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Chen N, Litts KM, Nikezic D, Langlo CS, Higgins BP, Lam BL, Fishman GA, Collison FT, Pennesi ME, Kay CN, Tarima S, Carroll J. Longitudinal Imaging of the Parafoveal Cone Mosaic in Congenital Achromatopsia. OPHTHALMOLOGY SCIENCE 2025; 5:100765. [PMID: 40291393 PMCID: PMC12022691 DOI: 10.1016/j.xops.2025.100765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 02/21/2025] [Accepted: 03/10/2025] [Indexed: 04/30/2025]
Abstract
Purpose To assess longitudinal changes in parafoveal cone density in individuals with congenital achromatopsia (ACHM). Design Retrospective longitudinal study. Participants Nineteen individuals (7 women and 12 men) with genetically confirmed ACHM. To be eligible, each had adaptive optics scanning light ophthalmoscope (AOSLO) images of the photoreceptor mosaic from ≥2 time points. Methods For each individual, follow-up AOSLO montages were aligned to their baseline montage. Notably, 100 × 100 μm regions of interest (ROIs) were extracted from the split-detection modality at locations 1°, 5°, and 10° temporal (T) from the peak cone density in each montage. All ROIs from follow-up visits were then manually aligned to their respective baseline ROI for that location. Cones were identified in each ROI by one observer, reviewed by a second observer, and confirmed together in a masked fashion. Cone density was calculated, and a linear mixed model was used to assess changes in density over time. A Wald test was performed to determine if the cone density changes were statistically significant. Main Outcome Measures Parafoveal cone spacing (at 1°, 5°, and 10° T) as a function of time. Results The mean (± standard deviation [SD]) age at baseline was 21.6 ± 10.7 years and the mean (±SD) follow-up period was 3.83 ± 2.93 years (range, 0.46-8.66 years). At 1° T, we observed a significant decrease of 352 cones/mm2 per year (P = 0.0003). At 5° T, the linear mixed model showed a nonstatistically significant decrease of 58 cones/mm2 per year (P = 0.504). At 10° T, we observed a significant decrease of 139 cones/mm2 per year (P = 0.0188). For a 100 × 100 μm ROI, these density changes correspond to a reduction of between about 0.5 and 4 cones per year, depending on the location. Conclusions Parafoveal cone density estimates in ACHM show a small decrease over time. These observed changes are within the previously reported longitudinal repeatability values for normal retinas, suggesting the observed average cone loss may not be clinically meaningful. Further studies with longer follow-up times and more genetically heterogeneous and age-diverse populations are needed to better understand factors contributing to changes in foveal and parafoveal cone structure in ACHM over time. Financial Disclosures Proprietary or commercial disclosures may be found in the Footnotes and Disclosures at the end of this article.
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Affiliation(s)
- Nickolas Chen
- School of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Katie M. Litts
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Danica Nikezic
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Christopher S. Langlo
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Brian P. Higgins
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Byron L. Lam
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida
| | - Gerald A. Fishman
- Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, Illinois
| | - Frederick T. Collison
- Chicago College of Optometry, Midwestern University, Downers Grove, Illinois
- The Chicago Lighthouse, Chicago, Illinois
| | - Mark E. Pennesi
- Casey Eye Institute, Oregon Health & Science University, Portland, Oregon
- Retina Foundation of the Southwest, Dallas, Texas
| | | | - Sergey Tarima
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Joseph Carroll
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
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Acosta-Alvear D, Harnoss JM, Walter P, Ashkenazi A. Homeostasis control in health and disease by the unfolded protein response. Nat Rev Mol Cell Biol 2025; 26:193-212. [PMID: 39501044 DOI: 10.1038/s41580-024-00794-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2024] [Indexed: 02/27/2025]
Abstract
Cells rely on the endoplasmic reticulum (ER) to fold and assemble newly synthesized transmembrane and secretory proteins - essential for cellular structure-function and for both intracellular and intercellular communication. To ensure the operative fidelity of the ER, eukaryotic cells leverage the unfolded protein response (UPR) - a stress-sensing and signalling network that maintains homeostasis by rebalancing the biosynthetic capacity of the ER according to need. The metazoan UPR can also redirect signalling from cytoprotective adaptation to programmed cell death if homeostasis restoration fails. As such, the UPR benefits multicellular organisms by preserving optimally functioning cells while removing damaged ones. Nevertheless, dysregulation of the UPR can be harmful. In this Review, we discuss the UPR and its regulatory processes as a paradigm in health and disease. We highlight important recent advances in molecular and mechanistic understanding of the UPR that enable greater precision in designing and developing innovative strategies to harness its potential for therapeutic gain. We underscore the rheostatic character of the UPR, its contextual nature and critical open questions for its further elucidation.
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Affiliation(s)
| | - Jonathan M Harnoss
- Department of General, Visceral, Thoracic and Transplant Surgery, University Hospital Giessen, Giessen, Germany
| | - Peter Walter
- Altos Labs, Inc., Bay Area Institute of Science, Redwood City, CA, USA.
| | - Avi Ashkenazi
- Research Oncology, Genentech, Inc., South San Francisco, CA, USA.
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Lee EJ, Kim K, Diaz-Aguilar MS, Min H, Chavez E, Steinbergs KJ, Safarta LA, Zhang G, Ryan AF, Lin JH. Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome. J Clin Invest 2025; 135:e175562. [PMID: 39570676 PMCID: PMC11785932 DOI: 10.1172/jci175562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/19/2024] [Indexed: 02/04/2025] Open
Abstract
Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both sexes. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomics analysis of Atf6-/- cochleae revealed a marked induction of the UPR, especially through the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they support the idea that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Last, our genetic findings indicate that ER stress is an important pathomechanism underlying cochlear damage and hearing loss, with clinical implications for patient lifestyle modifications that minimize environmental and physiological sources of ER stress to the ear.
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Affiliation(s)
- Eun-Jin Lee
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Kyle Kim
- Departments of Pathology and
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Monica Sophia Diaz-Aguilar
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
- Rush University Medical College, Chicago, Illinois, USA
| | - Hyejung Min
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Eduardo Chavez
- Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA
| | - Korina J. Steinbergs
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
| | - Lance A. Safarta
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
| | - Guirong Zhang
- Departments of Pathology and
- VA Palo Alto Healthcare System, Palo Alto, California, USA
| | - Allen F. Ryan
- Departments of Otolaryngology and Neuroscience, UCSD and Veterans Administration Medical Center, La Jolla, California, USA
| | - Jonathan H. Lin
- Departments of Pathology and
- Ophthalmology, Stanford University School of Medicine, Stanford, California, USA
- VA Palo Alto Healthcare System, Palo Alto, California, USA
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Joshi Y, Savas JN. A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response. J Clin Invest 2025; 135:e188708. [PMID: 39895634 PMCID: PMC11785913 DOI: 10.1172/jci188708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025] Open
Abstract
Sensorineural hearing loss (SNHL) is the most prevalent form of permanent hearing impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue of the JCI, Lee et al. reveal a link between mutations in ATF6 and SNHL in patients with achromatopsia. The study also shows that Atf6-deficient (Atf6-/-) mice exhibit disorganized stereocilia and age-related loss of outer hair cells. Additionally, the researchers show that Atf6 is critical for cochlear hair cell function. Mice lacking Atf6 expression experienced ER stress, which ultimately led to SNHL. Collectively, these findings enhance our understanding of the emerging role of protein homeostasis and ER stress in the pathogenesis of SNHL.
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Bradley A, Le M, Park S, Kroeger H, Wiseman RL, Lee EJ, Lin JH. Dysregulation of Retinal and Photoreceptor Structural Integrity Genes in ATF6 -/- Retinal Organoids. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1468:401-407. [PMID: 39930229 DOI: 10.1007/978-3-031-76550-6_66] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
ATF6 is a key regulator of the unfolded protein response (UPR) pathway that maintains cellular homeostasis during ER stress. In people, loss of ATF6 function causes cone dysfunction, manifesting as achromatopsia (ACHM). Previously, we generated ACHM retinal organoids (ROs) from patient induced pluripotent stem cells (iPSCs) carrying mutant ATF6 variants and gene-edited ATF6-knockout (KO) human embryonic stem cells (hESCs). ACHM and ATF6-KO ROs both showed severe stunting of cone inner and outer segments. RNA-Seq analysis of ACHM 290-day-old ROs showed downregulated cone gene expression and dysregulated mitochondria and ER stress gene expression. Here, we analyzed RNA-Seq analysis of 203-day-old ATF6-KO ROs. In younger ROs, we found dysregulation of genes involved in retinal and photoreceptor structural integrity, including CRB1, EGFLAM, and VTN. In addition, we found dysregulation of ATF6 and UPR-regulated transcriptional signatures. Dysregulation of retinal and photoreceptor structural integrity genes may underlie the observed stunting of cone inner/outer segments in ATF6-achromatopsia patients.
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Affiliation(s)
- Allyssa Bradley
- Department of Ophthalmology, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
- VA Palo Alto Healthcare System, Palo Alto, CA, USA
| | - Masako Le
- Department of Ophthalmology, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Soyeon Park
- Department of Ophthalmology, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Heike Kroeger
- Department of Cellular Biology, Franklin College of Arts and Sciences, Paul D. Coverdell Center for Biomedical Sciences, Athens, GA, USA
| | - R Luke Wiseman
- Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, CA, USA
| | - Eun-Jin Lee
- Department of Ophthalmology, Stanford University, Stanford, CA, USA
- Department of Pathology, Stanford University, Stanford, CA, USA
- VA Palo Alto Healthcare System, Palo Alto, CA, USA
| | - Jonathan H Lin
- Department of Ophthalmology, Stanford University, Stanford, CA, USA.
- Department of Pathology, Stanford University, Stanford, CA, USA.
- VA Palo Alto Healthcare System, Palo Alto, CA, USA.
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Galdamez A, Le M, Chiang WCJ, Lee EJ, Lin JH. Vulnerability of the Nrl -/- Cone-Dominant Retina to Endoplasmic Reticulum Stress. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1468:319-324. [PMID: 39930216 DOI: 10.1007/978-3-031-76550-6_53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Abstract
Neural retina leucine zipper (NRL) is essential for the development of rods. The Nrl knockout (Nrl-/-) mouse develops a cone-rich retina which facilitates investigations of cone biology. Previously, we identified the endoplasmic reticulum (ER) stress response gene ATF6 as a cause of cone dysfunction in people. Here, we investigated Atf6's influence on mouse cones in the cone-dominant Nrl-/- mouse. We find that cone development appears unaffected, but the cone-dominant Nrl-/- retina is highly vulnerable to ER stress-induced damage.
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Affiliation(s)
- Angela Galdamez
- Department of Ophthalmology, Stanford University, Palo Alto, CA, USA
- Department of Pathology, Stanford University, Palo Alto, CA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Masako Le
- Department of Ophthalmology, Stanford University, Palo Alto, CA, USA
- Department of Pathology, Stanford University, Palo Alto, CA, USA
| | - Wei-Chieh Jerry Chiang
- Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa, Japan
| | - Eun-Jin Lee
- Department of Ophthalmology, Stanford University, Palo Alto, CA, USA
- Department of Pathology, Stanford University, Palo Alto, CA, USA
- VA Palo Alto Health Care System, Palo Alto, CA, USA
| | - Jonathan H Lin
- Department of Ophthalmology, Stanford University, Palo Alto, CA, USA.
- Department of Pathology, Stanford University, Palo Alto, CA, USA.
- VA Palo Alto Health Care System, Palo Alto, CA, USA.
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Wu S, Lin W. The physiological role of the unfolded protein response in the nervous system. Neural Regen Res 2024; 19:2411-2420. [PMID: 38526277 PMCID: PMC11090440 DOI: 10.4103/1673-5374.393105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 12/12/2023] [Indexed: 03/26/2024] Open
Abstract
The unfolded protein response (UPR) is a cellular stress response pathway activated when the endoplasmic reticulum, a crucial organelle for protein folding and modification, encounters an accumulation of unfolded or misfolded proteins. The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity, reducing protein biosynthesis, and promoting protein degradation. It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress. Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system. Here, we provide an overview of recent findings that underscore the UPR's involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions, and highlight the critical role of the UPR in brain development, memory storage, retinal cone development, myelination, and maintenance of myelin thickness.
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Affiliation(s)
- Shuangchan Wu
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - Wensheng Lin
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA
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Huang CY, Liu YH. Sex difference, proteostasis and mitochondrial function impact stroke-related sarcopenia-A systematic review and meta-analysis. Ageing Res Rev 2024; 101:102484. [PMID: 39218079 DOI: 10.1016/j.arr.2024.102484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 08/11/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND The prevalence of stroke-related sarcopenia has been noted; however, epidemiological data and interventions that increase or reduce the incidence of stroke-related sarcopenia remain lacking. METHODS Studies on stroke-related sarcopenia were included in association or interventional analyses. All analyses were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two evaluators independently extracted the data. RESULTS Female stroke patients had a higher preference for sarcopenia than male patients (pooled odds ratio [OR] = 0.670, 95 % CI 0.533-0.842, p = 0.001). Although stroke patients without drug use have improved skeletal muscle mass index (SMI) (MD = 0.272, 95 % CI 0.087-0.457, p = 0.004), handgrip strength (HGS) was not significantly altered (MD = -0.068, 95 % CI -0.221-0.076, p = 0.354). Stroke patients with nutrient interventions have improved SMI (MD = -0.354, 95 % CI -0.635- -0.073, p = 0.014) and HGS (MD = -0.394, 95 % CI -0.678- -0.111, p = 0.006); the synergistic effect of rehabilitation exercise has not been ruled out. Whether a sex difference exists in these interventions remains to be investigated. The underlying pathological mechanisms and potential therapeutic strategies for this disease are discussed. CONCLUSION Sex difference, proteostasis, and mitochondrial function may impact the incidence of stroke-related sarcopenia. Understanding the underlying pathological mechanisms and potential therapeutic targets for this disease will provide new insights into disease treatment, prevention, and drug development.
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Affiliation(s)
- Chien-Yu Huang
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung 404328, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung 404333, Taiwan
| | - Yu-Huei Liu
- Graduate Institute of Integrated Medicine, China Medical University, Taichung 404333, Taiwan; Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404328, Taiwan; Drug Development Center, China Medical University, Taichung 404333, Taiwan.
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Gong X, Hertle RW. Infantile Nystagmus Syndrome-Associated Inherited Retinal Diseases: Perspectives from Gene Therapy Clinical Trials. Life (Basel) 2024; 14:1356. [PMID: 39598155 PMCID: PMC11595273 DOI: 10.3390/life14111356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/27/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024] Open
Abstract
Inherited retinal diseases (IRDs) are a clinically and genetically diverse group of progressive degenerative disorders that can result in severe visual impairment or complete blindness. Despite their predominantly monogenic inheritance patterns, the genetic complexity of over 300 identified disease-causing genes presents a significant challenge in correlating clinical phenotypes with genotypes. Achieving a molecular diagnosis is crucial for providing patients with definitive diagnostic clarity and facilitating access to emerging gene-based therapies and ongoing clinical trials. Recent advances in next-generation sequencing technologies have markedly enhanced our ability to identify genes and genetic defects leading to IRDs, thereby propelling the development of gene-based therapies. The clinical success of voretigene neparvovec (Luxturna), the first approved retinal gene therapy for RPE65-associated Leber congenital amaurosis (LCA), has spurred considerable research and development in gene-based therapies, highlighting the importance of reviewing the current status of gene therapy for IRDs, particularly those utilizing adeno-associated virus (AAV)-based therapies. As novel disease-causing mutations continue to be discovered and more targeted gene therapies are developed, integrating these treatment opportunities into the standard care for IRD patients becomes increasingly critical. This review provides an update on the diverse phenotypic-genotypic landscape of IRDs, with a specific focus on recent advances in the understanding of IRDs in children with infantile nystagmus syndrome (INS). We highlight the complexities of the genotypic-phenotypic landscape of INS-associated IRDs, including conditions such as achromatopsia, LCA, congenital stationary night blindness, and subtypes of retinitis pigmentosa. Additionally, we provide an updated overview of AAV-based gene therapies for these diseases and discuss the potential of gene-based therapies for underlying IRDs that lead to INS, offering a valuable resource for pediatric patients potentially eligible for ongoing clinical trials.
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Affiliation(s)
- Xiaoming Gong
- Department of Ophthalmology, Akron Children’s Hospital, Akron, OH 44308, USA;
- Vision Center of Excellence, Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, OH 44308, USA
| | - Richard W. Hertle
- Department of Ophthalmology, Akron Children’s Hospital, Akron, OH 44308, USA;
- Vision Center of Excellence, Rebecca D. Considine Research Institute, Akron Children’s Hospital, Akron, OH 44308, USA
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Cosmo E, Pilotto E, Convento E, Parolini F, Midena E. Microperimetry Sensitivity Correlates to Structural Macular Changes in Adolescents with Achromatopsia Unlike Other Visual Function Tests. J Clin Med 2024; 13:5968. [PMID: 39408028 PMCID: PMC11478056 DOI: 10.3390/jcm13195968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/05/2024] [Accepted: 10/07/2024] [Indexed: 10/20/2024] Open
Abstract
Objectives: Achromatopsia (ACHM) is a rare autosomal, recessively inherited disease that is characterized by cone dysfunction, for which several gene therapies are currently on trial. The aim of this study was to find correlations between the morphological macular changes identified using optical coherence tomography (OCT) and some visual functional parameters. Visual acuity (VA), contrast sensitivity (CS), and macular sensitivity obtained by means of microperimetry were assessed. Methods: Adolescents with ACHM underwent macular microperimetry (S-MAIA device) in mesopic condition, macular OCT, best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), near vision acuity (NVA), and CS measurement. Results: Eight patients (15 eyes) with ACHM were analyzed. The mean age was 17 ± 2.7 years, and genetic variants involved the CNGA3 gene (37.5%) and CNGB3 gene (62.5%). OCT staging significantly correlated with microperimetry sensitivity parameters, namely the sensitivity of the central foveal point (p = 0.0286) and of the first and second perifoveal rings (p = 0.0008 and p = 0.0014, respectively). No correlations were found between OCT staging and VA measurements, nor with CS value. Conclusions: Among the extensive evaluated visual function tests, only microperimetry sensitivity showed a correlation with morphological macular changes identified at OCT. Microperimetry sensitivity may thus represent a useful visual function tool in natural ACHM history studies considering the upcoming research on gene therapies for the treatment of ACHM.
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Affiliation(s)
- Eleonora Cosmo
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (E.C.); (E.C.); (F.P.); (E.M.)
| | - Elisabetta Pilotto
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (E.C.); (E.C.); (F.P.); (E.M.)
| | - Enrica Convento
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (E.C.); (E.C.); (F.P.); (E.M.)
| | - Federico Parolini
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (E.C.); (E.C.); (F.P.); (E.M.)
| | - Edoardo Midena
- Department of Neuroscience—Ophthalmology, University of Padova, 35128 Padova, Italy; (E.C.); (E.C.); (F.P.); (E.M.)
- IRCCS—Fondazione Bietti, 00198 Rome, Italy
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Kreis J, Carroll J. Applications of Adaptive Optics Imaging for Studying Conditions Affecting the Fovea. Annu Rev Vis Sci 2024; 10:239-262. [PMID: 38635871 DOI: 10.1146/annurev-vision-102122-100022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
The fovea is a highly specialized region of the central retina, defined by an absence of inner retinal layers and the accompanying vasculature, an increased density of cone photoreceptors, a near absence of rod photoreceptors, and unique private-line photoreceptor to midget ganglion cell circuitry. These anatomical specializations support high-acuity vision in humans. While direct study of foveal shape and size is routinely performed using optical coherence tomography, examination of the other anatomical specializations of the fovea has only recently become possible using an array of adaptive optics (AO)-based imaging tools. These devices correct for the eye's monochromatic aberrations and permit cellular-resolution imaging of the living retina. In this article, we review the application of AO-based imaging techniques to conditions affecting the fovea, with an emphasis on how imaging has advanced our understanding of pathophysiology.
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Affiliation(s)
- Joseph Kreis
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; ,
| | - Joseph Carroll
- Joint Department of Biomedical Engineering, Marquette University and the Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; ,
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12
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Andersen MKG, Bertelsen M, Gundestrup S, Grønskov K, Kessel L. Phenotypic characteristics of Danish patients with achromatopsia. Acta Ophthalmol 2024; 102:e893-e905. [PMID: 38348755 DOI: 10.1111/aos.16656] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/20/2023] [Accepted: 01/27/2024] [Indexed: 08/07/2024]
Abstract
PURPOSE To describe the phenotype of Danish patients with genetically verified achromatopsia (ACHM) with special focus on signs of progression on structural or functional parameters, and possible genotype-phenotype correlations. METHODS Forty-eight patients were identified, with disease-causing variants in five different genes: CNGA3, CNGB3, GNAT2, PDE6C and PDE6H. Longitudinal evaluation was possible for 11 patients and 27 patients participated in a renewed in-depth phenotyping consisting of visual acuity assessment, optical coherence tomography (OCT), fundus autofluorescence, colour vision evaluation, contrast sensitivity, mesopic microperimetry and full-field electroretinography. Foveal morphology was evaluated based on OCT images for all 48 patients using a grading system based on the integrity of the hyperreflective photoreceptor band, the inner segment ellipsoid zone (ISe). Signs of progression were evaluated based on longitudinal data and correlation with age. RESULTS We found a statistically significant positive correlation between OCT grade and age (Spearman ρ = 0.62, p < 0.0001) and we observed changes in the foveal morphology in 2 of 11 patients with ≥5 years of follow-up. We did not find any convincing correlation between age and functional parameters (visual acuity, retinal sensitivity and contrast sensitivity) nor did we find correlation between structural and functional parameters, or any clear genotype-phenotype correlation. CONCLUSIONS Some patients with ACHM demonstrate signs of progressive foveal changes in OCT characteristics with increasing age. This is relevant in terms of possible new treatments. However, functional characteristics, such as visual acuity, remained stable despite changing foveal structure. Thus, seen from a patient perspective, ACHM can still be considered a non-progressive condition.
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Affiliation(s)
- Mette K G Andersen
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
| | - Mette Bertelsen
- Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Svend Gundestrup
- Department of Multidisease, Copenhagen University Hospital, North Zealand, Denmark
| | - Karen Grønskov
- Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Line Kessel
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Del Pozo-Valero M, Almoallem B, Dueñas Rey A, Mahieu Q, Van Heetvelde M, Jeddawi L, Bauwens M, De Baere E. Autozygome-guided exome-first study in a consanguineous cohort with early-onset retinal disease uncovers an isolated RIMS2 phenotype and a retina-enriched RIMS2 isoform. Clin Genet 2024; 106:127-139. [PMID: 38468396 DOI: 10.1111/cge.14517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/19/2024] [Accepted: 02/23/2024] [Indexed: 03/13/2024]
Abstract
Leber congenital amaurosis (LCA) and early-onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early-onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run-of-homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype-driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina-enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell-type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non-consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non-coding regions or structural variants that remained undetected, warranting future WGS studies.
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Affiliation(s)
- Marta Del Pozo-Valero
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Basamat Almoallem
- Department of Ophthalmology, College of Medicine, King Saud University (KSU), Riyadh, Saudi Arabia
- Department of Ophthalmology, King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia
| | - Alfredo Dueñas Rey
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Quinten Mahieu
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Mattias Van Heetvelde
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Laila Jeddawi
- Pediatric Ophthalmology Division, Dr. Sulaiman AL Habib Medical Group, AL Khobar, Saudi Arabia
| | - Miriam Bauwens
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - Elfride De Baere
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
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14
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Righetti G, Kempf M, Kohl S, Wissinger B, Kühlewein L, Stingl K, Stingl K. S-cone contribution to oscillatory potentials in patients with blue cone monochromacy. Doc Ophthalmol 2024; 149:11-21. [PMID: 38871951 PMCID: PMC11236933 DOI: 10.1007/s10633-024-09981-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024]
Abstract
PURPOSE The aim of this exploratory study is to investigate the role of S-cones in oscillatory potentials (OPs) generation by individuals with blue-cone monochromacy (BCM), retaining S-cones, and achromatopsia (ACHM), lacking cone functions. METHODS This retrospective study analyzed data from 39 ACHM patients, 20 BCM patients, and 26 controls. Central foveal thickness was obtained using spectral-domain optical coherence tomography, while amplitude and implicit time (IT) of a- and b-waves were extracted from the ISCEV Standard dark-adapted 3 cd.s.m-2 full-field ERG (ffERG). Time-frequency analysis of the same measurement enabled the extraction of OPs, providing insights into the dynamic characteristics of the recorded signal. RESULTS Both ACHM and BCM groups showed a significant reduction (p < .00001) of a- and b-wave amplitudes and ITs as well as the power of the OPs compared to the control groups. The comparison between ACHM and BCM didn't show any statistically significant differences in the electrophysiological parameters. The analysis of covariance revealed significantly reduced central foveal thickness in the BCM group compared to ACHM and controls (p < .00001), and in ACHM compared to controls (p < .00001), after age correction and Tukey post-hoc analysis. CONCLUSIONS S-cones do not significantly influence OPs, and the decline in OPs' power is not solely due to a reduced a-wave. This suggests a complex non-linear network influenced by photoreceptor inputs. Morphological changes don't correlate directly with functional alterations, prompting further exploration of OPs' function and physiological role.
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Affiliation(s)
- Giulia Righetti
- Center for Ophthalmology, University Eye Hospital, University of Tübingen, 72076, Tübingen, Germany.
| | - Melanie Kempf
- Center for Ophthalmology, University Eye Hospital, University of Tübingen, 72076, Tübingen, Germany
- Center for Rare Eye Diseases, University of Tübingen, 72076, Tübingen, Germany
| | - Susanne Kohl
- Molecular Genetics Laboratory, Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, 72076, Tübingen, Germany
| | - Bernd Wissinger
- Molecular Genetics Laboratory, Center for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, 72076, Tübingen, Germany
| | - Laura Kühlewein
- Center for Ophthalmology, University Eye Hospital, University of Tübingen, 72076, Tübingen, Germany
- Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Katarina Stingl
- Center for Ophthalmology, University Eye Hospital, University of Tübingen, 72076, Tübingen, Germany
- Center for Rare Eye Diseases, University of Tübingen, 72076, Tübingen, Germany
| | - Krunoslav Stingl
- Center for Ophthalmology, University Eye Hospital, University of Tübingen, 72076, Tübingen, Germany
- Center for Rare Eye Diseases, University of Tübingen, 72076, Tübingen, Germany
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15
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Nouri Z, Sarmadi A, Narrei S, Kianersi H, Kianersi F, Tabatabaiefar MA. Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia. BMC Med Genomics 2024; 17:173. [PMID: 38956522 PMCID: PMC11218353 DOI: 10.1186/s12920-024-01942-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 06/19/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Autosomal recessive non-syndromic hearing loss (NSHL) and cone dystrophies (CODs) are highly genetically and phenotypically heterogeneous disorders. In this study, we applied the whole exome sequencing (WES) to find the cause of HL and COD in an Iranian consanguineous family with three affected individuals. METHODS Three members from an Iranian consanguineous family who were suffering from NSHL and visual impairment were ascertained in this study. Comprehensive clinical evaluations and genetic analysis followed by bioinformatic and co-segregation studies were performed to diagnose the cause of these phenotypes. Data were collected from 2020 to 2022. RESULTS All cases showed congenital bilateral NSHL, decreased visual acuity, poor color discrimination, photophobia and macular atrophy. Moreover, cornea, iris and anterior vitreous were within normal limit in both eyes, decreased foveal sensitivity, central scotoma and generalized depression of visual field were seen in three cases. WES results showed two variants, a novel null variant (p.Trp548Ter) in the PDE6C gene causing COD type 4 (Achromatopsia) and a previously reported variant (p.Ile84Thr) in the PDZD7 gene causing NSHL. Both variants were found in the cis configuration on chromosome 10 with a genetic distance of about 8.3 cM, leading to their co-inheritance. However, two diseases could appear independently in subsequent generations due to crossover during meiosis. CONCLUSIONS Here, we could successfully determine the etiology of a seemingly complex phenotype in two adjacent genes. We identified a novel variant in the PDE6C gene, related to achromatopsia. Interestingly, this variant could cooperatively cause visual disorders: cone dystrophy and cone-rod dystrophy.
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Affiliation(s)
- Zahra Nouri
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Akram Sarmadi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sina Narrei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Research and Development, Harmonic Medical Genetics Lab, Isfahan, Iran
| | - Hamidreza Kianersi
- Isfahan Eye Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Farzan Kianersi
- Department of Ophthalmology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
- University of Medical Sciences, Isfahan, 81746-73461, Iran.
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Brotherton C, Megaw R. Molecular Mechanisms Governing Sight Loss in Inherited Cone Disorders. Genes (Basel) 2024; 15:727. [PMID: 38927662 PMCID: PMC11202562 DOI: 10.3390/genes15060727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 05/28/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis. This review will discuss the known ICD genes, their molecular function, and the diseases they cause, with a focus on the most common forms of ICDs, including achromatopsia, progressive cone dystrophies (CODs), and cone-rod dystrophies (CORDs). It will discuss the gene-specific therapies that have emerged in recent years in order to treat patients with some of the more common ICDs.
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Affiliation(s)
- Chloe Brotherton
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU1, UK;
| | - Roly Megaw
- Princess Alexandra Eye Pavilion, NHS Lothian, Chalmers St., Edinburgh EH3 9HA, UK
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17
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Georgiou M, Robson AG, Fujinami K, de Guimarães TAC, Fujinami-Yokokawa Y, Daich Varela M, Pontikos N, Kalitzeos A, Mahroo OA, Webster AR, Michaelides M. Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes. Prog Retin Eye Res 2024; 100:101244. [PMID: 38278208 DOI: 10.1016/j.preteyeres.2024.101244] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 01/28/2024]
Abstract
Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.
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Affiliation(s)
- Michalis Georgiou
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
| | - Anthony G Robson
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Kaoru Fujinami
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
| | - Thales A C de Guimarães
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Yu Fujinami-Yokokawa
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Laboratory of Visual Physiology, Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Department of Health Policy and Management, Keio University School of Medicine, Tokyo, Japan.
| | - Malena Daich Varela
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Nikolas Pontikos
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Angelos Kalitzeos
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Omar A Mahroo
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Section of Ophthalmology, King s College London, St Thomas Hospital Campus, London, United Kingdom; Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, United Kingdom; Department of Translational Ophthalmology, Wills Eye Hospital, Philadelphia, PA, USA.
| | - Andrew R Webster
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
| | - Michel Michaelides
- Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom.
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18
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Wu S, Yu Y, Wang Y, Zhang L, Fang X, Ye P, Ma J. Novel ATF6 homozygous variant in a Chinese patient with achromatopsia. Ophthalmic Genet 2024; 45:153-158. [PMID: 38419580 DOI: 10.1080/13816810.2024.2322643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/19/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND ATF6-associated Achromatopsia (ACHM) is a rare autosomal recessive disorder characterized by reduction of visual acuity, photophobia, nystagmus, and poor color vision. METHODS Detailed ophthalmological examinations were performed in a Chinese patient with ACHM. Whole exome sequencing and Sanger sequencing were performed to detect the disease-causing gene in the patient. RESULTS A 6-year-old girl presented photophobia, low vision and reduced color discrimination. Small yellow lesion in the macula of both eyes was observed. FAF demonstrated hypofluorescence in the macular fovea. OCT images revealed interruption of ellipsoid and interdigitation zone in the foveal area and a loss of the foveal pit. ERG showed relatively normal rod responses and unrecordable cone responses. Sequencing result identified a novel splicing variant c.354 + 6T>C in the ATF6 gene (NM_007348.4). CONCLUSIONS We reported detailed clinical features and genetic analysis of a new Chinese ATF6-associated patient with ACHM.
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Affiliation(s)
- Shijing Wu
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yinhui Yu
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yao Wang
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Li Zhang
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoyun Fang
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Panpan Ye
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jian Ma
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Zhejiang University, Hangzhou, Zhejiang, China
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Grissim G, Walesa A, Follett HM, Higgins BP, Goetschel K, Heitkotter H, Carroll J. Longitudinal Assessment of OCT-Based Measures of Foveal Cone Structure in Achromatopsia. Invest Ophthalmol Vis Sci 2024; 65:16. [PMID: 38587442 PMCID: PMC11005076 DOI: 10.1167/iovs.65.4.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/24/2024] [Indexed: 04/09/2024] Open
Abstract
Purpose Achromatopsia (ACHM) is an autosomal recessive retinal disease associated with reduced or absent cone function. There is debate regarding the extent to which cone structure shows progressive degeneration in patients with ACHM. Here, we used optical coherence tomography (OCT) images to evaluate outer nuclear layer (ONL) thickness and ellipsoid zone (EZ) integrity over time in individuals with ACHM. Methods Sixty-three individuals with genetically confirmed ACHM with follow-up ranging from about 6 months to 10 years were imaged using either Bioptigen or Cirrus OCT. Foveal cone structure was evaluated by assessing EZ integrity and ONL thickness. Results A total of 470 OCT images were graded, 243 OD and 227 OS. The baseline distribution of EZ grades was highly symmetrical between eyes (P = 0.99) and there was no significant interocular difference in baseline ONL thickness (P = 0.12). The EZ grade remained unchanged over the follow-up period for 60 of 63 individuals. Foveal ONL thickness showed a clinically significant change in only 1 of the 61 individuals analyzed, although detailed adaptive optics imaging revealed no changes in cone density in this individual. Conclusions ACHM appears to be a generally stable condition, at least over the follow-up period assessed here. As cones are the cellular targets for emerging gene therapies, stable EZ and ONL thickness demonstrate therapeutic potential for ACHM, although other aspects of the visual system need to be considered when determining the best timing for therapeutic intervention.
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Affiliation(s)
- Garrett Grissim
- School of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Ashleigh Walesa
- Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Hannah M. Follett
- Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Brian P. Higgins
- Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Kaitlin Goetschel
- Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Heather Heitkotter
- Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Joseph Carroll
- Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
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Suga A, Mizobuchi K, Inooka T, Yoshitake K, Minematsu N, Tsunoda K, Kuniyoshi K, Kawai Y, Omae Y, Tokunaga K, Hayashi T, Ueno S, Iwata T. A homozygous structural variant of RPGRIP1 is frequently associated with achromatopsia in Japanese patients with IRD. GENETICS IN MEDICINE OPEN 2024; 2:101843. [PMID: 39669618 PMCID: PMC11613597 DOI: 10.1016/j.gimo.2024.101843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 12/14/2024]
Abstract
Purpose Achromatopsia (ACHM) is an early-onset cone dysfunction caused by 5 genes with cone-specific functions (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) and by ATF6, a transcription factor with ubiquitous expression. To improve the relatively low variant detection ratio in these genes in a cohort of exome-sequenced Japanese patients with inherited retinal diseases (IRD), we performed genome sequencing to detect structural variants and intronic variants in patients with ACHM. Methods Genome sequencing of 10 ACHM pedigrees was performed after exome sequencing. Structural, non-coding, and coding variants were filtered based on segregation between the affected and unaffected in each pedigree. Variant frequency and predicted damage scores were considered in identifying pathogenic variants. Results A homozygous deletion involving exon 18 of RPGRIP1 was detected in 5 of 10 ACHM probands, and variant inheritance from each parent was confirmed. This deletion was relatively frequent (minor allele frequency = 0.0023) in the Japanese population but was only homozygous in patients with ACHM among the 199 Japanese IRD probands analyzed by the same genome sequencing pipeline. Conclusion The deletion involving exon 18 of RPGRIP1 is a prevalent cause of ACHM in Japanese patients and contributes to the wide spectrum of RPGRIP1-associated IRD phenotypes, from Leber congenital amaurosis to ACHM.
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Affiliation(s)
- Akiko Suga
- Division of Molecular and Cellular Biology, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan
| | - Kei Mizobuchi
- Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan
| | - Taiga Inooka
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Kazutoshi Yoshitake
- Laboratory of Aquatic Molecular Biology and Biotechnology, Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Naoko Minematsu
- Division of Molecular and Cellular Biology, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan
| | - Kazushige Tsunoda
- Division of Vision Research, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan
| | - Kazuki Kuniyoshi
- Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yosuke Omae
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takaaki Hayashi
- Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shinji Ueno
- Department of Ophthalmology, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Takeshi Iwata
- Division of Molecular and Cellular Biology, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan
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Lei Y, Yu H, Ding S, Liu H, Liu C, Fu R. Molecular mechanism of ATF6 in unfolded protein response and its role in disease. Heliyon 2024; 10:e25937. [PMID: 38434326 PMCID: PMC10907738 DOI: 10.1016/j.heliyon.2024.e25937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 03/05/2024] Open
Abstract
Activating transcription factor 6 (ATF6), an important signaling molecule in unfolded protein response (UPR), plays a role in the pathogenesis of several diseases, including diseases such as congenital retinal disease, liver fibrosis and ankylosing spondylitis. After endoplasmic reticulum stress (ERS), ATF6 is activated after separation from binding immunoglobulin protein (GRP78/BiP) in the endoplasmic reticulum (ER) and transported to the Golgi apparatus to be hydrolyzed by site 1 and site 2 proteases into ATF6 fragments, which localize to the nucleus and regulate the transcription and expression of ERS-related genes. In these diseases, ERS leads to the activation of UPR, which ultimately lead to the occurrence and development of diseases by regulating the physiological state of cells through the ATF6 signaling pathway. Here, we discuss the evidence for the pathogenic importance of ATF6 signaling in different diseases and discuss preclinical results.
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Affiliation(s)
| | | | - Shaoxue Ding
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Chunyan Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
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Yang Z, Yan L, Zhang W, Qi J, An W, Yao K. Dyschromatopsia: a comprehensive analysis of mechanisms and cutting-edge treatments for color vision deficiency. Front Neurosci 2024; 18:1265630. [PMID: 38298913 PMCID: PMC10828017 DOI: 10.3389/fnins.2024.1265630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 01/02/2024] [Indexed: 02/02/2024] Open
Abstract
Color blindness is a retinal disease that mainly manifests as a color vision disorder, characterized by achromatopsia, red-green color blindness, and blue-yellow color blindness. With the development of technology and progress in theory, extensive research has been conducted on the genetic basis of color blindness, and various approaches have been explored for its treatment. This article aims to provide a comprehensive review of recent advances in understanding the pathological mechanism, clinical symptoms, and treatment options for color blindness. Additionally, we discuss the various treatment approaches that have been developed to address color blindness, including gene therapy, pharmacological interventions, and visual aids. Furthermore, we highlight the promising results from clinical trials of these treatments, as well as the ongoing challenges that must be addressed to achieve effective and long-lasting therapeutic outcomes. Overall, this review provides valuable insights into the current state of research on color blindness, with the intention of informing further investigation and development of effective treatments for this disease.
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Affiliation(s)
- Zihao Yang
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Lin Yan
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Wenliang Zhang
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Jia Qi
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Wenjing An
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
| | - Kai Yao
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China
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23
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Zhang SX, Wang JJ, Starr CR, Lee EJ, Park KS, Zhylkibayev A, Medina A, Lin JH, Gorbatyuk M. The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease. Prog Retin Eye Res 2024; 98:101231. [PMID: 38092262 PMCID: PMC11056313 DOI: 10.1016/j.preteyeres.2023.101231] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 12/19/2023]
Abstract
The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.
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Affiliation(s)
- Sarah X Zhang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States.
| | - Josh J Wang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States
| | - Christopher R Starr
- Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Eun-Jin Lee
- Department of Ophthalmology and Byers Eye Institute, Stanford University, Stanford, CA, United States; VA Palo Alto Healthcare System, Palo Alto, CA, United States; Department of Pathology, Stanford University, Stanford, CA, United States
| | - Karen Sophia Park
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States
| | - Assylbek Zhylkibayev
- Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andy Medina
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States
| | - Jonathan H Lin
- Department of Ophthalmology and Byers Eye Institute, Stanford University, Stanford, CA, United States; VA Palo Alto Healthcare System, Palo Alto, CA, United States; Department of Pathology, Stanford University, Stanford, CA, United States
| | - Marina Gorbatyuk
- Department of Optometry and Vision Science, University of Alabama at Birmingham, Birmingham, AL, United States
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Solaki M, Wissinger B, Kohl S, Reuter P. Functional evaluation allows ACMG/AMP-based re-classification of CNGA3 variants associated with achromatopsia. Genet Med 2023; 25:100979. [PMID: 37689994 DOI: 10.1016/j.gim.2023.100979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 09/11/2023] Open
Abstract
PURPOSE CNGA3 encoding the main subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors is one of the major disease-associated genes for achromatopsia. Most CNGA3 variants are missense variants with the majority being functionally uncharacterized and therefore hampering genetic diagnosis. In light of potential gene therapy, objective variant pathogenicity assessment is essential. METHODS We established a medium-throughput aequorin-based luminescence bioassay allowing mutant CNGA3 channel function assessment via quantification of CNGA3 channel-mediated calcium influx in a cell culture system, thereby enabling American College of Medical Genetics and Genomics/Association for Molecular Pathology-based variant re-classification. RESULTS We provide functional read-out obtained for 150 yet uncharacterized CNGA3 missense substitutions of which 55 were previously categorized as variants of uncertain significance (VUS) identifying 25 as functionally normal and 125 as functionally abnormal. These data enabled the American College of Medical Genetics and Genomics/ Association for Molecular Pathology-based variant re-classification of 52/55 VUS as either benign, likely benign, or likely pathogenic reaching a VUS re-classification rate of 94.5%. CONCLUSION Our aequorin-based bioassay allows functionally ensured clinical variant interpretation for 150 CNGA3 missense variants enabling and supporting VUS re-classification and assuring molecular diagnosis to patients affected by CNGA3-associated achromatopsia, hereby identifying patients eligible for future gene therapy trials on this disease.
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Affiliation(s)
- Maria Solaki
- Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Bernd Wissinger
- Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Susanne Kohl
- Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
| | - Peggy Reuter
- Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
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Li Z, Cheng W, Zi F, Wang J, Huang X, Sheng X, Rong W. Four different gene-related cone-rod dystrophy: clinical and genetic findings in six Chinese families with diverse modes of inheritance. Front Genet 2023; 14:1157156. [PMID: 38028590 PMCID: PMC10652761 DOI: 10.3389/fgene.2023.1157156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose: To investigate pathogenic variants in six families with cone-rod dystrophy (CORD) presenting various inheritance patterns by using whole-exome sequencing (WES) and analyzing phenotypic features. Methods: A total of six families with CORD were enrolled in Ningxia Eye Hospital for this study. The probands and their family members received comprehensive ophthalmic examinations, and DNA was abstracted from patients and family members. Whole-exome sequencing was performed on probands to screen the causative variants, and all suspected pathogenic variants were determined via Sanger sequencing. Furthermore, co-segregation analysis was performed on available family members. The pathogenicity of novel variants was predicted using in silico analysis and evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of the six families, two families were assigned as X-linked recessive (XL), two families were assigned as autosomal recessive (AR), and two families were assigned as autosomal dominant (AD). Pathogenic variants were detected in CACNA1F in two X-linked recessive probands, among which family 1 had a hemizygous frameshift variant c.2201del (p.Val734Glyfs*17) and family 2 had a hemizygous missense variant c.245G>A (p.Arg82Gln). Both probands had high myopia, with fundus tessellation accompanied by abnormalities in the outer structure of the macular area. The homozygous splice variant c.2373 + 5G>T in PROM1 and the homozygous nonsense variant c.604C>T (p.Arg202Ter) in ADAM9 were detected in two autosomal recessive families of the probands. Both probands showed different degrees of atrophy in the macular area, and the lesions showed hypofluorescence changes in autofluorescence. The heterozygous variation in CRX c.682C>T (p.Gln228Ter) was detected in two autosomal dominant families. The onset age of the two probands was late, with better vision and severe macular atrophy. According to ACMG guidelines and the analysis of online in silico tools, all variations were labeled as potentially harmful or pathogenic. Conclusion: Pathogenic variants in CACNA1F, PROM1, ADAM9, and CRX genes were identified in six families affected by the diverse inheritance patterns of CORD. Furthermore, the potential impact of the nonsense-mediated decay (NMD) mechanism on the manifestation of CORD phenotypes was examined and addressed. Simultaneously, the spectrum of pathogenic variants and clinical phenotypes associated with the CORD gene was extended.
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Affiliation(s)
- Zhen Li
- Ningxia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Yinchuan, China
| | - Wanyu Cheng
- Ningxia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Yinchuan, China
| | - Feiyin Zi
- Ningxia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Yinchuan, China
| | - Juan Wang
- Department of Ophthalmology, Qingdao West Coast New District Central Hospital, Qingdao, China
| | - Xiaoyu Huang
- Ningxia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Yinchuan, China
| | | | - Weining Rong
- Ningxia Eye Hospital, People’s Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Yinchuan, China
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26
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Lee EJ, Diaz-Aguilar MS, Min H, Choi J, Valdez Duran DA, Grandjean JM, Wiseman RL, Kroeger H, Lin JH. Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Patients with Vision Loss. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1721-1739. [PMID: 36535406 PMCID: PMC10616714 DOI: 10.1016/j.ajpath.2022.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/10/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022]
Abstract
Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response, plays a key role in endoplasmic reticulum function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones, clinically manifesting as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. Herein, this was investigated by analyzing bulk RNA-sequencing transcriptomes from retinal organoids generated from patients with ACHM, carrying homozygous loss-of-function ATF6 variants. Marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids were identified. This indicated that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, gene expression from control and ACHM retinal organoids were compared with transcriptome profiles of seven major retinal cell types generated from recent single-cell transcriptomic maps of nondiseased human retina. This indicated pronounced down-regulation of cone genes and up-regulation in Müller glia genes, with no significant effects on other retinal cells. Overall, the current analysis of ACHM patient retinal organoids identified new cellular and molecular phenotypes in addition to cone dysfunction: activation of Müller cells, increased endoplasmic reticulum stress, disrupted mitochondrial structure, and elevated respiratory chain activity gene expression.
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Affiliation(s)
- Eun-Jin Lee
- Department of Ophthalmology, Stanford University, Stanford, California; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California
| | - Monica S Diaz-Aguilar
- Department of Ophthalmology, Stanford University, Stanford, California; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California; Department of Medicine, Rush University Medical College, Chicago, Illinois
| | - Hyejung Min
- Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California
| | - Jihee Choi
- Department of Pathology, Stanford University, Stanford, California
| | | | - Julia M Grandjean
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California
| | - R Luke Wiseman
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California
| | - Heike Kroeger
- Department of Cellular Biology, University of Georgia, Athens, Georgia
| | - Jonathan H Lin
- Department of Ophthalmology, Stanford University, Stanford, California; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California.
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Keuthan CJ, Karma S, Zack DJ. Alternative RNA Splicing in the Retina: Insights and Perspectives. Cold Spring Harb Perspect Med 2023; 13:a041313. [PMID: 36690463 PMCID: PMC10547393 DOI: 10.1101/cshperspect.a041313] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Alternative splicing is a fundamental and highly regulated post-transcriptional process that enhances transcriptome and proteome diversity. This process is particularly important in neuronal tissues, such as the retina, which exhibit some of the highest levels of differentially spliced genes in the body. Alternative splicing is regulated both temporally and spatially during neuronal development, can be cell-type-specific, and when altered can cause a number of pathologies, including retinal degeneration. Advancements in high-throughput sequencing technologies have facilitated investigations of the alternative splicing landscape of the retina in both healthy and disease states. Additionally, innovations in human stem cell engineering, specifically in the generation of 3D retinal organoids, which recapitulate many aspects of the in vivo retinal microenvironment, have aided studies of the role of alternative splicing in human retinal development and degeneration. Here we review these advances and discuss the ongoing development of strategies for the treatment of alternative splicing-related retinal disease.
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Affiliation(s)
- Casey J Keuthan
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Sadik Karma
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
| | - Donald J Zack
- Departments of Ophthalmology, Wilmer Eye Institute, Neuroscience, Molecular Biology and Genetics, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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28
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Danish E, Alhashem A, Aljehani R, Aljawi A, Aldarwish MM, Al Mutairi F, Alfadhel M, Alrifai MT, Alobaisi S. Phenotype and genotype of 15 Saudi patients with achromatopsia: A case series. Saudi J Ophthalmol 2023; 37:301-306. [PMID: 38155673 PMCID: PMC10752271 DOI: 10.4103/sjopt.sjopt_108_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/23/2023] [Accepted: 07/27/2023] [Indexed: 12/30/2023] Open
Abstract
PURPOSE Achromatopsia is a rare stationary retinal disorder that primarily affects the cone photoreceptors. Individuals with achromatopsia present with photophobia, nystagmus, reduced visual acuity (VA), and color blindness. Multiple genes responsible for achromatopsia have been identified (e.g. cyclic nucleotide-gated channel subunit alpha 3 [CNGA3] and activating transcription factor 6). Studies have assessed the role of gene therapy in achromatopsia. Therefore, for treatment and prevention, the identification of phenotypes and genotypes is crucial. Here, we described the clinical manifestations and genetic mutations associated with achromatopsia in patients from Saudi Arabia. METHODS This case series study included 15 patients with clinical presentations, suggestive of achromatopsia, who underwent ophthalmological and systemic evaluations. Patients with typical achromatopsia phenotype underwent genetic evaluation using whole-exome testing. RESULTS All patients had nystagmus (n = 15) and 93.3% had photophobia (n = 14). In addition, all patients (n = 15) had poor VA. Hyperopia with astigmatism was observed in 93.3% (n = 14) and complete color blindness in 93.3% of the patients (n = 14). In the context of family history, both parents of all patients (n = 15) were genetic carriers, with a high consanguinity rate (82%, n = 9 families). Electroretinography showed cone dysfunction with normal rods in 66.7% (n = 10) and both cone-rod dysfunction in 33.3% (n = 5) patients. Regarding the genotypic features, 93% of patients had variants in CNGA3 (n = 14) categorized as pathogenic Class 1 (86.7%, n = 13). Further, 66.7% (n = 10) of patients also harbored the c.661C>T DNA variant. Further, the patients were homozygous for these mutations. Three other variants were also identified: c.1768G>A (13.3%, n = 2), c.830G>A (6.6%, n = 1), and c. 822G >T (6.6%, n = 1). CONCLUSION Consanguinity and belonging to the same tribe are major risk factors for disease inheritance. The most common genotype was CNGA3 with the c.661C>T DNA variant. We recommend raising awareness among families and providing genetic counseling for this highly debilitating disease.
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Affiliation(s)
- Enam Danish
- Department of Ophthalmology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
| | - Amal Alhashem
- Department of Pediatric, Division of Genetic and Metabolic Medicine, Prince Sultan Medical Military City, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Reham Aljehani
- Department of Ophthalmology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anan Aljawi
- Department of Ophthalmology, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Manar M. Aldarwish
- Department of Genetics and Precision Medicine, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Fuad Al Mutairi
- Department of Genetics and Precision Medicine, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Centre, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Majid Alfadhel
- Department of Genetics and Precision Medicine, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- Department of Medical Genomics Research, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Muhammad T. Alrifai
- King Abdullah International Medical Research Centre, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Pediatric Ophthalmology Division, Department of Pediatric Surgery, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Saif Alobaisi
- Pediatric Ophthalmology Division, Department of Pediatric Surgery, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
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Kugler SA, Valmaggia C, Sturm V, Schorderet DF, Todorova MG. Analysis of Suspected Achromatopsia by Multimodal Diagnostic Testing. Klin Monbl Augenheilkd 2023; 240:1158-1173. [PMID: 37714190 DOI: 10.1055/a-2176-4233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2023]
Abstract
BACKGROUND Achromatopsia (ACHM) as a hereditary cone disease might manifest in a stationary and progressive manner. The proper clinical and genetic diagnosis may allow an individual prognosis, accurate genetic counselling, and the optimal choice of low vision aids. The primary aim of the study was to determine the spectrum of clinical and genetic diagnostics required to characterize the ACHM. METHODS A retrospective analysis was performed in 8 patients from non-related families (5 ♀,3 ♂); age at diagnosis: 3 - 56 y, mean 18.13 (SD ± 18.22). Clinical phenotyping, supported by colour vision test, fundus photography-, autofluorescence- (FAF), infra-red- (IR), OCT imaging and electroretinography provided information on the current status and the course of the disease over the years. In addition, genetic examinations were performed with ACHM relevant testing (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H and the transcription factor ATF6). RESULTS All patients suffered photophobia and reduced visual acuity (mean: 0.16 [SD ± 0.08]). Nystagmus was identified in 7 from 8 subjects and in one patient a head-turn right helped to reduce the nystagmus amplitude. Colour vision testing confirmed complete achromatopsia in 7 out of 8 patients. Electrophysiology found severely reduced photopic- but also scotopic responses. Thinning and interruption of the inner segment ellipsoid (ISe) line within the macula but also FAF- and IR abnormalities in the fovea and/or parafovea were characteristic in all ACHM patients. Identification of pathogenic mutations in 7 patients helped to confirm the diagnosis of ACHM (3 adults, 4 children; 3 ♀ and 4 ♂). Achromatopsia was linked to CNGA3 (2 ♀, 1 ♂) and CNGB3 variants (2 ♀, 3 ♂). The youngest patient (♀, 10 y) had 3 different CNGB3 variants on different alleles. In a patient (♂, 29 y) carrying 2 pathogenic digenic-triallelic CNGA3- and CNGB3-mutations, a severe progression of ISe discontinuity to coloboma-like macular atrophy was observed during the 12-year follow-up. The oldest female (67 y) showed a compound homozygous CNGA3- and heterozygous CNGB3-, as well as a heterozygous GUCY2D variants. The destruction of her ISe line was significantly enlarged and represented a progressive cone-rod phenotype in comparison to other ACHM patients. In a patient (♂, 45 y) carrying a pathogenic CNGB3 and USH2 mutation, a severe macular oedema and a rod-cone phenotype was observed. In addition, two variants in C2ORF71 considered as VOS were found. One patient showed the rare ATF6 mutation, where a severe coloboma-like macular atrophy was observed on the left eye as early as at the age of three years. CONCLUSION Combining multimodal ophthalmological diagnostics and molecular genetics when evaluating patients with ACHM helps in characterizing the disease and associated modifiers, and is therefore strongly recommended for such patients.
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Affiliation(s)
- Sylvia A Kugler
- Department of Ophthalmology, Cantonal Hospital St. Gallen, Switzerland
| | - Christophe Valmaggia
- Department of Ophthalmology, Cantonal Hospital St. Gallen, Switzerland
- Department of Ophthalmology, University of Zürich, Switzerland
| | - Veit Sturm
- Department of Ophthalmology, University of Zürich, Switzerland
- Ophthalmology, Eye Center Rosengarten, Arbon, Switzerland
| | - Daniel F Schorderet
- Faculty of Biology and Medicine, University of Lausanne and Faculty of Life Sciences, École polytechnique fédérale de Lausanne, Switzerland
| | - Margarita G Todorova
- Department of Ophthalmology, Cantonal Hospital St. Gallen, Switzerland
- Department of Ophthalmology, University of Zürich, Switzerland
- Department of Ophthalmology, University Hospital Basel, Switzerland
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30
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Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther 2023; 8:352. [PMID: 37709773 PMCID: PMC10502142 DOI: 10.1038/s41392-023-01570-w] [Citation(s) in RCA: 247] [Impact Index Per Article: 123.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 06/17/2023] [Accepted: 07/14/2023] [Indexed: 09/16/2023] Open
Abstract
The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.
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Affiliation(s)
- Xingyi Chen
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chaoran Shi
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Meihui He
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Siqi Xiong
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Xiaobo Xia
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Fang F, Liu P, Huang H, Feng X, Li L, Sun Y, Kaufman RJ, Hu Y. RGC-specific ATF4 and/or CHOP deletion rescues glaucomatous neurodegeneration and visual function. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 33:286-295. [PMID: 37547290 PMCID: PMC10400881 DOI: 10.1016/j.omtn.2023.07.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 07/11/2023] [Indexed: 08/08/2023]
Abstract
Endoplasmic reticulum (ER) stress has been linked with various acute and chronic neurodegenerative diseases. We previously found that optic nerve (ON) injury and diseases induce neuronal ER stress in retinal ganglion cells (RGCs). We further demonstrated that germline deletion of CHOP preserves the structure and function of both RGC somata and axons in mouse glaucoma models. Here we report that RGC-specific deletion of CHOP and/or its upstream regulator ATF4 synergistically promotes RGC and ON survival and preserves visual function in mouse ON crush and silicone oil-induced ocular hypertension (SOHU) glaucoma models. Consistently, topical application of the ATF4/CHOP chemical inhibitor ISRIB or RGC-specific CRISPR-mediated knockdown of the ATF4 downstream effector Gadd45a also delivers significant neuroprotection in the SOHU glaucoma model. These studies suggest that blocking the neuronal intrinsic ATF4/CHOP axis of ER stress is a promising neuroprotection strategy for neurodegeneration.
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Affiliation(s)
- Fang Fang
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Pingting Liu
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Haoliang Huang
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Xue Feng
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Liang Li
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Yang Sun
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Randal J. Kaufman
- Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Yang Hu
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
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Wang H, Liu Z, Zhang Y, Tao D, Li L. Achromatopsia Showing Compound Heterozygous Mutations in ATF6 by Whole Exome Sequencing: A Rare Case Report. J Pediatr Ophthalmol Strabismus 2023; 60:e65-e69. [PMID: 37747165 DOI: 10.3928/01913913-20230814-02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Achromatopsia, inherited in an autosomal recessive manner, is a rare condition featured by dysfunction of cone photoreceptors responsible for high-acuity vision in daylight. To date, its pathogenesis and genetic mechanism are still not well defined due to the rarity of cases. In this study, the authors describe a patient with achromatopsia who was diagnosed based on the combination of whole exome sequencing, ocular examination, fundus photography, and fundus fluorescein angiography. A 1-year-old girl presented due to absence of the foveal reflex, severe photophobia, and pigment mottling. Fundus photography and fundus fluorescein angiography were performed on admission. Blood samples were extracted from the proband and her parents. Whole exome sequencing detected two ATF6 variants (c.533C>A and c.82+1G>T), which were confirmed through Sanger sequencing. According to the American College of Medical Genetics guidelines, both c.533C>A and c.82+1G>T variants in ATF6 were predicted as pathogenic mutations (PVS1, PM2, PM3). The patient was diagnosed as having achromatopsia with pathogenicity of ATF6 variants (c.533C>A and c.82+1G>T). [J Pediatr Ophthalmol Strabismus. 2023;60(5):e65-e69.].
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Wang Y, Snell A, Dyka FM, Colvin ER, Ildefonso C, Ash JD, Lobanova ES. Overexpression of Nfe2l1 increases proteasome activity and delays vision loss in a preclinical model of human blindness. SCIENCE ADVANCES 2023; 9:eadd5479. [PMID: 37450596 PMCID: PMC10348684 DOI: 10.1126/sciadv.add5479] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023]
Abstract
Proteasomes are the central proteolytic machines that are critical for breaking down most of the damaged and abnormal proteins in human cells. Although universally applicable drugs are not yet available, the stimulation of proteasomal activity is being analyzed as a proof-of-principle strategy to increase cellular resistance to a broad range of proteotoxic stressors. These approaches have included the stimulation of proteasomes through the overexpression of individual proteasome subunits, phosphorylation, or conformational changes induced by small molecules or peptides. In contrast to these approaches, we evaluated a transcription-driven increase in the total proteasome pool to enhance the proteolytic capacity of degenerating retinal neurons. We show that overexpression of nuclear factor erythroid-2-like 1 (Nfe2l1) transcription factor stimulated proteasome biogenesis and activity, improved the clearance of the ubiquitin-proteasomal reporter, and delayed photoreceptor neuron loss in a preclinical mouse model of human blindness caused by misfolded proteins. The findings highlight Nfe2l1 as an emerging therapeutic target to treat neurodegenerative diseases linked to protein misfolding.
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Affiliation(s)
- Yixiao Wang
- Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA
| | - Aaron Snell
- Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA
| | - Frank M. Dyka
- Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA
| | - Elizabeth R. Colvin
- Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA
| | - Cristhian Ildefonso
- Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA
| | - John D. Ash
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Ekaterina S. Lobanova
- Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA
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Rosarda JD, Giles S, Harkins-Perry S, Mills EA, Friedlander M, Wiseman RL, Eade KT. Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity. Nat Commun 2023; 14:4119. [PMID: 37433773 DOI: 10.1038/s41467-023-39775-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 06/23/2023] [Indexed: 07/13/2023] Open
Abstract
The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remain poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define biological pathways that modulate 1-dSL toxicity in human retinal organoids. Our results demonstrate that 1-dSLs differentially activate signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Müller glia. Using a combination of pharmacologic activators and inhibitors, we show that sustained PERK signaling through the integrated stress response (ISR) and deficiencies in signaling through the protective ATF6 arm of the UPR are implicated in 1-dSL-induced photoreceptor toxicity. Further, we demonstrate that pharmacologic activation of ATF6 mitigates 1-dSL toxicity without impacting PERK/ISR signaling. Collectively, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different arms of the UPR.
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Affiliation(s)
- Jessica D Rosarda
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Sarah Giles
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Lowy Medical Research Institute, La Jolla, CA, 92037, USA
| | - Sarah Harkins-Perry
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Lowy Medical Research Institute, La Jolla, CA, 92037, USA
| | - Elizabeth A Mills
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Lowy Medical Research Institute, La Jolla, CA, 92037, USA
| | - Martin Friedlander
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
- Lowy Medical Research Institute, La Jolla, CA, 92037, USA
| | - R Luke Wiseman
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Kevin T Eade
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
- Lowy Medical Research Institute, La Jolla, CA, 92037, USA.
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Chan C, Seitz B, Käsmann-Kellner B. Morphological and Functional Aspects and Quality of Life in Patients with Achromatopsia. J Pers Med 2023; 13:1106. [PMID: 37511719 PMCID: PMC10381746 DOI: 10.3390/jpm13071106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/02/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
(1) Background: Achromatopsia is a rare disease of which the natural course and impact on life are still unknown to this date. We aimed to assess the morphological, functional characteristics, and quality of life in a large sample size of patients with achromatopsia. (2) A total of 94 achromats were included in this retrospective cohort study. Sixty-four were patients of the Department of Ophthalmology, Saarland University Medical Centre in Homburg/Saar, Germany, between 2008 and 2021. Thirty further participants with achromatopsia from the national support group were included using an online questionnaire, which is available under 'Supplementary data'. Statistical analysis was performed using SPSS Version 25; (3) The 94 patients (37 males (39.4%) and 57 females (60.6%)) showed a mean age of 24.23 ± 18.53 years. Visual acuity was stable (SD ± 0.22 logMAR at 1.0 logMAR) over a time of observation from 2008 to 2021. Edge filter glasses were the most used optical aids, while enlarged reading glasses were the most used low vision aids. (4) Conclusions: Our findings give an insight into describing the natural process and the quality of life of achromatopsia. The results demonstrate that achromatopsia is a predominantly stationary disease. The individual prescription of edge filters and low-vision aids is essential following a personalised fitting.
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Affiliation(s)
- Caroline Chan
- Department of Ophthalmology, University of Saarland Medical Center in Homburg/Saar, 66421 Homburg/Saar, Germany
| | - Berthold Seitz
- Department of Ophthalmology, University of Saarland Medical Center in Homburg/Saar, 66421 Homburg/Saar, Germany
| | - Barbara Käsmann-Kellner
- Department of Ophthalmology, University of Saarland Medical Center in Homburg/Saar, 66421 Homburg/Saar, Germany
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Grainger RM, Lauderdale JD, Collins JL, Trout KL, McCullen Krantz S, Wolfe SS, Netland PA. Report on the 2021 Aniridia North America symposium on PAX6, aniridia, and beyond. Ocul Surf 2023; 29:423-431. [PMID: 37247841 DOI: 10.1016/j.jtos.2023.05.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 05/31/2023]
Abstract
The inaugural Aniridia North America (ANA) Symposium was held on the first weekend in November 2021 in Charlottesville, VA, at the University of Virginia. The purpose of this meeting was to bring together an international group of scientists, physicians, patient advocacy groups, and individuals with aniridia to discuss recent advances in knowledge about aniridia and other congenital eye diseases and the development of potential treatments for congenital eye disorders using personalized medicine. Leaders in several areas of eye research and clinical treatment provided a broad perspective on new research advances that impact an understanding of the causes of the damage to the eye associated with aniridia and the development of novel treatments for this and related disorders. Here we summarize the research discussed at the symposium.
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Affiliation(s)
- Robert M Grainger
- Aniridia North America, LaGrange, IL, 60525, USA; Department of Biology, 326 Gilmer Hall University of Virginia 485 McCormick Road P.O. Box 400328 Charlottesville, VA 22904, USA.
| | - James D Lauderdale
- Aniridia North America, LaGrange, IL, 60525, USA; Department of Cellular Biology, University of Georgia, Athens, GA, 30602, USA.
| | | | | | | | | | - Peter A Netland
- Aniridia North America, LaGrange, IL, 60525, USA; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
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McLaughlin T, Wang J, Jia L, Wu F, Wang Y, Wang JJ, Mu X, Zhang SX. Neuronal p58 IPK Protects Retinal Ganglion Cells Independently of Macrophage/Microglia Activation in Ocular Hypertension. Cells 2023; 12:1558. [PMID: 37371028 PMCID: PMC10297187 DOI: 10.3390/cells12121558] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 06/29/2023] Open
Abstract
p58IPK is a multifaceted endoplasmic reticulum (ER) chaperone and a regulator of eIF2α kinases involved in a wide range of cellular processes including protein synthesis, ER stress response, and macrophage-mediated inflammation. Systemic deletion of p58IPK leads to age-related loss of retinal ganglion cells (RGC) and exacerbates RGC damage induced by ischemia/reperfusion and increased intraocular pressure (IOP), suggesting a protective role of p58IPK in the retina. However, the mechanisms remain elusive. Herein, we investigated the cellular mechanisms underlying the neuroprotection action of p58IPK using conditional knockout (cKO) mouse lines where p58IPK is deleted in retinal neurons (Chx10-p58IPK cKO) or in myeloid cells (Lyz2-p58IPK cKO). In addition, we overexpressed p58IPK by adeno-associated virus (AAV) in the retina to examine the effect of p58IPK on RGC survival after ocular hypertension (OHT) in wild type (WT) mice. Our results show that overexpression of p58IPK by AAV significantly improved RGC survival after OHT in WT mice, suggesting a protective effect of p58IPK on reducing RGC injury. Conditional knockout of p58IPK in retinal neurons or in myeloid cells did not alter retinal structure or cellular composition. However, a significant reduction in the b wave of light-adapted electroretinogram (ERG) was observed in Chx10-p58IPK cKO mice. Deletion of p58IPK in retinal neurons exacerbates RGC loss at 14 days after OHT. In contrast, deficiency of p58IPK in myeloid cells increased the microglia/macrophage activation but had no effect on RGC loss. We conclude that deletion of p58IPK in macrophages increases their activation, but does not influence RGC survival. These results suggest that the neuroprotective action of p58IPK is mediated by its expression in retinal neurons, but not in macrophages. Therefore, targeting p58IPK specifically in retinal neurons is a promising approach for the treatment of neurodegenerative retinal diseases including glaucoma.
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Affiliation(s)
- Todd McLaughlin
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
| | - Jinli Wang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
| | - Liyun Jia
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
- Beijing Tongren Hospital, Capital Medical University, Beijing 100005, China
| | - Fuguo Wu
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
| | - Yaqin Wang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
- Taihe Hospital, Hubei University of Medicine, Shiyan 442005, China
| | - Joshua J. Wang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
| | - Xiuqian Mu
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
- Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
| | - Sarah X. Zhang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
- Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
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Petrosyan E, Fares J, Fernandez LG, Yeeravalli R, Dmello C, Duffy JT, Zhang P, Lee-Chang C, Miska J, Ahmed AU, Sonabend AM, Balyasnikova IV, Heimberger AB, Lesniak MS. Endoplasmic Reticulum Stress in the Brain Tumor Immune Microenvironment. Mol Cancer Res 2023; 21:389-396. [PMID: 36652630 PMCID: PMC10159901 DOI: 10.1158/1541-7786.mcr-22-0920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/05/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
Immunotherapy has emerged as a powerful strategy for halting cancer progression. However, primary malignancies affecting the brain have been exempt to this success. Indeed, brain tumors continue to portend severe morbidity and remain a globally lethal disease. Extensive efforts have been directed at understanding how tumor cells survive and propagate within the unique microenvironment of the central nervous system (CNS). Cancer genetic aberrations and metabolic abnormalities provoke a state of persistent endoplasmic reticulum (ER) stress that in turn promotes tumor growth, invasion, therapeutic resistance, and the dynamic reprogramming of the infiltrating immune cells. Consequently, targeting ER stress is a potential therapeutic approach. In this work, we provide an overview of how ER stress response is advantageous to brain tumor development, discuss the significance of ER stress in governing antitumor immunity, and put forth therapeutic strategies of regulating ER stress to augment the effect of immunotherapy for primary CNS tumors.
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Affiliation(s)
- Edgar Petrosyan
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jawad Fares
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Luis G. Fernandez
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Ragini Yeeravalli
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Crismita Dmello
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Joseph T. Duffy
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Peng Zhang
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Catalina Lee-Chang
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jason Miska
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Atique U. Ahmed
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Adam M. Sonabend
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Irina V. Balyasnikova
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Amy B. Heimberger
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Maciej S. Lesniak
- Department of Neurological Surgery
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
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Genetic and Clinical Characterization of Danish Achromatopsia Patients. Genes (Basel) 2023; 14:genes14030690. [PMID: 36980963 PMCID: PMC10048638 DOI: 10.3390/genes14030690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/07/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023] Open
Abstract
Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945–2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: CNGA3; CNGB3; GNAT2; PDE6C and PDE6H; and novel variants were identified in CNGB3 and PDE6C. Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in CNGB3 and PDE6C. The results indicate that myopia could be more frequently occurring with variants in GNAT2, PDE6C and PDE6H and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.
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Priglinger CS, Rudolph G, Schmid I, Mazzola P, Haack TB, Reith M, Stingl K, Weisschuh N. Characterization of a novel non-canonical splice site variant (c.886-5T>A) in NBAS and description of the associated phenotype. Mol Genet Genomic Med 2023; 11:e2120. [PMID: 36479642 PMCID: PMC10009903 DOI: 10.1002/mgg3.2120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/28/2022] [Accepted: 11/29/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Biallelic pathogenic variants in the neuroblastoma-amplified sequence (NBAS) gene manifest in a broad spectrum of disorders, including, but not limited to recurrent acute liver failure, skeletal dysmorphism, susceptibility to infections, and SOPH syndrome with its cardinal symptoms of short stature, optic atrophy, and Pelger-Huët anomaly. We aimed to present clinical and genetic characteristics of two sisters (20 and 15 years old) who were diagnosed with optic atrophy and cone dystrophy in childhood. Genome sequencing revealed two novel variants in NBAS in compound heterozygous state in both sisters, namely a 1-bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non-canonical splice site variant of unclear significance (c.886-5T>A; p.?). RESULTS Clinical examination and history revealed cone dystrophy, optic atrophy, and Pelger-Huët anomaly, but no short stature, recurrent acute liver failure, or susceptibility to infections. RNA analysis revealed that the c.886-5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the β-propeller region of the protein. CONCLUSION We hypothesize that the phenotype of our subjects, which appears to be at the end of the spectrum of NBAS-related disorders, could be explained by residual protein function mediated by the non-canonical splice site variant c.886-5T>A. Our study contributes to the existing knowledge on the genotypic and phenotypic spectrum of NBAS-related disorders.
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Affiliation(s)
- Claudia S Priglinger
- University Eye Hospital, Ludwig Maximilians University of Munich, Munich, Germany
| | - Günter Rudolph
- University Eye Hospital, Ludwig Maximilians University of Munich, Munich, Germany
| | - Irene Schmid
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Pascale Mazzola
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Tobias B Haack
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.,Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
| | - Milda Reith
- Centre for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany
| | - Katarina Stingl
- Centre for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany
| | - Nicole Weisschuh
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
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Hu R, Jiang X, Yang H, Liu G. Selection signature analysis reveals RDH5 performed key function in vision during sheep domestication process. Arch Anim Breed 2023. [DOI: 10.5194/aab-66-81-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Abstract. As one of the most successful domesticated animals in the Neolithic age,
sheep gradually migrated all over the world with human activities. During the
domestication process, remarkable changes have taken place in morphology,
physiology, and behavior, resulting in different breeds with different
characters via artificial and natural selection. However, the genetic
background responsible for these phenotypic variations remains largely
unclear. Here, we used whole genome resequencing technology to compare and
analyze the genome differences between Asiatic mouflon wild sheep (Ovis orientalis) and Hu
sheep (Ovis aries). A total of 755 genes were positively selected in the process of
domestication and selection, and the genes related to sensory perception had
directional evolution in the autosomal region, such as OPRL1, LEF1, TAS1R3, ATF6, VSX2, MYO1A, RDH5, and some novel
genes. A missense mutation of c.T722C/p.M241T in exon 4 of RDH5 existing in sheep
were found, and the T allele was completely fixed in Hu sheep. In addition, the
mutation with the C allele reduced the retinol dehydrogenase activity encoding
by RDH5, which can impair retinoic acid metabolism and further influenced the visual
cycle. Overall, our results showed significant enrichment for positively
selected genes involved in sensory perception development during sheep
domestication; RDH5 and its variants may be related to the retinal degeneration
in sheep. We infer that the wild sheep ancestors with weaker visual sensitivity
were weeded out by humans, and the mutation was selective, swept by the dual
pressures of natural and artificial selection.
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Atypical Foveal Hypoplasia in Best Disease. J Pers Med 2023; 13:jpm13020337. [PMID: 36836571 PMCID: PMC9959407 DOI: 10.3390/jpm13020337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
PURPOSE To determine the prevalence and characteristics of foveal hypoplasia (also called fovea plana) in patients with Best disease using spectral-domain (SD) optical coherence tomography (OCT) and OCT-angiography (OCT-A). DESIGN A retrospective observational study including patients diagnosed with Best disease. SUBJECTS AND PARTICIPANTS Fifty-nine eyes of thirty-two patients (fifteen females (46.9%) and seventeen males (53.1%), p = 0.9) diagnosed with Best disease were included. Patients' eyes were categorized into two groups: Eyes with a fovea plana appearance ('FP group') and eyes without fovea plana appearance ('no FP group'), based on the foveal appearance on B-scan SD-OCT. METHODS AND MAIN OUTCOME MEASURES Cross-sectional OCT images were assessed for the persistence of inner retinal layers (IRL) and OCT-A was analyzed for the presence of a foveal avascular zone (FAZ), the size of which was determined when applicable. RESULTS Overall, 16 eyes (27.1%) of 9 patients had a fovea plana appearance ('FP group') with the persistence of IRL, and 43 eyes (72.9%) of 23 patients did not have fovea plana appearance ('no FP group'). Among FP eyes, OCT-A performed in 13 eyes showed bridging vessels through the FAZ in 100% of eyes with OCT-A. Using Thomas classification, 14 out of the 16 eyes with fovea plana (87.5%) had atypical foveal hypoplasia, and the 2 others (12.5%) had a grade 1b fovea plana. CONCLUSION In our series, foveal hypoplasia was present in 27.1% of patients with Best disease. OCT-A showed bridging vessels through the FAZ in all eyes. These findings highlight the microvascular changes associated with Best disease, which can be an early sign of the disease in patients with a family history.
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Siles L, Gaudó P, Pomares E. High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs. Int J Mol Sci 2023; 24:ijms24043655. [PMID: 36835061 PMCID: PMC9964936 DOI: 10.3390/ijms24043655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/03/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies that currently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous PDE6C pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia.
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Affiliation(s)
- Laura Siles
- Fundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, Spain
- Departament de Genètica, IMO Grupo Miranza, 08035 Barcelona, Spain
| | - Paula Gaudó
- Fundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, Spain
- Departament de Genètica, IMO Grupo Miranza, 08035 Barcelona, Spain
| | - Esther Pomares
- Fundació de Recerca de l’Institut de Microcirurgia Ocular, 08035 Barcelona, Spain
- Departament de Genètica, IMO Grupo Miranza, 08035 Barcelona, Spain
- Correspondence:
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Ali S, Ali U, Qamar A, Zafar I, Yaqoob M, Ain QU, Rashid S, Sharma R, Nafidi HA, Bin Jardan YA, Bourhia M. Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function. Front Chem 2023; 11:1173624. [PMID: 37153521 PMCID: PMC10160440 DOI: 10.3389/fchem.2023.1173624] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
The HRAS gene plays a crucial role in regulating essential cellular processes for life, and this gene's misregulation is linked to the development of various types of cancers. Nonsynonymous single nucleotide polymorphisms (nsSNPs) within the coding region of HRAS can cause detrimental mutations that disrupt wild-type protein function. In the current investigation, we have employed in-silico methodologies to anticipate the consequences of infrequent genetic variations on the functional properties of the HRAS protein. We have discovered a total of 50 nsSNPs, of which 23 were located in the exon region of the HRAS gene and denoting that they were expected to cause harm or be deleterious. Out of these 23, 10 nsSNPs ([G60V], [G60D], [R123P], [D38H], [I46T], [G115R], [R123G], [P11OL], [A59L], and [G13R]) were identified as having the most delterious effect based on results of SIFT analysis and PolyPhen2 scores ranging from 0.53 to 69. The DDG values -3.21 kcal/mol to 0.87 kcal/mol represent the free energy change associated with protein stability upon mutation. Interestingly, we identified that the three mutations (Y4C, T58I, and Y12E) were found to improve the structural stability of the protein. We performed molecular dynamics (MD) simulations to investigate the structural and dynamic effects of HRAS mutations. Our results showed that the stable model of HRAS had a significantly lower energy value of -18756 kj/mol compared to the initial model of -108915 kj/mol. The RMSD value for the wild-type complex was 4.40 Å, and the binding energies for the G60V, G60D, and D38H mutants were -107.09 kcal/mol, -109.42 kcal/mol, and -107.18 kcal/mol, respectively as compared to wild-type HRAS protein had -105.85 kcal/mol. The result of our investigation presents convincing corroboration for the potential functional significance of nsSNPs in augmenting HRAS expression and adding to the activation of malignant oncogenic signalling pathways.
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Affiliation(s)
- Sadaqat Ali
- Medical Department, DHQ Hospital Bhawalnagr, Punjab, Pakistan
| | | | - Adeem Qamar
- Department of Pathology, Sahiwal Medical College Sahiwal, Punjab, Pakistan
| | - Imran Zafar
- Department of Bioinformatics and Computational Biology, Virtual University of Pakistan, Punjab, Pakistan
| | - Muhammad Yaqoob
- Department of Life Sciences, ARID University-Barani Institute of Sciences Burewala Campus, Punjab, Pakistan
| | - Qurat ul Ain
- Department of Chemistry, Government College Women University, Faisalabad, Pakistan
| | - Summya Rashid
- Department of Bioinformatics and Computational Biology, Virtual University of Pakistan, Punjab, Pakistan
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
- *Correspondence: Mohammed Bourhia, ; Rohit Sharma,
| | - Hiba-Allah Nafidi
- Department of Food Science, Faculty of Agricultural and Food Sciences, Laval University, Quebec City, QC, Canada
| | - Yousef A. Bin Jardan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Bourhia
- Laboratory of Chemistry and Biochemistry, Faculty of Medicine and Pharmacy, Ibn Zohr University, Agadir, Morocco
- *Correspondence: Mohammed Bourhia, ; Rohit Sharma,
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The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome. Int J Mol Sci 2022; 24:ijms24010230. [PMID: 36613674 PMCID: PMC9820298 DOI: 10.3390/ijms24010230] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of "poorly folded proteins", namely, the induction of pathogenic ER stress in pancreatic β-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic β-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction.
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Gao L, Jin N, Ye Z, Ma T, Huang Y, Li H, Du J, Li Z. A possible connection between reactive oxygen species and the unfolded protein response in lens development: From insight to foresight. Front Cell Dev Biol 2022; 10:820949. [PMID: 36211466 PMCID: PMC9535091 DOI: 10.3389/fcell.2022.820949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 08/31/2022] [Indexed: 11/28/2022] Open
Abstract
The lens is a relatively special and simple organ. It has become an ideal model to study the common developmental characteristics among different organic systems. Lens development is a complex process influenced by numerous factors, including signals from the intracellular and extracellular environment. Reactive oxygen species (ROS) are a group of highly reactive and oxygen-containing molecules that can cause endoplasmic reticulum stress in lens cells. As an adaptive response to ER stress, lens cells initiate the unfolded protein response (UPR) to maintain normal protein synthesis by selectively increasing/decreasing protein synthesis and increasing the degradation of misfolded proteins. Generally, the UPR signaling pathways have been well characterized in the context of many pathological conditions. However, recent studies have also confirmed that all three UPR signaling pathways participate in a variety of developmental processes, including those of the lens. In this review, we first briefly summarize the three stages of lens development and present the basic profiles of ROS and the UPR. We then discuss the interconnections between lens development and these two mechanisms. Additionally, the potential adoption of human pluripotent stem-cell-based lentoids in lens development research is proposed to provide a novel perspective on future developmental studies.
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Affiliation(s)
- Lixiong Gao
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ni Jin
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
- Department of Endocrinology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, The Chinese PLA General Hospital, Beijing, China
| | - Zi Ye
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Tianju Ma
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yang Huang
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hongyu Li
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jinlin Du
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhaohui Li
- Senior Department of Ophthalmology, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
- *Correspondence: Zhaohui Li,
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Solaki M, Baumann B, Reuter P, Andreasson S, Audo I, Ayuso C, Balousha G, Benedicenti F, Birch D, Bitoun P, Blain D, Bocquet B, Branham K, Català-Mora J, De Baere E, Dollfus H, Falana M, Giorda R, Golovleva I, Gottlob I, Heckenlively JR, Jacobson SG, Jones K, Jägle H, Janecke AR, Kellner U, Liskova P, Lorenz B, Martorell-Sampol L, Messias A, Meunier I, Belga Ottoni Porto F, Papageorgiou E, Plomp AS, de Ravel TJL, Reiff CM, Renner AB, Rosenberg T, Rudolph G, Salati R, Sener EC, Sieving PA, Stanzial F, Traboulsi EI, Tsang SH, Varsanyi B, Weleber RG, Zobor D, Stingl K, Wissinger B, Kohl S. Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia. Hum Mutat 2022; 43:832-858. [PMID: 35332618 DOI: 10.1002/humu.24371] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 02/23/2022] [Accepted: 03/22/2022] [Indexed: 11/06/2022]
Abstract
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
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Affiliation(s)
- Maria Solaki
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Britta Baumann
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Peggy Reuter
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Sten Andreasson
- Department of Ophthalmology, University Hospital Lund, Lund, Sweden
| | - Isabelle Audo
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
- CHNO des Quinze-Vingts, Centre de Référence Maladies Rares REFERET, and INSERM-DGOS CIC1423, Paris, France
| | - Carmen Ayuso
- Department of Genetics & Genomics, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz University Hospital - Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Ghassan Balousha
- Department of Pathology and Histology, Faculty of Medicine, Al-Quds University, Eastern Jerusalem, Palestine
| | - Francesco Benedicenti
- Clinical Genetics Service and South Tyrol Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | - David Birch
- Retina Foundation of the Southwest, Dallas, Texas, USA
| | - Pierre Bitoun
- Genetique Medicale, CHU Paris Nord, Hopital Jean Verdier, Bondy Cedex, France
| | | | - Beatrice Bocquet
- National Reference Centre for Inherited Sensory Diseases, Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France
| | - Kari Branham
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Jaume Català-Mora
- Unitat de Distròfies Hereditàries de Retina Hospital Sant Joan de Déu, Barcelona, Esplugues de Llobregat, Spain
| | - Elfride De Baere
- Department of Biomolecular Medicine, Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium
| | - Helene Dollfus
- CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- U-1112, Inserm, Faculté de Médecine, Université de Strasbourg, Strasbourg, France
| | - Mohammed Falana
- Department of Pathology and Histology, Faculty of Medicine, Al-Quds University, Eastern Jerusalem, Palestine
| | - Roberto Giorda
- Molecular Biology Laboratory, Scientific Institute IRCCS E. Medea, Bosisio Parini, Lecco, Italy
| | - Irina Golovleva
- Department of Medical Biosciences/Medical and Clinical Genetics, University of Umea, Umea, Sweden
| | - Irene Gottlob
- The University of Leicester Ulverscroft Eye Unit, Leicester Royal Infirmary, Leicester, UK
| | - John R Heckenlively
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Samuel G Jacobson
- Department of Ophthalmology, Perelman School of Medicine, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kaylie Jones
- Retina Foundation of the Southwest, Dallas, Texas, USA
| | - Herbert Jägle
- Department of Ophthalmology, University of Regensburg, Regensburg, Germany
| | - Andreas R Janecke
- Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
| | - Ulrich Kellner
- Zentrum für Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Siegburg, Germany
- RetinaScience, Bonn, 53192, Germany
| | - Petra Liskova
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Birgit Lorenz
- Department of Ophthalmology, Justus-Liebig University Giessen, Giessen, Germany
- Department of Ophthalmology, Universitaetsklinikum Bonn, Bonn, Germany
| | | | - André Messias
- Department of Ophthalmology, Otorhinolaryngology, and Head and Neck Surgery, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Isabelle Meunier
- National Reference Centre for Inherited Sensory Diseases, Montpellier University Hospital, University of Montpellier, Montpellier, France
- Sensgene Care Network, France
| | | | - Eleni Papageorgiou
- Department of Ophthalmology, University Hospital of Larissa, Mezourlo, Larissa, Greece
| | - Astrid S Plomp
- Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Thomy J L de Ravel
- Centre for Medical Genetics, University Hospital Brussels, Brussels, Belgium
| | | | | | - Thomas Rosenberg
- Department of Ophthalmology, National Eye Clinic, Glostrup Hospital, Glostrup, Denmark
| | - Günther Rudolph
- University Eye Hospital, Ludwig Maximilians University, Munich, Germany
| | - Roberto Salati
- Scientific Institute, IRCCS Eugenio Medea, Pediatric Ophthalmology Unit, Bosisio Parini, Lecco, Italy
| | - E Cumhur Sener
- Strabismus and Pediatric Ophthalmology, Private Practice, Ankara, Turkey
| | - Paul A Sieving
- Center for Ocular Regenerative Therapy, School of Medicine, University of California Davis, Sacramento, USA
| | - Franco Stanzial
- Clinical Genetics Service and South Tyrol Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy
| | - Elias I Traboulsi
- Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Stephen H Tsang
- Department of Ophthalmology, Pathology and Cell Biology, College of Physicians and Surgeons, Columbia Stem Cell Initiative, Columbia University, New York City, New York, USA
| | - Balázs Varsanyi
- Department of Ophthalmology, Medical School, University of Pécs and Ganglion Medical Center, Pécs, Pécs, Hungary
| | - Richard G Weleber
- Oregon Health & Science University, Ophthalmic Genetics Service of the Casey Eye Institute, 515 SW Campus Drive, 97239, Portland, Oregon, USA
| | - Ditta Zobor
- Centre for Ophthalmology, Institute for Ophthalmic Research, University Hospital Tübingen, Tübingen, Germany
- Department of Ophthalmology, Semmelweis University Budapest, Budapest, Hungary
| | - Katarina Stingl
- Center for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany
- Center for Rare Eye Diseases, University of Tübingen, Tübingen, Germany
| | - Bernd Wissinger
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Susanne Kohl
- Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
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48
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Emerging roles of endoplasmic reticulum proteostasis in brain development. Cells Dev 2022; 170:203781. [DOI: 10.1016/j.cdev.2022.203781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 04/12/2022] [Accepted: 04/20/2022] [Indexed: 11/21/2022]
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Thomas MG, Papageorgiou E, Kuht HJ, Gottlob I. Normal and abnormal foveal development. Br J Ophthalmol 2022; 106:593-599. [PMID: 33148537 DOI: 10.1136/bjophthalmol-2020-316348] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 10/13/2020] [Accepted: 10/17/2020] [Indexed: 01/06/2023]
Abstract
Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal lamination of the IRLs sometimes with persistent IRLs. Morphology of FH provides clues to diagnoses, and grading correlates to visual acuity. The outer segment thickness is a surrogate marker for cone density and in foveal hypoplasia this correlates strongly with visual acuity. In preverbal children grading FH can help predict future visual acuity.
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Affiliation(s)
- Mervyn G Thomas
- Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK
| | - Eleni Papageorgiou
- Department of Ophthalmology, University Hospital of Larissa, Larissa, Greece
| | - Helen J Kuht
- Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK
| | - Irene Gottlob
- Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK
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50
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McLaughlin T, Medina A, Perkins J, Yera M, Wang JJ, Zhang SX. Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications. Mol Neurodegener 2022; 17:25. [PMID: 35346303 PMCID: PMC8962104 DOI: 10.1186/s13024-022-00528-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 03/04/2022] [Indexed: 12/22/2022] Open
Abstract
Background The retina, as part of the central nervous system (CNS) with limited capacity for self-reparation and regeneration in mammals, is under cumulative environmental stress due to high-energy demands and rapid protein turnover. These stressors disrupt the cellular protein and metabolic homeostasis, which, if not alleviated, can lead to dysfunction and cell death of retinal neurons. One primary cellular stress response is the highly conserved unfolded protein response (UPR). The UPR acts through three main signaling pathways in an attempt to restore the protein homeostasis in the endoplasmic reticulum (ER) by various means, including but not limited to, reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation. Moreover, recent work has identified a novel function of the UPR in regulation of cellular metabolism and mitochondrial function, disturbance of which contributes to neuronal degeneration and dysfunction. The role of the UPR in retinal neurons during aging and under disease conditions in age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma, and diabetic retinopathy (DR) has been explored over the past two decades. Each of the disease conditions and their corresponding animal models provide distinct challenges and unique opportunities to gain a better understanding of the role of the UPR in the maintenance of retinal health and function. Method We performed an extensive literature search on PubMed and Google Scholar using the following keywords: unfolded protein response, metabolism, ER stress, retinal degeneration, aging, age-related macular degeneration, retinitis pigmentosa, glaucoma, diabetic retinopathy. Results and conclusion We summarize recent advances in understanding cellular stress response, in particular the UPR, in retinal diseases, highlighting the potential roles of UPR pathways in regulation of cellular metabolism and mitochondrial function in retinal neurons. Further, we provide perspective on the promise and challenges for targeting the UPR pathways as a new therapeutic approach in age- and disease-related retinal degeneration.
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Affiliation(s)
- Todd McLaughlin
- Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 955 Main Street, Buffalo, NY, 14203, USA
| | - Andy Medina
- Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 955 Main Street, Buffalo, NY, 14203, USA
| | - Jacob Perkins
- Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 955 Main Street, Buffalo, NY, 14203, USA
| | - Maria Yera
- Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 955 Main Street, Buffalo, NY, 14203, USA.,Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Joshua J Wang
- Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 955 Main Street, Buffalo, NY, 14203, USA.,Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Sarah X Zhang
- Department of Ophthalmology and Ira G. Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 955 Main Street, Buffalo, NY, 14203, USA. .,Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA. .,Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
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