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

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 (31 January 2020) | Viewed by 28011

Special Issue Editors

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
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 (6 papers)

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Research

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12 pages, 1760 KiB  
Article
Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles
by Aneta Ścieżyńska, Marta Soszyńska, Michał Komorowski, Anna Podgórska, Natalia Krześniak, Aleksandra Nogowska, Martyna Smolińska, Kamil Szulborski, Jacek P. Szaflik, Bartłomiej Noszczyk, Monika Ołdak and Jacek Malejczyk
Int. J. Mol. Sci. 2020, 21(10), 3430; https://doi.org/10.3390/ijms21103430 - 13 May 2020
Cited by 7 | Viewed by 3234
Abstract
ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required [...] Read more.
ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies. Full article
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14 pages, 6188 KiB  
Article
Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy
by Kazuki Kuniyoshi, Takaaki Hayashi, Shuhei Kameya, Satoshi Katagiri, Kei Mizobuchi, Toshiaki Tachibana, Daiki Kubota, Hiroyuki Sakuramoto, Kazushige Tsunoda, Kaoru Fujinami, Kazutoshi Yoshitake, Takeshi Iwata, Tadashi Nakano and Shunji Kusaka
Int. J. Mol. Sci. 2020, 21(4), 1331; https://doi.org/10.3390/ijms21041331 - 16 Feb 2020
Cited by 3 | Viewed by 2785
Abstract
DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state [...] Read more.
DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations. Full article
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17 pages, 992 KiB  
Article
Prevalence of ABCA4 Deep-Intronic Variants and Related Phenotype in An Unsolved “One-Hit” Cohort with Stargardt Disease
by Marco Nassisi, Saddek Mohand-Saïd, Camille Andrieu, Aline Antonio, Christel Condroyer, Cécile Méjécase, Juliette Varin, Juliette Wohlschlegel, Claire-Marie Dhaenens, José-Alain Sahel, Christina Zeitz and Isabelle Audo
Int. J. Mol. Sci. 2019, 20(20), 5053; https://doi.org/10.3390/ijms20205053 - 11 Oct 2019
Cited by 23 | Viewed by 2984
Abstract
We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic [...] Read more.
We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of ABCA4. Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients’ selection for clinical trials. Full article
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18 pages, 19162 KiB  
Article
Phenotype Analysis of Retinal Dystrophies in Light of the Underlying Genetic Defects: Application to Cone and Cone-Rod Dystrophies
by Elise Boulanger-Scemama, Saddek Mohand-Saïd, Said El Shamieh, Vanessa Démontant, Christel Condroyer, Aline Antonio, Christelle Michiels, Fiona Boyard, Jean-Paul Saraiva, Mélanie Letexier, José-Alain Sahel, Christina Zeitz and Isabelle Audo
Int. J. Mol. Sci. 2019, 20(19), 4854; https://doi.org/10.3390/ijms20194854 - 30 Sep 2019
Cited by 15 | Viewed by 4933
Abstract
Phenotypes observed in a large cohort of patients with cone and cone-rod dystrophies (COD/CORDs) are described based on multimodal retinal imaging features in order to help in analyzing massive next-generation sequencing data. Structural abnormalities of 58 subjects with molecular diagnosis of COD/CORDs were [...] Read more.
Phenotypes observed in a large cohort of patients with cone and cone-rod dystrophies (COD/CORDs) are described based on multimodal retinal imaging features in order to help in analyzing massive next-generation sequencing data. Structural abnormalities of 58 subjects with molecular diagnosis of COD/CORDs were analyzed through specific retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (BAF/IRAF). Findings were analyzed with the underlying genetic defects. A ring of increased autofluorescence was mainly observed in patients with CRX and GUCY2D mutations (33% and 22% of cases respectively). “Speckled” autofluorescence was observed with mutations in three different genes (ABCA4 64%; C2Orf71 and PRPH2, 18% each). Peripapillary sparing was only found in association with mutations in ABCA4, although only present in 40% of such genotypes. Regarding SD-OCT, specific outer retinal abnormalities were more commonly observed in particular genotypes: focal retrofoveal interruption and GUCY2D mutations (50%), foveal sparing and CRX mutations (50%), and outer retinal atrophy associated with hyperreflective dots and ABCA4 mutations (69%). This study outlines the phenotypic heterogeneity of COD/CORDs hampering statistical correlations. A larger study correlating retinal imaging with genetic results is necessary to identify specific clinical features that may help in selecting pathogenic variants generated by high-throughput sequencing. Full article
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16 pages, 2217 KiB  
Article
X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers
by Kentaro Kurata, Katsuhiro Hosono, Takaaki Hayashi, Kei Mizobuchi, Satoshi Katagiri, Daisuke Miyamichi, Sachiko Nishina, Miho Sato, Noriyuki Azuma, Tadashi Nakano and Yoshihiro Hotta
Int. J. Mol. Sci. 2019, 20(6), 1518; https://doi.org/10.3390/ijms20061518 - 26 Mar 2019
Cited by 27 | Viewed by 5162
Abstract
X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese [...] Read more.
X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan. Full article
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Review

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22 pages, 1154 KiB  
Review
Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa
by Michalitsa Diakatou, Gaël Manes, Beatrice Bocquet, Isabelle Meunier and Vasiliki Kalatzis
Int. J. Mol. Sci. 2019, 20(10), 2542; https://doi.org/10.3390/ijms20102542 - 23 May 2019
Cited by 42 | Viewed by 8135
Abstract
Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of diseases with more than 250 causative genes. The most common form is retinitis pigmentosa. IRDs lead to vision impairment for which there is no universal cure. Encouragingly, a first gene supplementation [...] Read more.
Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of diseases with more than 250 causative genes. The most common form is retinitis pigmentosa. IRDs lead to vision impairment for which there is no universal cure. Encouragingly, a first gene supplementation therapy has been approved for an autosomal recessive IRD. However, for autosomal dominant IRDs, gene supplementation therapy is not always pertinent because haploinsufficiency is not the only cause. Disease-causing mechanisms are often gain-of-function or dominant-negative, which usually require alternative therapeutic approaches. In such cases, genome-editing technology has raised hopes for treatment. Genome editing could be used to (i) invalidate both alleles, followed by supplementation of the wild type gene, (ii) specifically invalidate the mutant allele, with or without gene supplementation, or (iii) to correct the mutant allele. We review here the most prevalent genes causing autosomal dominant retinitis pigmentosa and the most appropriate genome-editing strategy that could be used to target their different causative mutations. Full article
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