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Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 38444

Special Issue Editors

Prof. Dr. Isabelle Audo

E-Mail Website
Guest Editor
INSERM, CNRS, Institut de la Vision, Sorbonne Université, F-75012 Paris, France
Interests: inherited stationary and progressive retinal diseases; genetic mechanisms; phenotyping including electrophysiology; psychophysics; fundus autofluorescence imaging; OCT; genotyping and gene identification including next generation sequencing; phenotype-genotype correlation; cellular biology and biochemical techniques applied to retinal physiology and pathology; disease modeling on cellular (including iPS) and animal models; innovative therapies
Special Issues, Collections and Topics in MDPI journals
Dr. Christina Zeitz

E-Mail Website
Guest Editor
INSERM, CNRS, Institut de la Vision, Sorbonne Université, F-75012 Paris, France
Interests: gene identification; next generation sequencing; phenotype–genotype correlations in patients with different retinal diseases; congenital stationary night blindness; using genetics to dissect retinal signaling; decipher signaling from photoreceptors to bipolar cells; molecular biology; human genetics; functional in vitro and in vivo characterization of retinal proteins; gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The past decades have seen significant developments in inherited retinal diseases (IRD), with the advent of next generation sequencing, as well as innovative therapies. Nevertheless, despite this progress, the genetic defect is still missing in about 30% of non-syndromic IRD, even with comprehensive testing, including classical linkage analyses, positional cloning, candidate gene, and Sanger sequencing approaches or, more recently, targeted next generation sequencing, whole exome (WES), or whole genome sequencing (WGS). In these cases, mutations may be located in novel genes, in untranslated exonic or intronic regions, or may represent genomic rearrangements overlooked with commonly used sequencing methods. The bottle-neck to fill in the knowledge gap is to replicate findings in large cohorts and to develop relevant and rapid tests to validate the pathogenicity of newly identified variants, especially for those in regulatory regions. In the future, efforts should be made to identify these missing defects, to provide accurate genetic counseling and disease prognosis, and to prepare patients for therapeutic trials, but also to improve our basic understanding of retinal physiology. In this Special Issue, we welcome original research or review articles related to gene identification, functional studies to validate pathogenic mechanisms, and comprehensive phenotype–genotype correlations underlying inherited retina disorders.

Prof. Isabelle Audo
Dr. Christina Zeitz
Guest Editors

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Keywords

  • inherited retinal dystrophies
  • gene identification
  • next generation sequencing
  • functional assay
  • phenotype–genotype correlation

Published Papers (15 papers)

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Research

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24 pages, 3663 KiB  
Article
Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation
by Arnau Navinés-Ferrer, Sheila Ruiz-Nogales, Rafael Navarro and Esther Pomares
Int. J. Mol. Sci. 2022, 23(13), 7432; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137432 - 04 Jul 2022
Cited by 2 | Viewed by 2557
Abstract
Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia [...] Read more.
Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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17 pages, 3679 KiB  
Article
Retrospective Natural History Study of RPGR-Related Cone- and Cone-Rod Dystrophies While Expanding the Mutation Spectrum of the Disease
by Marco Nassisi, Giuseppe De Bartolo, Saddek Mohand-Said, Christel Condroyer, Aline Antonio, Marie-Elise Lancelot, Kinga Bujakowska, Vasily Smirnov, Thomas Pugliese, John Neidhardt, José-Alain Sahel, Christina Zeitz and Isabelle Audo
Int. J. Mol. Sci. 2022, 23(13), 7189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137189 - 28 Jun 2022
Cited by 7 | Viewed by 1708
Abstract
Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGRORF15) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While RPGR-related RCDs have been frequently evaluated, [...] Read more.
Variants in the X-linked retinitis pigmentosa GTPase regulator gene (RPGR) and, specifically, in its retinal opening reading frame-15 isoform (RPGRORF15) may cause rod-cone (RCD), cone, and cone-rod dystrophies (CDs and CRDs). While RPGR-related RCDs have been frequently evaluated, the characteristics and progression of RPGR-related CD/CRDs are largely unknown. Therefore, the goal of our work was to perform genotype–phenotype correlations specifically in RPGRORF15-related CD/CRDs. This retrospective longitudinal study included 34 index patients and two affected relatives with a molecular diagnosis of RPGR-related CD/CRDs. Patients were recruited at the “Quinze-Vingts” Hospital, Paris, France and screened for mutations in RPGRORF15 at the Institut de la Vision, Paris, France. We identified 29 distinct variants, of which 27 were truncating. All were located in the 3′ half of the RPGRORF15 transcript. Twenty of them were novel. Fifteen subjects were affected by CD, the remaining had CRD. When analyzing the longitudinal data, a progressive decline in visual acuity (VA) was noted, with more than 60% of the patients reaching VA ≥ 1 LogMar in the best eye after the fifth decade of life. To our knowledge, this is the largest described study of a cohort of CD/CRD patients affected by RPGRORF15 variants. Longitudinal data showed a rapidly progressive disease, possibly locating an optimal window of intervention for future therapies in younger ages. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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15 pages, 3032 KiB  
Article
Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging
by Jasdeep S. Gill, Vasileios Theofylaktopoulos, Andreas Mitsios, Sarah Houston, Ahmed M. Hagag, Adam M. Dubis and Mariya Moosajee
Int. J. Mol. Sci. 2022, 23(8), 4198; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084198 - 11 Apr 2022
Cited by 5 | Viewed by 2172
Abstract
Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on [...] Read more.
Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 μm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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17 pages, 7345 KiB  
Article
Whole Genome Sequencing, Focused Assays and Functional Studies Increasing Understanding in Cryptic Inherited Retinal Dystrophies
by Benjamin M. Nash, Alan Ma, Gladys Ho, Elizabeth Farnsworth, Andre E. Minoche, Mark J. Cowley, Christopher Barnett, Janine M. Smith, To Ha Loi, Karen Wong, Luke St Heaps, Dale Wright, Marcel E. Dinger, Bruce Bennetts, John R. Grigg and Robyn V. Jamieson
Int. J. Mol. Sci. 2022, 23(7), 3905; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073905 - 31 Mar 2022
Cited by 4 | Viewed by 2210
Abstract
The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the [...] Read more.
The inherited retinal dystrophies (IRDs) are a clinically and genetically complex group of disorders primarily affecting the rod and cone photoreceptors or other retinal neuronal layers, with emerging therapies heralding the need for accurate molecular diagnosis. Targeted capture and panel-based strategies examining the partial or full exome deliver molecular diagnoses in many IRD families tested. However, approximately one in three families remain unsolved and unable to obtain personalised recurrence risk or access to new clinical trials or therapy. In this study, we investigated whole genome sequencing (WGS), focused assays and functional studies to assist with unsolved IRD cases and facilitate integration of these approaches to a broad molecular diagnostic clinical service. The WGS approach identified variants not covered or underinvestigated by targeted capture panel-based clinical testing strategies in six families. This included structural variants, with notable benefit of the WGS approach in repetitive regions demonstrated by a family with a hybrid gene and hemizygous missense variant involving the opsin genes, OPN1LW and OPN1MW. There was also benefit in investigation of the repetitive GC-rich ORF15 region of RPGR. Further molecular investigations were facilitated by focused assays in these regions. Deep intronic variants were identified in IQCB1 and ABCA4, with functional RNA based studies of the IQCB1 variant revealing activation of a cryptic splice acceptor site. While targeted capture panel-based methods are successful in achieving an efficient molecular diagnosis in a proportion of cases, this study highlights the additional benefit and clinical value that may be derived from WGS, focused assays and functional genomics in the highly heterogeneous IRDs. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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11 pages, 1588 KiB  
Article
Receptive Field Sizes of Nyxnob Mouse Retinal Ganglion Cells
by Maj-Britt Hölzel, Marcus H. C. Howlett and Maarten Kamermans
Int. J. Mol. Sci. 2022, 23(6), 3202; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063202 - 16 Mar 2022
Cited by 1 | Viewed by 1738
Abstract
Patients with congenital nystagmus, involuntary eye movements, often have a reduced visual acuity. Some of these patients have a retinal-specific mutation in the protein nyctalopin, which is also present in the Nyxnob mouse. In these mice, retinal ganglion cells (RGCs) have oscillatory [...] Read more.
Patients with congenital nystagmus, involuntary eye movements, often have a reduced visual acuity. Some of these patients have a retinal-specific mutation in the protein nyctalopin, which is also present in the Nyxnob mouse. In these mice, retinal ganglion cells (RGCs) have oscillatory activity, which leads to expanded axonal projections towards the dLGN and consequently to a desegregation of retinal projections to the brain. In this study, we investigate whether the receptive fields of Nyxnob RGCs have also expanded by measuring the size of their receptive fields using MEA recordings. Contrary to our expectation, relative to wild-type (WT) mice we found receptive field sizes in the Nyxnob retina had not increased but instead had decreased for green-light preferring RGCs. Additionally, we also found the receptive fields of UV-light preferring RGCs are larger than green-light preferring RGCs in both WT and Nyxnob mice. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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15 pages, 16928 KiB  
Article
A Novel, Apparently Silent Variant in MFSD8 Causes Neuronal Ceroid Lipofuscinosis with Marked Intrafamilial Variability
by Milda Reith, Lena Zeltner, Karin Schäferhoff, Dennis Witt, Theresia Zuleger, Tobias B. Haack, Antje Bornemann, Michael Alber, Susanne Ruf, Ludger Schoels, Katarina Stingl and Nicole Weisschuh
Int. J. Mol. Sci. 2022, 23(4), 2271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042271 - 18 Feb 2022
Cited by 3 | Viewed by 2116
Abstract
Variants in MFSD8 can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to [...] Read more.
Variants in MFSD8 can cause neuronal ceroid lipofuscinoses (NCLs) as well as nonsyndromic retinopathy. The mutation spectrum includes mainly missense and stop variants, but splice sites and frameshift variants have also been reported. To date, apparently synonymous substitutions have not been shown to cause MFSD8-associated diseases. We report two closely related subjects from a consanguineous Turkish family who presented classical features of NCLs but demonstrated marked intrafamilial variability in age at the onset and severity of symptoms. In fact, the difference in the onset of first neurologic symptoms was 15 years and that of ophthalmologic symptoms was 12 years. One subject presented an intellectual disability and a considerable cerebellar ataxia syndrome, while the other subject showed no intellectual disability and only a mild atactic syndrome. The diagnostic genetic testing of both subjects based on genome sequencing prioritized a novel, apparently synonymous variant in MFSD8, which was found in homozygosity in both subjects. The variant was not located within an integral part of the splice site consensus sequences. However, the bioinformatic analyses suggested that the mutant allele is more likely to cause exon skipping due to an altered ratio of exonic splice enhancer and silencer motifs. Exon skipping was confirmed in vitro by minigene assays and in vivo by RNA analysis from patient lymphocytes. The mutant transcript is predicted to result in a frameshift and, if translated, in a truncated protein. Synonymous variants are often given a low priority in genetic diagnostics because of their expected lack of functional impact. This study highlights the importance of investigating the impact of synonymous variants on splicing. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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16 pages, 6000 KiB  
Article
Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing
by Kirk A. J. Stephenson, Julia Zhu, Adrian Dockery, Laura Whelan, Tomás Burke, Jacqueline Turner, James J. O’Byrne, G. Jane Farrar and David J. Keegan
Int. J. Mol. Sci. 2022, 23(2), 995; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020995 - 17 Jan 2022
Cited by 7 | Viewed by 2654
Abstract
Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and [...] Read more.
Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70–80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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14 pages, 2797 KiB  
Article
The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A
by Luke Mansard, David Baux, Christel Vaché, Catherine Blanchet, Isabelle Meunier, Marjolaine Willems, Valérie Faugère, Corinne Baudoin, Melody Moclyn, Julie Bianchi, Helene Dollfus, Brigitte Gilbert-Dussardier, Delphine Dupin-Deguine, Dominique Bonneau, Isabelle Drumare, Sylvie Odent, Xavier Zanlonghi, Mireille Claustres, Michel Koenig, Vasiliki Kalatzis and Anne-Françoise Rouxadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(24), 13294; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413294 - 10 Dec 2021
Cited by 7 | Viewed by 2637
Abstract
Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and MYO7A and USH2A represent the two major causal genes involved in Usher type I, the [...] Read more.
Usher syndrome is an autosomal recessive disorder characterized by congenital hearing loss combined with retinitis pigmentosa, and in some cases, vestibular areflexia. Three clinical subtypes are distinguished, and MYO7A and USH2A represent the two major causal genes involved in Usher type I, the most severe form, and type II, the most frequent form, respectively. Massively parallel sequencing was performed on a cohort of patients in the context of a molecular diagnosis to confirm clinical suspicion of Usher syndrome. We report here 231 pathogenic MYO7A and USH2A genotypes identified in 73 Usher type I and 158 Usher type II patients. Furthermore, we present the ACMG classification of the variants, which comprise all types. Among them, 68 have not been previously reported in the literature, including 12 missense and 16 splice variants. We also report a new deep intronic variant in USH2A. Despite the important number of molecular studies published on these two genes, we show that during the course of routine genetic diagnosis, undescribed variants continue to be identified at a high rate. This is particularly pertinent in the current era, where therapeutic strategies based on DNA or RNA technologies are being developed. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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13 pages, 4244 KiB  
Article
Viral Transduction of Human Rod Opsin or Channelrhodopsin Variants to Mouse ON Bipolar Cells Does Not Impact Retinal Anatomy or Cause Measurable Death in the Targeted Cells
by Phillip Wright, Jessica Rodgers, Jonathan Wynne, Paul N. Bishop, Robert J. Lucas and Nina Milosavljevic
Int. J. Mol. Sci. 2021, 22(23), 13111; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313111 - 03 Dec 2021
Cited by 4 | Viewed by 2357
Abstract
The viral gene delivery of optogenetic actuators to the surviving inner retina has been proposed as a strategy for restoring vision in advanced retinal degeneration. We investigated the safety of ectopic expression of human rod opsin (hRHO), and two channelrhodopsins (enhanced sensitivity CoChR-3M [...] Read more.
The viral gene delivery of optogenetic actuators to the surviving inner retina has been proposed as a strategy for restoring vision in advanced retinal degeneration. We investigated the safety of ectopic expression of human rod opsin (hRHO), and two channelrhodopsins (enhanced sensitivity CoChR-3M and red-shifted ReaChR) by viral gene delivery in ON bipolar cells of the mouse retina. Adult Grm6Cre mice were bred to be retinally degenerate or non-retinally degenerate (homozygous and heterozygous for the rd1Pde6b mutation, respectively) and intravitreally injected with recombinant adeno-associated virus AAV2/2(quad Y-F) serotype containing a double-floxed inverted transgene comprising one of the opsins of interest under a CMV promoter. None of the opsins investigated caused changes in retinal thickness; induced apoptosis in the retina or in transgene expressing cells; or reduced expression of PKCα (a specific bipolar cell marker). No increase in retinal inflammation at the level of gene expression (IBA1/AIF1) was found within the treated mice compared to controls. The expression of hRHO, CoChR or ReaChR under a strong constitutive promoter in retinal ON bipolar cells following intravitreal delivery via AAV2 does not cause either gross changes in retinal health, or have a measurable impact on the survival of targeted cells. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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21 pages, 3429 KiB  
Article
CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms
by Kévin Mairot, Vasily Smirnov, Béatrice Bocquet, Gilles Labesse, Carl Arndt, Sabine Defoort-Dhellemmes, Xavier Zanlonghi, Dalil Hamroun, Danièle Denis, Marie-Christine Picot, Thierry David, Olivier Grunewald, Mako Pégart, Hélèna Huguet, Anne-Françoise Roux, Vasiliki Kalatzis, Claire-Marie Dhaenens and Isabelle Meunier
Int. J. Mol. Sci. 2021, 22(23), 12642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312642 - 23 Nov 2021
Cited by 11 | Viewed by 2604
Abstract
Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to [...] Read more.
Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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19 pages, 6083 KiB  
Article
Relative Contribution of Different Mitochondrial Oxidative Phosphorylation Components to the Retinal Pigment Epithelium Barrier Function: Implications for RPE-Related Retinal Diseases
by Michael H. Guerra, Thangal Yumnamcha, Lalit P. Singh and Ahmed S. Ibrahim
Int. J. Mol. Sci. 2021, 22(15), 8130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158130 - 29 Jul 2021
Cited by 6 | Viewed by 2981
Abstract
Disruption of retinal pigment epithelial (RPE) barrier integrity is involved in the pathology of several blinding retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy (DR), but the underlying causes and pathophysiology are not completely well-defined. Mitochondria dysfunction has often been considered [...] Read more.
Disruption of retinal pigment epithelial (RPE) barrier integrity is involved in the pathology of several blinding retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy (DR), but the underlying causes and pathophysiology are not completely well-defined. Mitochondria dysfunction has often been considered as a potential candidate implicated in such a process. In this study, we aimed to dissect the role of different mitochondrial components; specifically, those of oxidative phosphorylation (OxPhos), in maintaining the barrier functionality of RPE. Electric cell-substrate impedance sensing (ECIS) technology was used to collect multi-frequency electrical impedance data to assess in real-time the barrier formation of the RPE cells. For this purpose, the human retinal pigment epithelial cell line—ARPE-19—was used and treated with varying concentrations of specific mitochondrial inhibitors that target different steps in OxPhos: Rotenone for complex I (the largest protein complex in the electron transport chain (ETC)); oligomycin for ATP synthase; and carbonyl cyanide-p-trifluoromethoxyphenyl hydrazone (FCCP) for uncoupling ATP synthesis from the accompanying ETC. Furthermore, data were modeled using the ECIS-Zθ software to investigate in depth the effects of these inhibitors on three separate barrier parameters: cell–cell interactions (Rb), cell–matrix interactions (α), and the cell membrane capacitance (Cm). The viability of ARPE-19 cells was determined by lactate dehydrogenase (LDH) Cytotoxicity Assay. The ECIS program’s modeling demonstrated that FCCP and thus OxPhos uncoupling disrupt the barrier function in the ARPE-19 cells across all three components of the total resistance (Rb, α, and Cm) in a dose-dependent manner. On the other hand, oligomycin and thus ATP synthase inhibition mostly affects the ARPE-19 cells’ attachment to their substrate evident by a significant decrease in α resistance in a dose-dependent manner, both at the end and throughout the duration of the experiment. On the contrary, rotenone and complex I inhibition mostly affect the ARPE-19 paracellular resistance Rb in a dose-dependent manner compared to basolateral resistance α or Cm. Our results clearly demonstrate differential roles for different mitochondrial components in maintaining RPE cell functionality in which uncoupling of OxPhos is a major contributing factor to the disruption barrier function. Such differences can be used in investigating gene expression as well as for screening of selective agents that improve the OxPhos coupling efficiency to be used in the therapeutic approach for treating RPE-related retinal diseases. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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19 pages, 3338 KiB  
Article
Mutated CCDC51 Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy
by Christina Zeitz, Cécile Méjécase, Christelle Michiels, Christel Condroyer, Juliette Wohlschlegel, Marine Foussard, Aline Antonio, Vanessa Démontant, Lisa Emmenegger, Audrey Schalk, Marion Neuillé, Elise Orhan, Sébastien Augustin, Crystel Bonnet, Amrit Estivalet, Frédéric Blond, Steven Blanchard, Camille Andrieu, Sandra Chantot-Bastaraud, Thierry Léveillard, Saddek Mohand-Saïd, José-Alain Sahel and Isabelle Audoadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(15), 7875; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157875 - 23 Jul 2021
Cited by 3 | Viewed by 2384
Abstract
The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA [...] Read more.
The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4); predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, although usually in association with syndromic disease, unlike our present case. Together, our findings add another ultra-rare mutation implicated in non-syndromic IRD, whose pathogenic mechanism in the retina needs to be further elucidated. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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16 pages, 1668 KiB  
Article
Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy
by Vasily Smirnov, Olivier Grunewald, Jean Muller, Christina Zeitz, Carolin D. Obermaier, Aurore Devos, Valérie Pelletier, Béatrice Bocquet, Camille Andrieu, Jean-Louis Bacquet, Elodie Lebredonchel, Saddek Mohand-Saïd, Sabine Defoort-Dhellemmes, José-Alain Sahel, Hélène Dollfus, Xavier Zanlonghi, Isabelle Audo, Isabelle Meunier, Elise Boulanger-Scemama and Claire-Marie Dhaenens
Int. J. Mol. Sci. 2021, 22(12), 6410; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126410 - 15 Jun 2021
Cited by 10 | Viewed by 2987
Abstract
Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report [...] Read more.
Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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18 pages, 4901 KiB  
Article
A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Gpr179 Deficiency
by Elise Orhan, Marion Neuillé, Miguel de Sousa Dias, Thomas Pugliese, Christelle Michiels, Christel Condroyer, Aline Antonio, José-Alain Sahel, Isabelle Audo and Christina Zeitz
Int. J. Mol. Sci. 2021, 22(9), 4424; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094424 - 23 Apr 2021
Cited by 3 | Viewed by 2169
Abstract
Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for [...] Read more.
Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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Review

Jump to: Research

25 pages, 5794 KiB  
Review
Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy
by Juliette Varin, Clément Morival, Noémien Maillard, Oumeya Adjali and Therese Cronin
Int. J. Mol. Sci. 2021, 22(23), 12818; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312818 - 26 Nov 2021
Cited by 3 | Viewed by 3133
Abstract
Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high [...] Read more.
Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high clinical vector stocks, and the relatively immune-privileged environment of the eye explain such success. However, adverse effects due to AAV-delivery, though rare in the retina have led to the interruption of clinical trials. Risk mitigation, as the key to safe and efficient GT, has become the focus of ‘bedside-back-to-bench’ studies. Herein, we overview the inflammatory adverse events described in retinal GT trials and analyze which components of the retinal immunological environment might be the most involved in these immune responses, with a focus on the innate immune system composed of microglial surveillance. We consider the factors that can influence inflammation in the retina after GT such as viral sensors in the retinal tissue and CpG content in promoters or transgene sequences. Finally, we consider options to reduce the immunological risk, including dose, modified capsids or exclusion criteria for clinical trials. A better understanding and mitigation of immune risk factors inducing host immunity in AAV-mediated retinal GT is the key to achieving safe and efficient GT. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 2.0)
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