Integrin Expression by Human Epidermal Keratinocytes Can Be Modulated by Interferon-γ, Transforming Growth Factor-β, Tumor Necrosis Factor-α, and Culture on a Dermal Equivalent

Receptors of the integrin family are largely confined to the basal layer of keratinocytes, both in human epidermis and in stratified cultures of human keratinocytes. However, suprabasal integrin expression is observed during epidermal wound healing and in psoriatic lesions. We have investigated potential stimuli of suprabasal expression. Addition of transforming growth factor-β (TGF-β), interferon-γ (IFN-γ or tumor necrosis factor-α (TNF-α) to keratinocytes cultured with a 3T3 feeder layer did not induce suprabasal expression. The cytokines caused small changes in the levels of α2β1 or α3β1 on the surface of basal keratinocytes but had no significant effect on the proportion of cells adhering to fibronectin, type IV collagen, and laminin, and did not cause changes in the mobility of integrin subunits on polyacrylamide gels. Injection of TNF-α or IFN-γ intradermally into healthy human volunteers induced an inflammatory response but did not induce suprabasal integrin expression. However, we did observe transient suprabasal Integrin expression when keratinocytes were grown on a dermal equivalent consisting of fibroblasts in a collagen gel. One week after raising the cultures to the air-liquid interface, β1 integrins were found in all the viable cell layers, with suprabasal cells co-expressing integrins and involucrin; 1 week later integrins were confined to the basal layer. Addition of TGF-β, IFN-γ, or TNF-α to the dermal equivalents neither induced nor inhibited suprabasal integrin expression. We conclude that suprabasal integrin expression is not induced by the inflammatory cytokines tested, and instead may reflect the proliferation/differentiation status of the epidermis

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus (ICN) is characterised by involuntary, periodic, predominantly horizontal, oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 ICN singleton cases (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina suggesting a specific role in the control of eye movement and gaze stability

Ophthalmology

To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Multicenter, observational study. A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value

Clinical and electrophysiological results of eye muscle surgery in 17 patients with downbeat nystagmus

Purpose: To test the hypothesis that eye muscle surgery in treatment of patients with acquired downbeat nystagmus results in improvement measures of visual and ocular motor function. Methods: This is a prospective, interventional case series analysis of clinical and electrophyisological data before and after eye muscle surgery in 17 patients with acquired downbeat nystagmus who did not respond to medical treatments. Outcome measures included: 1) routine demography and clinical characteristics, 2) subjective oscillopsia (SO), 3) binocular best-corrected visual acuity in the null position (BVA), 3) primary position strabismic deviation (SD), 5) anomalous head posture (AHP), 6) contrast sensitivity function (CS), and 7) nystagmus slow phase velocity (SPV). All patients were followed at least 12 months. Parametric and non-parametric statistical analysis of outcome measure data above pre- and post-treatment were perfomed using standard software on grouped data using computerized software. Results: Patients' age ranged from 5 to 85 years (average 27 years). About 59% were male. Follow up ranged from 1–10 years (average 2.0 years). Around 70% had an associated central nervous systemic diagnosis, 100% had an AHP, oscillopsia and decreased CS, 53% had other eye disease, and 59% had strabismus. There were no complications from surgery. There were signficant post-treatment improvements in mean/median group BVA, SO, SD, AHP, CS, and SPV. Conclusion: This study supports the hypothesis that eye muscle surgery as treatments for patients with acquired downbeat nystagmus can result in improvements in multiple aspects of ocular motor and visual functions

Appendix C: Illustrative Cases and Treatment

Nystagmus in infancy and childhood outlines the understanding, evaluation, and treatments of nystagmus in infancy and childhood. Aligning this condition with advanced concepts of developmental brain-eye diseases and summarizing novel treatment paradigms, the authors provide an authoritative resource for both clinicians and scientists in the care of infants and children with nystagmus. The chapters comprised here offer valuable coverage in all relevant areas related to nystagmus: algorithms for examination; descriptions of diagnostic techniques; medical, surgical, and alternative treatments of the visual system in infants and children; methodologies for investigation, including analysis software, models of the ocular motor system, and current hypotheses on the pathophysiology of ocular motor oscillations. Unlike earlier works on this topic, emphasis is placed on the motor mechanisms that cause the various types of nystagmus rather than the diagnosis or treatment of the afferent visual deficits that may accompany them. The study of each type of nystagmus using accurate eye-movement recordings serves as the foundation for differential diagnosis and treatment options. Each chapter summarizes the results of ocular motor research in a narrative manner, identifying the important ideas and observations that point to underlying neurophysiological mechanisms. Based on insights from the authors' combined 75 years of clinical experience, Nystagmus in Infancy and Childhood is a valuable clinical reference for ophthalmologists, neurologists, and other specialists in the treatment of this condition.(RWH) Director of the Children's Vision Center, Chief of; Pediatric Ophthalmology; Children's Hospital Medical Center, Akron, Ohio; (LFD) Professor Emeritus, Department of Neurology, Case Western Reserve University, Director Emeritus of the Daroff-Dell'Osso Ocular Motility Laborator

Preface

Nystagmus in infancy and childhood outlines the understanding, evaluation, and treatments of nystagmus in infancy and childhood. Aligning this condition with advanced concepts of developmental brain-eye diseases and summarizing novel treatment paradigms, the authors provide an authoritative resource for both clinicians and scientists in the care of infants and children with nystagmus. The chapters comprised here offer valuable coverage in all relevant areas related to nystagmus: algorithms for examination; descriptions of diagnostic techniques; medical, surgical, and alternative treatments of the visual system in infants and children; methodologies for investigation, including analysis software, models of the ocular motor system, and current hypotheses on the pathophysiology of ocular motor oscillations. Unlike earlier works on this topic, emphasis is placed on the motor mechanisms that cause the various types of nystagmus rather than the diagnosis or treatment of the afferent visual deficits that may accompany them. The study of each type of nystagmus using accurate eye-movement recordings serves as the foundation for differential diagnosis and treatment options. Each chapter summarizes the results of ocular motor research in a narrative manner, identifying the important ideas and observations that point to underlying neurophysiological mechanisms. Based on insights from the authors' combined 75 years of clinical experience, Nystagmus in Infancy and Childhood is a valuable clinical reference for ophthalmologists, neurologists, and other specialists in the treatment of this condition.(RWH) Director of the Children's Vision Center, Chief of; Pediatric Ophthalmology; Children's Hospital Medical Center, Akron, Ohio; (LFD) Professor Emeritus, Department of Neurology, Case Western Reserve University, Director Emeritus of the Daroff-Dell'Osso Ocular Motility Laborator

Chapter 7: Treatment

Nystagmus in infancy and childhood outlines the understanding, evaluation, and treatments of nystagmus in infancy and childhood. Aligning this condition with advanced concepts of developmental brain-eye diseases and summarizing novel treatment paradigms, the authors provide an authoritative resource for both clinicians and scientists in the care of infants and children with nystagmus. The chapters comprised here offer valuable coverage in all relevant areas related to nystagmus: algorithms for examination; descriptions of diagnostic techniques; medical, surgical, and alternative treatments of the visual system in infants and children; methodologies for investigation, including analysis software, models of the ocular motor system, and current hypotheses on the pathophysiology of ocular motor oscillations. Unlike earlier works on this topic, emphasis is placed on the motor mechanisms that cause the various types of nystagmus rather than the diagnosis or treatment of the afferent visual deficits that may accompany them. The study of each type of nystagmus using accurate eye-movement recordings serves as the foundation for differential diagnosis and treatment options. Each chapter summarizes the results of ocular motor research in a narrative manner, identifying the important ideas and observations that point to underlying neurophysiological mechanisms. Based on insights from the authors' combined 75 years of clinical experience, Nystagmus in Infancy and Childhood is a valuable clinical reference for ophthalmologists, neurologists, and other specialists in the treatment of this condition.(RWH) Director of the Children's Vision Center, Chief of; Pediatric Ophthalmology; Children's Hospital Medical Center, Akron, Ohio; (LFD) Professor Emeritus, Department of Neurology, Case Western Reserve University, Director Emeritus of the Daroff-Dell'Osso Ocular Motility Laborator