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Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0

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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 May 2023) | Viewed by 13065

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Prof. Dr. Isabelle Audo

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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
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Dr. Christina Zeitz

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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 bottleneck to filling in the knowledge gap is replicating findings in large cohorts and developing 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.

As Volumes 1 and 2 of the Special Issue “Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them” were incredibly successful, we will be exploring this issue further in the International Journal of Molecular Sciences (ISSN 1422-0067, IF 5.924, JCR Category Q1). In this third 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.

For more information:
https://www.mdpi.com/journal/ijms/special_issues/inherited_retinal_disease_genetics
https://www.mdpi.com/journal/ijms/special_issues/Inherited_Retinal_Diseases

Prof. Dr. 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

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Published Papers (6 papers)

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Research

15 pages, 6592 KiB

Open AccessArticle

Selective Block of Upregulated Kv1.3 Potassium Channels in ON-Bipolar Cells of the Blind Retina Enhances Optogenetically Restored Signaling

by Giulia Schilardi, Jakub Kralik and Sonja Kleinlogel

Int. J. Mol. Sci. 2023, 24(18), 14207; https://doi.org/10.3390/ijms241814207 - 18 Sep 2023

Cited by 3 | Viewed by 1356

Abstract

Loss of photoreceptors in retinal degenerative diseases also impacts the inner retina: bipolar cell dendrites retract, neurons rewire, and protein expression changes. ON-bipolar cells (OBCs) represent an attractive target for optogenetic vision restoration. However, the above-described maladaptations may negatively impact the quality of restored vision. To investigate this question, we employed human post-mortem retinas and transgenic rd1_Opto-mGluR6 mice expressing the optogenetic construct Opto-mGluR6 in OBCs and carrying the retinal degeneration rd1 mutation. We found significant changes in delayed rectifier potassium channel expression in OBCs of degenerative retinas. In particular, we found an increase in Kv1.3 expression already in early stages of degeneration. Immunohistochemistry localized Kv1.3 channels specifically to OBC axons. In whole-cell patch-clamp experiments, OBCs in the degenerated murine retina were less responsive, which could be reversed by application of the specific Kv1.3 antagonist Psora-4. Notably, Kv1.3 block significantly increased the amplitude and kinetics of Opto-mGluR6-mediated light responses in OBCs of the blind retina and increased the signal-to-noise ratio of light-triggered responses in retinal ganglion cells. We propose that reduction in Kv1.3 activity in the degenerated retina, either by pharmacological block or by KCNA3 gene silencing, could improve the quality of restored vision. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0)

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35 pages, 8918 KiB

Open AccessArticle

Genetic Characteristics and Long-Term Follow-Up of Slovenian Patients with RPGR Retinal Dystrophy

by Vlasta Hadalin, Maša Buscarino, Jana Sajovic, Andrej Meglič, Martina Jarc-Vidmar, Marko Hawlina, Marija Volk and Ana Fakin

Int. J. Mol. Sci. 2023, 24(4), 3840; https://doi.org/10.3390/ijms24043840 - 14 Feb 2023

Cited by 1 | Viewed by 1694

Abstract

Genetic characteristics and a long-term clinical follow-up of 18 Slovenian retinitis pigmentosa GTPase regulator (RPGR) patients from 10 families with retinitis pigmentosa (RP) or cone/cone-rod dystrophy (COD/CORD) are reported. RP (eight families) was associated with two already known (p.(Ser407Ilefs*46) and p.(Glu746Argfs*23)) and five novel variants (c.1245+704_1415-2286del, p.(Glu660*), p.(Ala153Thr), c.1506+1G>T, and p.(Arg780Serfs*54)). COD (two families) was associated with p.(Ter1153Lysext*38). The median age of onset in males with RP (N = 9) was 6 years. At the first examination (median age of 32 years), the median best corrected visual acuity (BCVA) was 0.30 logMAR, and all patients had a hyperautofluorescent ring on fundus autofluorescence (FAF) encircling preserved photoreceptors. At the last follow-up (median age of 39 years), the median BCVA was 0.48 logMAR, and FAF showed ring constriction transitioning to patch in 2/9. Among females (N = 6; median age of 40 years), two had normal/near-normal FAF, one had unilateral RP (male pattern), and three had a radial and/or focal pattern of retinal degeneration. After a median of 4 years (4–21) of follow-up, 2/6 exhibited disease progression. The median age of onset in males with COD was 25 years. At first examination (median age of 35 years), the median BCVA was 1.00 logMAR, and all patients had a hyperautofluorescent FAF ring encircling foveal photoreceptor loss. At the last follow-up (median age of 42 years), the median BCVA was 1.30 logMAR, and FAF showed ring enlargement. The majority of the identified variants (75%; 6/8) had not been previously reported in other RPGR cohorts, which suggested the presence of distinct RPGR alleles in the Slovenian population. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0)

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11 pages, 3813 KiB

Open AccessArticle

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

by Karen E. Lee, Rebecca Procopio, Jose S. Pulido and Kammi B. Gunton

Int. J. Mol. Sci. 2023, 24(2), 1060; https://doi.org/10.3390/ijms24021060 - 5 Jan 2023

Cited by 2 | Viewed by 1515

Abstract

Intrinsically disordered regions (IDRs) are protein regions that are unable to fold into stable tertiary structures, enabling their involvement in key signaling and regulatory functions via dynamic interactions with diverse binding partners. An understanding of IDRs and their association with biological function may help elucidate the pathogenesis of inherited retinal diseases (IRDs). The main focus of this work was to investigate the degree of disorder in 14 proteins implicated in IRDs and their relationship with the number of pathogenic missense variants. Metapredict, an accurate, high-performance predictor that reproduces consensus disorder scores, was used to probe the degree of disorder as a function of the amino acid sequence. Publicly available data on gnomAD and ClinVar was used to analyze the number of pathogenic missense variants. We show that proteins with an over-representation of missense variation exhibit a high degree of disorder, and proteins with a high amount of disorder tolerate a higher degree of missense variation. These proteins also exhibit a lower amount of pathogenic missense variants with respect to total missense variants. These data suggest that protein function may be related to the overall level of disorder and could be used to refine variant interpretation in IRDs. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0)

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14 pages, 4035 KiB

Open AccessArticle

Correlation between the Serum Concentration of Vitamin A and Disease Severity in Patients Carrying p.G90D in RHO, the Most Frequent Gene Associated with Dominant Retinitis Pigmentosa: Implications for Therapy with Vitamin A

by Tjaša Krašovec, Nina Kobal, Maja Šuštar Habjan, Marija Volk, Marko Hawlina and Ana Fakin

Int. J. Mol. Sci. 2023, 24(1), 780; https://doi.org/10.3390/ijms24010780 - 2 Jan 2023

Cited by 2 | Viewed by 2701

Abstract

The pathogenic variant p.G90D in RHO is believed to be responsible for a spectrum of phenotypes, including congenital stationary blindness (for the purpose of this study termed night blindness without degeneration; NBWD), Sector RP, Pericentral RP, and Classic RP. We present a correlation between the serum concentration of vitamin A and disease severity in patients with this variant. This prospective study involved 30 patients from 7 families (17 male; median age 46 years, range 8–73). Full ophthalmological examination including visual acuity, Goldmann perimetry, slit-lamp exam, optical coherence tomography, fundus autofluorescence, and electrophysiology was performed to determine the presenting phenotype. The serum concentration of vitamin A was determined from a fasting blood sample taken on the day of the exam, where it was found that 23.3% (7/30) of patients had NBWD, 13.3% (4/30) had Sector RP, 3.3% (1/30) had Pericentral RP, and 60% (18/30) had Classic RP. Multiple logistic regression revealed a significantly higher probability of having a milder phenotype (NBWD or Sector RP) in association with younger age (p < 0.05) and a higher concentration of vitamin A (p < 0.05). We hypothesize that vitamin A in its 11-cis-retinal form plays a role in stabilizing the constitutively active p.G90D rhodopsin and its supplementation could be a potential treatment strategy for p.G90D RHO patients. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0)

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14 pages, 1169 KiB

Open AccessArticle

Mice Lacking Gpr179 with Complete Congenital Stationary Night Blindness Are a Good Model for Myopia

by Baptiste Wilmet, Jacques Callebert, Robert Duvoisin, Ruben Goulet, Christophe Tourain, Christelle Michiels, Helen Frederiksen, Frank Schaeffel, Olivier Marre, José Alain Sahel, Isabelle Audo, Serge Picaud and Christina Zeitz

Int. J. Mol. Sci. 2023, 24(1), 219; https://doi.org/10.3390/ijms24010219 - 22 Dec 2022

Cited by 8 | Viewed by 2539

Abstract

Mutations in GPR179 are one of the most common causes of autosomal recessive complete congenital stationary night blindness (cCSNB). This retinal disease is characterized in patients by impaired dim and night vision, associated with other ocular symptoms, including high myopia. cCSNB is caused by a complete loss of signal transmission from photoreceptors to ON-bipolar cells. In this study, we hypothesized that the lack of Gpr179 and the subsequent impaired ON-pathway could lead to myopic features in a mouse model of cCSNB. Using ultra performance liquid chromatography, we show that adult Gpr179^−/− mice have a significant decrease in both retinal dopamine and 3,4-dihydroxyphenylacetic acid, compared to Gpr179^+/+ mice. This alteration of the dopaminergic system is thought to be correlated with an increased susceptibility to lens-induced myopia but does not affect the natural refractive development. Altogether, our data added a novel myopia model, which could be used to identify therapeutic interventions. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0)

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10 pages, 418 KiB

Open AccessArticle

Signal Peptide Variants in Inherited Retinal Diseases: A Multi-Institutional Case Series

by Hiram J. Jimenez, Rebecca A. Procopio, Tobin B. T. Thuma, Molly H. Marra, Natalio Izquierdo, Michael A. Klufas, Aaron Nagiel, Mark E. Pennesi and Jose S. Pulido

Int. J. Mol. Sci. 2022, 23(21), 13361; https://doi.org/10.3390/ijms232113361 - 1 Nov 2022

Cited by 3 | Viewed by 2163

Abstract

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients’ disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: How Can We Move Forward in Understanding and Treating Them 3.0)

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