Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.8
5.6
Journals
IJMS
Special Issues
Inherited Retinal Diseases
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Inherited Retinal Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (22 March 2022) | Viewed by 58398

Special Issue Editors

Prof. Dr. Tamar Ben-Yosef

E-Mail Website
Guest Editor
Technion—Israel Institute of Technology, Haifa, Israel
Interests: inherited retinal diseases; retinal biology
Dr. Susanne Roosing

E-Mail Website1 Website2
Guest Editor
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Interests: inherited retinal disease; retinitis pigmentosa; blindness; genetics; retinal gene discovery; whole genome sequencing

Special Issue Information

Dear colleagues,

Inherited retinal diseases (IRDs), which are among the most common genetic diseases in humans, define a clinically and genetically heterogeneous group of disorders that cause visual loss due to improper development, improper function, or premature death of the retinal photoreceptors. IRDs are distinguished by several factors, including the type and location of affected cells and the timing of disease onset. However, these heterogeneous clinical entities lie along a spectrum, and in some cases, the diagnostic boundaries between them are not distinct. Over 260 genes have been implicated in IRDs. However, the contribution of each of these genes to the overall prevalence of the disease is relatively small, and for many of them, pathogenic mutations have been reported in only a few families worldwide. Moreover, in approximately 30% of IRD patients, the underlying genes are yet to be found. These factors make both the clinical and the molecular diagnosis of IRDs very challenging. In addition, the biological function and disease etiology of many of the genes associated with IRD are not fully understood. This Special Issue will focus on IRD clinical genetics, molecular genetics, diagnosis, bioinformatics, and functional studies, among other topics.

Prof. Dr. Tamar Ben-Yosef
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • retina
  • retinal degeneration
  • genetics
  • photoreceptors

Published Papers (20 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

3 pages, 2297 KiB  
Editorial
Inherited Retinal Diseases
by Tamar Ben-Yosef
Int. J. Mol. Sci. 2022, 23(21), 13467; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113467 - 03 Nov 2022
Cited by 8 | Viewed by 1662
Abstract
Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases that cause vision loss due to abnormal development or due to the dysfunction or degeneration of the photoreceptors or the retinal pigment epithelium [...] Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

Research

Jump to: Editorial, Review

9 pages, 1165 KiB  
Article
The Natural History of CNGB1-Related Retinopathy: A Longitudinal Phenotypic Analysis
by Daniel J. Jackson, Adam M. Dubis and Mariya Moosajee
Int. J. Mol. Sci. 2022, 23(12), 6785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126785 - 17 Jun 2022
Cited by 2 | Viewed by 1554
Abstract
Cyclic nucleotide-gated channel β 1 (CNGB1) encodes a subunit of the rod cyclic nucleotide-gated channel. Pathogenic variants in CNGB1 are responsible for 4% of autosomal recessive retinitis pigmentosa (RP). Several treatment strategies show promise for treating inherited retinal degenerations, however relevant metrics of [...] Read more.
Cyclic nucleotide-gated channel β 1 (CNGB1) encodes a subunit of the rod cyclic nucleotide-gated channel. Pathogenic variants in CNGB1 are responsible for 4% of autosomal recessive retinitis pigmentosa (RP). Several treatment strategies show promise for treating inherited retinal degenerations, however relevant metrics of progression and sensitive clinical trial endpoints are needed to assess therapeutic efficacy. This study reports the natural history of CNGB1-related RP with a longitudinal phenotypic analysis of 33 molecularly-confirmed patients with a mean follow-up period of 4.5 ± 3.9 years (range 0–17). The mean best corrected visual acuity (BCVA) of the right eye was 0.31 ± 0.43 logMAR at baseline and 0.47 ± 0.63 logMAR at the final visit over the study period. The ellipsoid zone (EZ) length was measurable in at least one eye of 23 patients and had a mean rate of constriction of 178 ± 161 µm per year (range 1.0–661 µm), with 57% of patients having a decrease in EZ length of greater than 250 µm in a simulated two-year trial period. Hyperautofluorescent outer ring (hyperAF) area was measurable in 17 patients, with 10 patients not displaying a ring phenotype. The results support previous findings of CNGB1-related RP being a slowly progressive disease with patients maintaining visual acuity. Prospective deep phenotyping studies assessing multimodal retinal imaging and functional measures are now required to determine clinical endpoints to be used in a trial. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

18 pages, 4068 KiB  
Article
Functional Characterization of an In-Frame Deletion in the Basic Domain of the Retinal Transcription Factor ATOH7
by David Atac, Lucas Mohn, Silke Feil, Kevin Maggi, Dominik Haenni, Britta Seebauer, Samuel Koller and Wolfgang Berger
Int. J. Mol. Sci. 2022, 23(3), 1053; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031053 - 19 Jan 2022
Cited by 2 | Viewed by 2026
Abstract
Basic helix–loop–helix (bHLH) transcription factors are evolutionarily conserved and structurally similar proteins important in development. The temporospatial expression of atonal bHLH transcription factor 7 (ATOH7) directs the differentiation of retinal ganglion cells and mutations in the human gene lead to vitreoretinal [...] Read more.
Basic helix–loop–helix (bHLH) transcription factors are evolutionarily conserved and structurally similar proteins important in development. The temporospatial expression of atonal bHLH transcription factor 7 (ATOH7) directs the differentiation of retinal ganglion cells and mutations in the human gene lead to vitreoretinal and/or optic nerve abnormalities. Characterization of pathogenic ATOH7 mutations is needed to understand the functions of the conserved bHLH motif. The published ATOH7 in-frame deletion p.(Arg41_Arg48del) removes eight highly conserved amino acids in the basic domain. We functionally characterized the mutant protein by expressing V5-tagged ATOH7 constructs in human embryonic kidney 293T (HEK293T) cells for subsequent protein analyses, including Western blot, cycloheximide chase assays, Förster resonance energy transfer fluorescence lifetime imaging, enzyme-linked immunosorbent assays and dual-luciferase assays. Our results indicate that the in-frame deletion in the basic domain causes mislocalization of the protein, which can be rescued by a putative dimerization partner transcription factor 3 isoform E47 (E47), suggesting synergistic nuclear import. Furthermore, we observed (i) increased proteasomal degradation of the mutant protein, (ii) reduced protein heterodimerization, (iii) decreased DNA-binding and transcriptional activation of a reporter gene, as well as (iv) inhibited E47 activity. Altogether our observations suggest that the DNA-binding basic domain of ATOH7 has additional roles in regulating the nuclear import, dimerization, and protein stability. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

12 pages, 1797 KiB  
Article
Molecular Inversion Probe-Based Sequencing of USH2A Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases
by Janine Reurink, Adrian Dockery, Dominika Oziębło, G. Jane Farrar, Monika Ołdak, Jacoline B. ten Brink, Arthur A. Bergen, Tuula Rinne, Helger G. Yntema, Ronald J. E. Pennings, L. Ingeborgh van den Born, Marco Aben, Jaap Oostrik, Hanka Venselaar, Astrid S. Plomp, M. Imran Khan, Erwin van Wijk, Frans P. M. Cremers, Susanne Roosing and Hannie Kremer
Int. J. Mol. Sci. 2021, 22(12), 6419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126419 - 15 Jun 2021
Cited by 7 | Viewed by 3195
Abstract
A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future [...] Read more.
A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

15 pages, 6188 KiB  
Article
Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants
by Nicole Weisschuh, Pascale Mazzola, Miriam Bertrand, Tobias B. Haack, Bernd Wissinger, Susanne Kohl and Katarina Stingl
Int. J. Mol. Sci. 2021, 22(10), 5396; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105396 - 20 May 2021
Cited by 13 | Viewed by 2161
Abstract
Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy [...] Read more.
Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

17 pages, 1310 KiB  
Article
Antisense Oligonucleotide-Based Rescue of Aberrant Splicing Defects Caused by 15 Pathogenic Variants in ABCA4
by Tomasz Z. Tomkiewicz, Nuria Suárez-Herrera, Frans P. M. Cremers, Rob W. J. Collin and Alejandro Garanto
Int. J. Mol. Sci. 2021, 22(9), 4621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094621 - 28 Apr 2021
Cited by 27 | Viewed by 3612
Abstract
The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In [...] Read more.
The discovery of novel intronic variants in the ABCA4 locus has contributed significantly to solving the missing heritability in Stargardt disease (STGD1). The increasing number of variants affecting pre-mRNA splicing makes ABCA4 a suitable candidate for antisense oligonucleotide (AON)-based splicing modulation therapies. In this study, AON-based splicing modulation was assessed for 15 recently described intronic variants (three near-exon and 12 deep-intronic variants). In total, 26 AONs were designed and tested in vitro using a midigene-based splice system. Overall, partial or complete splicing correction was observed for two variants causing exon elongation and all variants causing pseudoexon inclusion. Together, our results confirm the high potential of AONs for the development of future RNA therapies to correct splicing defects causing STGD1. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Graphical abstract

15 pages, 1475 KiB  
Article
Clinical Phenotype of PDE6B-Associated Retinitis Pigmentosa
by Laura Kuehlewein, Ditta Zobor, Katarina Stingl, Melanie Kempf, Fadi Nasser, Antje Bernd, Saskia Biskup, Frans P.M. Cremers, Muhammad Imran Khan, Pascale Mazzola, Karin Schäferhoff, Tilman Heinrich, Tobias B. Haack, Bernd Wissinger, Eberhart Zrenner, Nicole Weisschuh and Susanne Kohl
Int. J. Mol. Sci. 2021, 22(5), 2374; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052374 - 27 Feb 2021
Cited by 13 | Viewed by 3215
Abstract
In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic [...] Read more.
In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

11 pages, 1682 KiB  
Article
New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform
by Víctor Abad-Morales, Ana Wert, María Ángeles Ruiz Gómez, Rafael Navarro and Esther Pomares
Int. J. Mol. Sci. 2021, 22(5), 2262; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052262 - 24 Feb 2021
Cited by 5 | Viewed by 2727
Abstract
This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) [...] Read more.
This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

24 pages, 10502 KiB  
Article
Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant
by Ulrich Kellner, Nicole Weisschuh, Silke Weinitz, Ghazaleh Farmand, Sebastian Deutsch, Friederike Kortüm, Pascale Mazzola, Karin Schäferhoff, Valerio Marino and Daniele Dell’Orco
Int. J. Mol. Sci. 2021, 22(4), 2089; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042089 - 19 Feb 2021
Cited by 9 | Viewed by 2174
Abstract
We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. [...] Read more.
We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

12 pages, 4054 KiB  
Article
Leber Congenital Amaurosis Due to GUCY2D Mutations: Longitudinal Analysis of Retinal Structure and Visual Function
by Samuel G. Jacobson, Artur V. Cideciyan, Alexander Sumaroka, Alejandro J. Roman, Vivian Wu, Malgorzata Swider, Rebecca Sheplock, Arun K. Krishnan and Alexandra V. Garafalo
Int. J. Mol. Sci. 2021, 22(4), 2031; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22042031 - 18 Feb 2021
Cited by 8 | Viewed by 2427
Abstract
Gene augmentation therapy is being planned for GUCY2D-associated Leber congenital amaurosis (LCA). To increase our understanding of the natural history of GUCY2D-LCA, patients were evaluated twice with an interval of 4 to 7 years between visits using safety and efficacy outcome [...] Read more.
Gene augmentation therapy is being planned for GUCY2D-associated Leber congenital amaurosis (LCA). To increase our understanding of the natural history of GUCY2D-LCA, patients were evaluated twice with an interval of 4 to 7 years between visits using safety and efficacy outcome measures previously determined to be useful for monitoring this disorder. In this group of molecularly-identified LCA patients (n = 10; ages 7–37 years at first visit), optical coherence tomography (OCT) was used to measure foveal cone outer nuclear layer (ONL) thickness and rod ONL at a superior retinal locus. Full-field stimulus testing (FST) with chromatic stimuli in dark- and light-adapted states was used to assay rod and cone vision. Changes in OCT and FST over the interval were mostly attributable to inter-visit variability. There were no major negative changes in structure or function across the cohort and over the intervals studied. Variation in severity of disease expression between patients occurs; however, despite difficulties in quantifying structure and function in such seriously visually impaired individuals with nystagmus, the present work supports the use of OCT as a safety outcome and FST as an efficacy outcome in a clinical trial of GUCY2D-LCA. A wide age spectrum for therapy was confirmed, and there was relative stability of structure and function during a typical time interval for clinical trials. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

12 pages, 1909 KiB  
Article
X-Linked Retinitis Pigmentosa Caused by Non-Canonical Splice Site Variants in RPGR
by Friederike Kortüm, Sinja Kieninger, Pascale Mazzola, Susanne Kohl, Bernd Wissinger, Holger Prokisch, Katarina Stingl and Nicole Weisschuh
Int. J. Mol. Sci. 2021, 22(2), 850; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020850 - 16 Jan 2021
Cited by 7 | Viewed by 1986
Abstract
We aimed to validate the effect of non-canonical splice site variants in the RPGR gene in five patients from four families diagnosed with retinitis pigmentosa. Four variants located in intron 2 (c.154 + 3_154 + 6del), intron 3 (c.247 + 5G>A), intron 7 [...] Read more.
We aimed to validate the effect of non-canonical splice site variants in the RPGR gene in five patients from four families diagnosed with retinitis pigmentosa. Four variants located in intron 2 (c.154 + 3_154 + 6del), intron 3 (c.247 + 5G>A), intron 7 (c.779-5T>G), and intron 13 (c.1573-12A>G), respectively, were analyzed by means of in vitro splice assays. Splicing analysis revealed different aberrant splicing events, including exon skipping and intronic nucleotide addition, which are predicted to lead either to an in-frame deletion affecting relevant protein domains or to a frameshift of the open reading frame. Our data expand the landscape of pathogenic variants in RPGR, thereby increasing the genetic diagnostic rate in retinitis pigmentosa and allowing patients harboring the analyzed variants to be enrolled in clinical trials. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

19 pages, 9521 KiB  
Article
Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families
by Giancarlo Iarossi, Valerio Marino, Paolo Enrico Maltese, Leonardo Colombo, Fabiana D’Esposito, Elena Manara, Kristjana Dhuli, Antonio Mattia Modarelli, Gilda Cennamo, Adriano Magli, Daniele Dell’Orco and Matteo Bertelli
Int. J. Mol. Sci. 2021, 22(1), 381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010381 - 31 Dec 2020
Cited by 7 | Viewed by 2277
Abstract
The small Ras-related GTPase Rab-28 is highly expressed in photoreceptor cells, where it possibly participates in membrane trafficking. To date, six alterations in the RAB28 gene have been associated with autosomal recessive cone-rod dystrophies. Confirmed variants include splicing variants, missense and nonsense mutations. [...] Read more.
The small Ras-related GTPase Rab-28 is highly expressed in photoreceptor cells, where it possibly participates in membrane trafficking. To date, six alterations in the RAB28 gene have been associated with autosomal recessive cone-rod dystrophies. Confirmed variants include splicing variants, missense and nonsense mutations. Here, we present a thorough phenotypical and genotypical characterization of five individuals belonging to four Italian families, constituting the largest cohort of RAB28 patients reported in literature to date. All probands displayed similar clinical phenotype consisting of photophobia, decreased visual acuity, central outer retinal thinning, and impaired color vision. By sequencing the four probands, we identified: a novel homozygous splicing variant; two novel nonsense variants in homozygosis; a novel missense variant in compound heterozygous state with a previously reported nonsense variant. Exhaustive molecular dynamics simulations of the missense variant p.(Thr26Asn) in both its active and inactive states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity for GTP. The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state. The loss-of-function mutation p.(Thr26Asn) was present in a compound heterozygosis with the nonsense variant p.(Arg137*), which does not cause mRNA-mediated decay, but is rather likely degraded due to its incomplete folding. The frameshift p.(Thr26Valfs4*) and nonsense p.(Leu13*) and p.(Trp107*) variants, if translated, would lack several key structural components necessary for the correct functioning of the encoded protein. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

16 pages, 3995 KiB  
Article
The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia
by Mirja Koch, Constanze Scheel, Hongwei Ma, Fan Yang, Michael Stadlmeier, Andrea F. Glück, Elisa Murenu, Franziska R. Traube, Thomas Carell, Martin Biel, Xi-Qin Ding and Stylianos Michalakis
Int. J. Mol. Sci. 2021, 22(1), 52; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010052 - 23 Dec 2020
Cited by 10 | Viewed by 2886
Abstract
Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of [...] Read more.
Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Graphical abstract

21 pages, 2069 KiB  
Article
A Multi-Strategy Sequencing Workflow in Inherited Retinal Dystrophies: Routine Diagnosis, Addressing Unsolved Cases and Candidate Genes Identification
by Marta Martín-Sánchez, Nereida Bravo-Gil, María González-del Pozo, Cristina Méndez-Vidal, Elena Fernández-Suárez, Enrique Rodríguez-de la Rúa, Salud Borrego and Guillermo Antiñolo
Int. J. Mol. Sci. 2020, 21(24), 9355; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249355 - 08 Dec 2020
Cited by 6 | Viewed by 2837
Abstract
The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, [...] Read more.
The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate loci (WDFY3 and a X-linked region including CITED1), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

18 pages, 4554 KiB  
Article
Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene
by Karsten Hufendiek, Katerina Hufendiek, Herbert Jägle, Heidi Stöhr, Marius Book, Georg Spital, Günay Rustambayova, Carsten Framme, Bernhard H. F. Weber, Agnes B. Renner and Ulrich Kellner
Int. J. Mol. Sci. 2020, 21(24), 9353; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249353 - 08 Dec 2020
Cited by 11 | Viewed by 2388
Abstract
Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating [...] Read more.
Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02–1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

9 pages, 14696 KiB  
Article
TULP1 and TUB Are Required for Specific Localization of PRCD to Photoreceptor Outer Segments
by Lital Remez, Ben Cohen, Mariela J. Nevet, Leah Rizel and Tamar Ben-Yosef
Int. J. Mol. Sci. 2020, 21(22), 8677; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228677 - 17 Nov 2020
Cited by 6 | Viewed by 1772
Abstract
Photoreceptor disc component (PRCD) is a small protein which is exclusively localized to photoreceptor outer segments, and is involved in the formation of photoreceptor outer segment discs. Mutations in PRCD are associated with retinal degeneration in humans, mice, and dogs. The purpose of [...] Read more.
Photoreceptor disc component (PRCD) is a small protein which is exclusively localized to photoreceptor outer segments, and is involved in the formation of photoreceptor outer segment discs. Mutations in PRCD are associated with retinal degeneration in humans, mice, and dogs. The purpose of this work was to identify PRCD-binding proteins in the retina. PRCD protein-protein interactions were identified when implementing the Ras recruitment system (RRS), a cytoplasmic-based yeast two-hybrid system, on a bovine retina cDNA library. An interaction between PRCD and tubby-like protein 1 (TULP1) was identified. Co-immunoprecipitation in transfected mammalian cells confirmed that PRCD interacts with TULP1, as well as with its homolog, TUB. These interactions were mediated by TULP1 and TUB highly conserved C-terminal tubby domain. PRCD localization was altered in the retinas of TULP1- and TUB-deficient mice. These results show that TULP1 and TUB, which are involved in the vesicular trafficking of several photoreceptor proteins from the inner segment to the outer segment, are also required for PRCD exclusive localization to photoreceptor outer segment discs. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

14 pages, 9358 KiB  
Article
Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients
by Akira Inaba, Akiko Maeda, Akiko Yoshida, Kanako Kawai, Yasuhiko Hirami, Yasuo Kurimoto, Shinji Kosugi and Masayo Takahashi
Int. J. Mol. Sci. 2020, 21(21), 7817; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217817 - 22 Oct 2020
Cited by 12 | Viewed by 2731
Abstract
USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and [...] Read more.
USH2A is a common causal gene of retinitis pigmentosa (RP), a progressive blinding disease due to retinal degeneration. Genetic alterations in USH2A can lead to two types of RP, non-syndromic and syndromic RP, which is called Usher syndrome, with impairments of vision and hearing. The complexity of the genotype–phenotype correlation in USH2A-associated RP (USH2A-RP) has been reported. Genetic and clinical characterization of USH2A-RP has not been performed in Japanese patients. In this study, genetic analyses were performed using targeted panel sequencing in 525 Japanese RP patients. Pathogenic variants of USH2A were identified in 36 of 525 (6.9%) patients and genetic features of USH2A-RP were characterized. Among 36 patients with USH2A-RP, 11 patients had syndromic RP with congenital hearing problems. Amino acid changes due to USH2A alterations were similarly located throughout entire regions of the USH2A protein structure in non-syndromic and syndromic RP cases. Notably, truncating variants were detected in all syndromic patients with a more severe retinal phenotype as compared to non-syndromic RP cases. Taken together, truncating variants could contribute to more serious functional and tissue damages in Japanese patients, suggesting important roles for truncating mutations in the pathogenesis of syndromic USH2A-RP. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

25 pages, 1588 KiB  
Review
Usher Syndrome: Genetics of a Human Ciliopathy
by Carla Fuster-García, Belén García-Bohórquez, Ana Rodríguez-Muñoz, Elena Aller, Teresa Jaijo, José M. Millán and Gema García-García
Int. J. Mol. Sci. 2021, 22(13), 6723; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136723 - 23 Jun 2021
Cited by 37 | Viewed by 5611
Abstract
Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to [...] Read more.
Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the “Usher interactome”. In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype–phenotype correlation. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Graphical abstract

27 pages, 2725 KiB  
Review
The Impact of Modern Technologies on Molecular Diagnostic Success Rates, with a Focus on Inherited Retinal Dystrophy and Hearing Loss
by Suzanne E. de Bruijn, Zeinab Fadaie, Frans P. M. Cremers, Hannie Kremer and Susanne Roosing
Int. J. Mol. Sci. 2021, 22(6), 2943; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062943 - 14 Mar 2021
Cited by 6 | Viewed by 4321
Abstract
The identification of pathogenic variants in monogenic diseases has been of interest to researchers and clinicians for several decades. However, for inherited diseases with extremely high genetic heterogeneity, such as hearing loss and retinal dystrophies, establishing a molecular diagnosis requires an enormous effort. [...] Read more.
The identification of pathogenic variants in monogenic diseases has been of interest to researchers and clinicians for several decades. However, for inherited diseases with extremely high genetic heterogeneity, such as hearing loss and retinal dystrophies, establishing a molecular diagnosis requires an enormous effort. In this review, we use these two genetic conditions as examples to describe the initial molecular genetic identification approaches, as performed since the early 90s, and subsequent improvements and refinements introduced over the years. Next, the history of DNA sequencing from conventional Sanger sequencing to high-throughput massive parallel sequencing, a.k.a. next-generation sequencing, is outlined, including their advantages and limitations and their impact on identifying the remaining genetic defects. Moreover, the development of recent technologies, also coined “third-generation” sequencing, is reviewed, which holds the promise to overcome these limitations. Furthermore, we outline the importance and complexity of variant interpretation in clinical diagnostic settings concerning the massive number of different variants identified by these methods. Finally, we briefly mention the development of novel approaches such as optical mapping and multiomics, which can help to further identify genetic defects in the near future. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

28 pages, 2472 KiB  
Review
The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease
by Izarbe Aísa-Marín, Rocío García-Arroyo, Serena Mirra and Gemma Marfany
Int. J. Mol. Sci. 2021, 22(4), 1855; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041855 - 12 Feb 2021
Cited by 17 | Viewed by 4923
Abstract
Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely [...] Read more.
Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely complex splicing programs and display the highest number of alternative splicing events. As an extension of the central nervous system, the retina constitutes an excellent system to illustrate the high diversity of neural transcripts. The retina expresses retinal specific splicing factors and produces a large number of alternative transcripts, including exclusive tissue-specific exons, which require an exquisite regulation. In fact, a current challenge in the genetic diagnosis of inherited retinal diseases stems from the lack of information regarding alternative splicing of retinal genes, as a considerable percentage of mutations alter splicing or the relative production of alternative transcripts. Modulation of alternative splicing in the retina is also instrumental in the design of novel therapeutic approaches for retinal dystrophies, since it enables precision medicine for specific mutations. Full article
(This article belongs to the Special Issue Inherited Retinal Diseases)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-20
Back to TopTop