgroundTo determine if tobacco smoking is a risk factor for early-onset cataracts.MethodsThis was a prospective population-based cohort study. A total of 70,886 participants aged 45–55 years in the 45 and Up Study were included in our analysis. Early-onset cataracts (EOC) were defined as cataract surgeries performed before 65 years old, based on participant data linked to the Medicare Benefits Schedule (MBS). Smoking habits were assessed at baseline, based on a self-administered questionnaire. A Cox proportional hazards model was used to evaluate the association between tobacco smoking and the risk of early-onset cataracts over the follow-up period.ResultsAt baseline recruitment, 59.9% of study participants never smoked, 30.5% were former smokers, and 9.6% were current smokers. A total of 1,713 participants underwent cataract surgery over a mean follow-up of 625,042 person-years, with an incidence of 2.74 cases per 1,000 person-years. For current smokers, patients with EOC had longer smoking durations (P=0.019). For former smokers, patients with EOC had higher smoking intensities (P=0.001), were older at smoking commencement (P=0.011), and longer times since quitting (P=0.04). The risk of EOC was not found to be significantly different between current smokers or former smokers, compared to those who had never smoked. Both stratification and sensitivity analyses by gender, surgery year, alcohol intake, physical activity, and income yielded similar results.ConclusionsSmoking has neither a beneficial nor harmful effect on the long-term incidence of EOC.

Effect of hydrophilic and lipophilic statins on early onset cataract: A nationwide case-control study

BackgroundStatin is biologically plausible in cataract development, but inconclusive associations between statin and cataract are presented in human studies. Given most early onset cataract (EOC) occurs in regions with high cholesterol composition, we therefore aimed to assess the association between statin and EOC. MethodsA population based case-control study was performed using the Taiwan National Health Insurance Research Database (NHIRD). The case involved patients aged 20–55 years with EOC. Controls were 1:1 matched by age, gender, year of index date, and propensity score estimated from comorbidities and comedications. Statin exposure, including intensity, properties and cumulative exposure one year before the index date were tracked. The odds ratios (ORs) of EOC associated with statin were estimated by conditional logistic regression. ResultsA total of 4213 cases and 4213 controls were included. Statins were associated with EOC (OR = 3.257, 95% CI 2.519–4.211). The ORs of cataract was positively associated with cumulative exposure. Subgroup analysis indicated that the ORs of cataract were significant both in lipophilic (OR = 3.485, 95% CI 2.606–4.659) and hydrophilic (OR = 3.241, 95% CI 1.975–5.321) statin users. ConclusionsStatins were associated with an increased risk of cataract in young populations.

Novel Ocular Features in a Child with Marinesco-Sj\xf6gren Syndrome: Case Report and Literature Review

To report novel ocular findings in unique Marinesco-Sjögren syndrome (early-onset cataracts, cerebellar ataxia, and a progressive myopathy), review literature, and discuss causes of vision decrease in this rare entity. A 3-year-old girl diagnosed with Marinesco-Sjögren syndrome underwent uneventful cataract surgery in both eyes within 1 week of her 2nd birthday. This was exactly similar to her sister and other two related family members. Additionally, she had prominent corneal nerves and subtle corneal subepithelial deposits in both eyes. Cataracts are one of the primary diagnostic criteria for the Marinesco-Sjögren syndrome, and their early diagnosis and treatment are important for prevention of additional permanent visual loss. Prominent corneal nerves and mild corneal subepithelial defects are described in this report and may occasionally be helpful in making the diagnosis.

Genome-Wide Analysis of Differentially Expressed miRNAs and Their Associated Regulatory Networks in Lenses Deficient for the Congenital Cataract-Linked Tudor Domain Containing Protein TDRD7.

Mutations/deficiency of TDRD7, encoding a tudor domain protein involved in post-transcriptional gene expression control, causes early onset cataract in humans. While Tdrd7 is implicated in the control of key lens mRNAs, the impact of Tdrd7 deficiency on microRNAs (miRNAs) and how this contributes to transcriptome misexpression and to cataracts, is undefined. We address this critical knowledge-gap by investigating Tdrd7-targeted knockout (Tdrd7-/-) mice that exhibit fully penetrant juvenile cataracts. We performed Affymetrix miRNA 3.0 microarray analysis on Tdrd7-/- mouse lenses at postnatal day (P) 4, a stage preceding cataract formation. This analysis identifies 22 miRNAs [14 over-expressed (miR-15a, miR-19a, miR-138, miR-328, miR-339, miR-345, miR-378b, miR-384, miR-467a, miR-1224, miR-1935, miR-1946a, miR-3102, miR-3107), 8 reduced (let-7b, miR-34c, miR-298, miR-382, miR-409, miR-1198, miR-1947, miR-3092)] to be significantly misexpressed (fold-change ≥ ± 1.2, p-value < 0.05) in Tdrd7-/- lenses. To understand how these misexpressed miRNAs impact Tdrd7-/- cataract, we predicted their mRNA targets and examined their misexpression upon Tdrd7-deficiency by performing comparative transcriptomics analysis on P4 and P30 Tdrd7-/- lens. To prioritize these target mRNAs, we used various stringency filters (e.g., fold-change in Tdrd7-/- lens, iSyTE-based lens-enriched expression) and identified 98 reduced and 89 elevated mRNA targets for overexpressed and reduced miRNAs, respectively, which were classified as “top-priority” “high-priority,” and “promising” candidates. For Tdrd7-/- lens overexpressed miRNAs, this approach identified 18 top-priority reduced target mRNAs: Alad, Ankrd46, Ceacam10, Dgat2, Ednrb, H2-Eb1, Klhl22, Lin7a, Loxl1, Lpin1, Npc1, Olfm1, Ppm1e, Ppp1r1a, Rgs8, Shisa4, Snx22 and Wnk2. Majority of these targets were also altered in other gene-specific perturbation mouse models (e.g., Brg1, E2f1/E2f2/E2f3, Foxe3, Hsf4, Klf4, Mafg/Mafk, Notch) of lens defects/cataract, suggesting their importance to lens biology. Gene ontology (GO) provided further insight into their relevance to lens pathology. For example, the Tdrd7-deficient lens capsule defect may be explained by reduced mRNA targets (e.g., Col4a3, Loxl1, Timp2, Timp3) associated with “basement membrane”. GO analysis also identified new genes (e.g., Casz1, Rasgrp1) recently linked to lens biology/pathology. Together, these analyses define a new Tdrd7-downstream miRNA-mRNA network, in turn, uncovering several new mRNA targets and their associated pathways relevant to lens biology and offering molecular insights into the pathology of congenital cataract.

Mutation of the TRPM3 cation channel underlies progressive cataract development and lens calcification associated with pro-fibrotic and immune cell responses.

Transient-receptor-potential cation channel, subfamily M, member 3 (TRPM3) serves as a polymodal calcium sensor in diverse mammalian cell-types. Mutation of the human TRPM3 gene (TRPM3) has been linked with inherited forms of early-onset cataract with or without other eye abnormalities. Here, we have characterized the ocular phenotypes of germline "knock-in" mice that harbor a human cataract-associated isoleucine-to-methionine mutation (p.I65M) in TRPM3 (Trpm3-mutant) compared with germline "knock-out" mice that functionally lack TRPM3 (Trpm3-null). Despite strong expression of Trpm3 in lens epithelial cells, neither heterozygous (Trpm3+/- ) nor homozygous (Trpm3-/- ) Trpm3-null mice developed cataract; however, the latter exhibited a mild impairment of lens growth. In contrast, homozygous Trpm3-M/M mutants developed severe, progressive, anterior pyramid-like cataract with microphthalmia, whereas heterozygous Trpm3-I/M and hemizygous Trpm3-M/- mutants developed anterior pyramidal cataract with delayed onset and progression-consistent with a semi-dominant lens phenotype. Histochemical staining revealed abnormal accumulation of calcium phosphate-like deposits and collagen fibrils in Trpm3-mutant lenses and immunoblotting detected increased αII-spectrin cleavage products consistent with calpain hyper-activation. Immunofluorescent confocal microscopy of Trpm3-M/M mutant lenses revealed fiber cell membrane degeneration that was accompanied by accumulation of alpha-smooth muscle actin positive (α-SMA+ve) myofibroblast-like cells and macrosialin positive (CD68+ve) macrophage-like cells. Collectively, our mouse model data support an ocular disease association for TRPM3 in humans and suggest that (1) Trpm3 deficiency impaired lens growth but not lens transparency and (2) Trpm3 dysfunction resulted in progressive lens degeneration and calcification coupled with pro-fibrotic (α-SMA+ve) and immune (CD68+ve) cell responses.

Imbalances in the eye lens proteome are linked to cataract formation.

The prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The α-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in α-, β-, or γ-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the α-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins.

Cataract formation in transgenic HO-1 G143H mutant mice: Involvement of oxidative stress and endoplasmic reticulum stress

Oxidative stress and endoplasmic reticulum (ER) stress are the key contributing factors for cataract progression. In our previous studies, we demonstrated that the nuclear factor erythroid 2-like-2 (Nrf-2)/heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis protects lens epithelial cells (LECs) against oxidants and ER stress. In the present study, transgenic FVB/N mice overexpressing the negative dominant mutant HO-1 G143H (TgHO-1 G143H) were generated to evaluate the crosstalk among HO-1, oxidative stress and ER stress in maintaining lens transparency. Slit-lamp examination revealed that nuclear cataracts occurred at 4 months in the TgHO-1 G143H mice, which was 5 months earlier than that of the control mice. The lenses of the transgenic mice showed an accumulation of malondialdehyde and protein carbonyl with a decrease in glutathione and protein sulfhydryl levels. Elevated concentrations of ER stress biomarkers (Bip, PERK, ATF6, IRE1, CHOP, caspase-12 and caspase-3) in the lenses of the TgHO-1 G143H mice were identified by western blotting. Furthermore, we confirmed that overexpressed HO-1 G143H in LECs resulted in oxidative insult and apoptosis in vitro. All of these data suggested that HO-1 enzymatic activity loss induces early-onset nuclear cataracts by activating oxidative stress and ER stress.