Functional analysis of large MAF transcription factors and elucidation of their relationships with human diseases.

The large MAF transcription factor group is a group of transcription factors with an acidic region, a basic region, and a leucine zipper region. Four types of MAF, MAFA, MAFB, c-MAF, and NRL, have been identified in humans and mice. In order to elucidate the functions of the large MAF transcription factor group in vivo, our research group created genetically modified MAFA-, MAFB-, and c-MAF-deficient mice and analyzed their phenotypes. MAFA is expressed in pancreatic ß cells and is essential for insulin transcription and secretion. MAFB is essential for the development of pancreatic endocrine cells, formation of inner ears, podocyte function in the kidneys, and functional differentiation of macrophages. c-MAF is essential for lens formation and osteoblast differentiation. Furthermore, a single-base mutation in genes encoding the large MAF transcription factor group causes congenital renal disease, eye disease, bone disease, diabetes, and tumors in humans. This review describes the functions of large MAF transcription factors in vivo and their relationships with human diseases.

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders.

Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and transcriptomic datasets to gain insights into variable penetrance in IED. Variants in a curated set of 340 IED-implicated genes were extracted from the Human Gene Mutation Database (HGMD) 2019.1 and cross-checked with the Genome Aggregation Database (gnomAD) 2.1 control-only dataset. Genes for which >1 variants were encountered in both HGMD and gnomAD were considered to be associated with variable penetrance (n = 56). Variability in gene expression levels was then estimated for the subset of these genes that was found to be adequately expressed in two relevant resources: the Genotype-Tissue Expression (GTEx) and Eye Genotype Expression (EyeGEx) datasets. We found that genes suspected to be associated with variable penetrance tended to have significantly more variability in gene expression levels in the general population (p = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of cis and/or trans-acting elements on the expressivity of variants causing Mendelian disorders. They also highlight the potential utility of quantifying gene expression as part of the investigation of families showing evidence of variable penetrance.

Up-Regulation of SorCS1, an Important Sorting Receptor, in the Retina of a Form-Deprivation Rat Model.

Visually guided regulation is a sophisticated and active process, whereby sensory input helps to shape ocular development. Here, we sought to investigate the potential involvement of SorCS1, an important protein in synaptic transmission in neuron, in retinal development. A form-deprivation (FD) rat model was established. Ocular variations induced by FD were examined, including changes to eye axial length and retinal thickness. Scotopic electroretinogram (ERG) was used to examine retinal function. RD-PCR assays were screened for differentially expressed genes in FD rat eyes. Immunofluorescence staining identified the expression pattern and localization of SorCS1 in rat retina, with or without FD treatment. Additionally, primary retinal neural cells were cultured and incubated with or without a light-dark cycle, and western blot and real-time PCR assays were used to examine the expression of SorCS1. Retinal neural cells were treated with recombinant SorCS1 (h-SorCS1) coated with beads in serum-free conditions to test for effects on cellular physiology and expression of neurotransmitters involved in visual development. To monitor cell viability, a CCK8 assay was employed. Our data demonstrated that FD led to ocular axial elongation and retinal thinning. ERG tests showed FD impaired electrophysiological function in rat. An age-related expression pattern of SorCS1 was observed in the rat retina, and SorCS1 was significantly up-regulated in the FD rat retina. In addition, in vitro evidence suggested a strong correlation between light exposure and SorCS1 expression. Furthermore, treatment of retinal neural cells with h-SorCS1-beads promoted cell viability, neurite outgrowth, and up-regulation of inhibitory neurotransmitter expression, which implies that over-expression of SorCS1 may cause abnormal retinal development. Our findings suggest that SorCS1 is involved in the physiological processes of light/visually guided ocular growth.

Clinicopathologic Features and Treatment Characteristics of Congenital Corneal Opacity Infants and Children Aged 3 Years or Less: A Retrospective Single Institution Analysis.

OBJECTIVE: In this retrospective single institution study, we investigated the clinicopathologic features and treatment characteristics of 90 patients with congenital corneal opacities (CCO) (117 eyes) who were 3 years and younger and treated at our hospital. SUBJECT AND METHODS: We reviewed the clinical data of patients with CCO who presented for the first time for treatment at our hospital between January 1, 2017, and December 31, 2017. CCO were classified using the "STUMPED" (Sclerocornea, Tears in Descement's membrane, Metabolic, Peters, Endothelial dystrophy and Dermoid) method and confirmed by pathological examination. -Results: Seventy percent of the patients had unilateral CCO. Iridocorneal adhesions (61 eyes, 52.1%) and cataracts (22 eyes, 18.8%) were the 2 most common ocular abnormalities. Systemic abnormalities were present in 5 patients (5.6%), including growth retardation (4 patients) and congenital brain defects (1 patient). Eighty-five eyes (72.6%) underwent penetrating keratoplasty (PK), and lamellar keratoplasty (LK) was performed in 30 (25.6%) eyes. Forty-seven (95.9%) eyes with Peters anomaly and all 16 eyes with sclerocornea received PK, and all 24 eyes with dermoids were treated with LK. CONCLUSION: Our study demonstrates that CCO has varied manifestations in infants and young children in China. A thorough medical history, careful clinical examination, and the use of accessory examinations such as ultrasound biomicroscopy are critical for the accurate diagnosis and classification of CCO and to provide guidance on therapeutic choices.

Reliability of objective ocular torsion assessment using fundus photography in infantile esotropia.

PURPOSE: To evaluate the interobserver reproducibility of objective ocular torsion measurements in infantile esotropia using fundus photography analysis. MATERIALS AND METHODS: This retrospective observational study was conducted in our ophthalmology department at the University Hospital in Tours from 2009 to 2015. OBJECTIVE: Ocular torsion was assessed using fundus photography and analysed on Adobe Photoshop software within a population of children with infantile esotropia. Two observers, an orthoptist and an ophthalmologist, carried out the evaluation separately. The interobserver agreement was calculated for quantitative measurement by the interclass correlation coefficient (ICC) and by Cohen's Kappa coefficient for qualitative assessment. RESULTS: A total of 200 eyes (100 subjects, mean age: 6.88 years) were assessed. Statistical analyses for quantitative measurements resulted in an ICC of 0.98 (95% CI, 0.97-0.99) for right eyes, 0.96 (95% CI, 0.95-0.97) for left eyes, 0.98 (CI 95%, 0.97-0.98) for pre- operative eyes and 0.96 (95% CI, 0.95-0.97) for postoperative eyes. The ICC calculated on all four hundred fundus photographs was 0.97 (95% CI, 0.97-0.98). The interobserver agreement for qualitative measurements resulted in a Kappa coefficient of 0.91 for right eyes, 0.85 for left eyes, 0.90 for preoperative eyes and 0.86 for postoperative eyes. The analysis of all four hundred eyes returned a Kappa coefficient of 0.88. CONCLUSIONS: Objective ocular torsion assessment using our procedure, whether by an orthoptist or ophthalmologist, is a reliable and reproducible method for the management of infantile esotropia.

Associations between red reflex abnormality, consanguinity and intensive care hospitalization of newborns in Turkey.

BACKGROUND: Red reflex screening is the primary but unheeded test for the detection of vision- and life-threatening eye conditions. AIMS: To evaluate the red reflex of newborns, percentage of ocular diseases resulting in red reflex abnormality, and their relation with consanguinity in Southeast Turkey. METHODS: Newborns (n = 1358) were examined with pencil light and direct ophthalmoscopy. RESULTS: Eight hundred of these newborns were hospitalized in a rooming-in unit. (RIU) and 558 were in the neonatal intensive care service (NICS). In the RIU there were 7 (0.88%) newborns with abnormal red reflex and in the NICS there were 14 (2.51%). Sensitivity of pencil light examination was 71.4%. Studies from the Middle East have shown potential recessive genetic causes of common paediatric ocular conditions. In our study, consanguineous marriage was found to have a significant association with red reflex abnormality (P = 0.017). CONCLUSIONS: Red reflex screening test is important in the early diagnosis of vision- and life-threatening eye disorders in Southeast Turkey where consanguinity is common.

Zika virus exposure in pregnancy and its association with newborn visual anomalies and hearing loss.

Exposure to Zika virus (ZIKV) in pregnancy leads to a spectrum of congenital effects in the newborn. Recent studies have begun to evaluate the impact of ZIKV during pregnancy. Among 39 relevant studies, nine were related specifically to clinical studies of ophthalmologic disorders and one was related to hearing loss impairment; most of these studies were case reports and case series reports. Importantly, congenital toxoplasmosis was ruled out in all studies. The data show that, in addition to microcephaly, ZIKV exposure in pregnancy may result in subtle ocular impairments in the newborn. The most common anomalies are macular pigment mottling and/or chorioretinal atrophy, and optic nerve disorders. Sensorineural hearing loss has also been noted in 5.8% of infants with microcephaly. The effects of ZIKV infection during pregnancy are potentially devastating to the fetus and newborn. Although microcephaly is an important signal, the current information emphasizes the importance of ocular and auditory screenings, otherwise sight and hearing anomalies may be underestimated. Healthcare providers should fully understand the spectrum of anomalies related to ZIKV exposure in pregnancy in order to counsel pregnant women living in high-risk areas, in addition to those wanting to become pregnant.

Maternal Inheritance of a Recessive RBP4 Defect in Canine Congenital Eye Disease.

Maternally skewed transmission of traits has been associated with genomic imprinting and oocyte-derived mRNA. We report canine congenital eye malformations, caused by an amino acid deletion (K12del) near the N terminus of retinol-binding protein (RBP4). The disease is only expressed when both dam and offspring are deletion homozygotes. RBP carries vitamin A (retinol) from hepatic stores to peripheral tissues, including the placenta and developing eye, where it is required to synthesize retinoic acid. Gestational vitamin A deficiency is a known risk factor for ocular birth defects. The K12del mutation disrupts RBP folding in vivo, decreasing its secretion from hepatocytes to serum. The maternal penetrance effect arises from an impairment in the sequential transfer of retinol across the placenta, via RBP encoded by maternal and fetal genomes. Our results demonstrate a mode of recessive maternal inheritance, with a physiological basis, and they extend previous observations on dominant-negative RBP4 alleles in humans.

An overlap case of Parry-Romberg syndrome and en coup de sabre with striking ocular involvement and anti-double-stranded DNA positivity.

Parry-Romberg syndrome (PRS) may overlap localized scleroderma (morphea) lesions with linear depression (en coup de sabre [ECDS]). Overlap case with PRS and ECDS was presented. Enophthalmos, uveitis, ocular torticollis, keratic linear precipitates, and anti-double-stranded DNA positivity were identified. Subendothelial keratic precipitates detected by an in vivo laser scanning confocal microscopy were the first profiled in the literature. Patients must be evaluated and followed up carefully by their clinics to prevent misdiagnosis and unnecessary procedures such as surgery of ocular torticollis as muscular torticollis.

[Ultrasound Manifestations of Eyes of Pediatric Patients with Morning Glory Syndrome].

OBJECTIVE: To analyze ultrasonic manifestations of eyes of pediatric patients with morning glory syndrome (MGS). METHODS: Clinical data and ultrasound (US) findings for six children (4 males and 2 females, 5-60 months old) diagnosed with MGS between 2005 and 2016 were reviewed. RESULTS: Of the 12 eyes, seven were diagnosed with MGS; one with cataract; the other four were normal. One child had both eyes diagnosed with MGS. Of the seven eyes with MGS (5 right, 2 left), one was small associated with persistent hyperplastic primary vitreous (PHPV); 2 had retinal detachment. Findings of high frequency ultrasound included local anechoic lesions with distinct boundary showing a convert bottle-neck shape that appeared in the area of optic disk of posterior pole. The lesions communicated with the vitreous caicy and extended to the optic nerves. The lesions had a maximum depth of 4-15 mm [(8.29±4.42) mm] and a maximum width of 4-11 mm [(6.86±2.67) mm]. Hypoecho material was found in the bottom of five of the seven lesions. The distance between the end of the optic nerves and the bottom of the lesions ranged from 0 to 4.5 mm. Lower levels (Adler 0-1 grade) of blood flow in the bottom of the lesions were found compared with those (3-5 grade) in the rim of the lesions. CONCLUSION: MGS is rare and usual occurs in young children, especially infants. It is often associated with various eye complications. The ultrasound manifestations of MGS are characterized with a local anechoic lesion mimicking a convert bottle-neck shape in the area of optic disk of posterior pole.

The refractive state of the eye in Icelandic horses with the Silver mutation.

BACKGROUND: The syndrome Multiple Congenital Ocular Anomalies (MCOA) is a congenital eye disorder in horses. Both the MCOA syndrome and the Silver coat colour in horses are caused by the same missense mutation in the premelanosome protein (PMEL) gene. Horses homozygous for the Silver mutation (TT) are affected by multiple ocular defects causing visual impairment or blindness. Horses heterozygous for the Silver mutation (CT) have less severe clinical signs, usually cysts arising from the ciliary body iris or retina temporally. It is still unknown if the vision is impaired in horses heterozygous for the Silver mutation. A recent study reported that Comtois horses carrying the Silver mutation had significantly deeper anterior chambers of the eye compared to wild-type horses. This could potentially cause refractive errors. The purpose of the present study was to investigate if Icelandic horses with the Silver mutation have refractive errors compared to wild-type horses. One hundred and fifty-two Icelandic horses were included in the study, 71 CT horses and five TT horses. All horses were genotyped for the missense mutation in PMEL. Each CT and TT horse was matched by a wild-type (CC) horse of the same age ± 1 year. Skiascopy and a brief ophthalmic examination were performed in all horses. Association between refraction and age, eye, genotype and sex was tested by linear mixed-effect model analysis. TT horses with controls were not included in the statistical analyses as they were too few. RESULTS: The interaction between age and genotype had a significant impact on the refractive state (P = 0.0001). CT horses older than 16 years were on average more myopic than wild-type horses of the same age. No difference in the refractive state could be observed between genotypes (CT and CC) in horses younger than 16 years. TT horses were myopic (-2 D or more) in one or both eyes regardless of age. CONCLUSION: Our results indicate that an elderly Icelandic horse (older than 16 years) carrying the Silver mutation is more likely to be myopic than a wild-type horse of the same age.

RNA-binding proteins in eye development and disease: implication of conserved RNA granule components.

The molecular biology of metazoan eye development is an area of intense investigation. These efforts have led to the surprising recognition that although insect and vertebrate eyes have dramatically different structures, the orthologs or family members of several conserved transcription and signaling regulators such as Pax6, Six3, Prox1, and Bmp4 are commonly required for their development. In contrast, our understanding of posttranscriptional regulation in eye development and disease, particularly regarding the function of RNA-binding proteins (RBPs), is limited. We examine the present knowledge of RBPs in eye development in the insect model Drosophila as well as several vertebrate models such as fish, frog, chicken, and mouse. Interestingly, of the 42 RBPs that have been investigated for their expression or function in vertebrate eye development, 24 (~60%) are recognized in eukaryotic cells as components of RNA granules such as processing bodies, stress granules, or other specialized ribonucleoprotein (RNP) complexes. We discuss the distinct developmental and cellular events that may necessitate potential RBP/RNA granule-associated RNA regulon models to facilitate posttranscriptional control of gene expression in eye morphogenesis. In support of these hypotheses, three RBPs and RNP/RNA granule components Tdrd7, Caprin2, and Stau2 are linked to ocular developmental defects such as congenital cataract, Peters anomaly, and microphthalmia in human patients or animal models. We conclude by discussing the utility of interdisciplinary approaches such as the bioinformatics tool iSyTE (integrated Systems Tool for Eye gene discovery) to prioritize RBPs for deriving posttranscriptional regulatory networks in eye development and disease. WIREs RNA 2016, 7:527-557. doi: 10.1002/wrna.1355 For further resources related to this article, please visit the WIREs website.

Treatment of Inherited Eye Defects by Systemic Hematopoietic Stem Cell Transplantation.

PURPOSE: Cystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin (CTNS gene), resulting in cystine crystal accumulation in tissues. In eyes, crystals accumulate in the cornea causing photophobia and eventually blindness. Hematopoietic stem progenitor cells (HSPCs) rescue the kidney in a mouse model of cystinosis. We investigated the potential for HSPC transplantation to treat corneal defects in cystinosis. METHODS: We isolated HSPCs from transgenic DsRed mice and systemically transplanted irradiated Ctns-/- mice. A year posttransplantation, we investigated the fate and function of HSPCs by in vivo confocal and fluorescence microscopy (IVCM), quantitative RT-PCR (RT-qPCR), mass spectrometry, histology, and by measuring the IOP. To determine the mechanism by which HSPCs may rescue disease cells, we transplanted Ctns-/- mice with Ctns-/- DsRed HSPCs virally transduced to express functional CTNS-eGFP fusion protein. RESULTS: We found that a single systemic transplantation of wild-type HSPCs prevented ocular pathology in the Ctns-/- mice. Engraftment-derived HSPCs were detected within the cornea, and also in the sclera, ciliary body, retina, choroid, and lens. Transplantation of HSPC led to substantial decreases in corneal cystine crystals, restoration of normal corneal thickness, and lowered IOP in mice with high levels of donor-derived cell engraftment. Finally, we found that HSPC-derived progeny differentiated into macrophages, which displayed tunneling nanotubes capable of transferring cystinosin-bearing lysosomes to diseased cells. CONCLUSIONS: To our knowledge, this is the first demonstration that HSPCs can rescue hereditary corneal defects, and supports a new potential therapeutic strategy for treating ocular pathologies.

Optical coherence tomography in a patient with congenital vitreous cyst.

A case of congenital vitreous cyst is presented. An optical coherence tomography scan has been performed, which has shown that the cyst is free floating and is multilobular. Its content was hyper-reflective.