Research

24 pages, 6053 KiB

Open AccessFeature PaperArticle

by Rosa M. Coco-Martin, Hortensia T. Sanchez-Tocino, Carmen Desco, Ricardo Usategui-Martín and Juan J. Tellería

Genes 2020, 11(7), 773; https://doi.org/10.3390/genes11070773 - 09 Jul 2020

Cited by 17 | Viewed by 3988

Abstract

Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, [...] Read more.

Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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18 pages, 7964 KiB

Open AccessArticle

Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish

by Samuel Morales-Cámara, Susana Alexandre-Moreno, Juan-Manuel Bonet-Fernández, Raquel Atienzar-Aroca, José-Daniel Aroca-Aguilar, Jesús-José Ferre-Fernández, Carmen-Dora Méndez, Laura Morales, Laura Fernández-Sánchez, Nicolas Cuenca, Miguel Coca-Prados, José-María Martínez-de-la-Casa, Julián Garcia-Feijoo and Julio Escribano

Genes 2020, 11(5), 550; https://doi.org/10.3390/genes11050550 - 14 May 2020

Cited by 9 | Viewed by 3971

Abstract

Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > [...] Read more.

Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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14 pages, 3616 KiB

Open AccessArticle

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants

by Vasileios Toulis, Vianney Cortés-González, Marta de Castro-Miró, Juliana Ferraz Sallum, Jaume Català-Mora, Cristina Villanueva-Mendoza, Marcela Ciccioli, Roser Gonzàlez-Duarte, Rebeca Valero and Gemma Marfany

Genes 2020, 11(4), 378; https://doi.org/10.3390/genes11040378 - 31 Mar 2020

Cited by 11 | Viewed by 3240

Abstract

Aims: We aimed to validate the pathogenicity of genetic variants identified in inherited retinal dystrophy (IRD) patients, which were located in non-canonical splice sites (NCSS). Methods: After next generation sequencing (NGS) analysis (target gene panels or whole exome sequencing (WES)), NCSS variants were [...] Read more.

Aims: We aimed to validate the pathogenicity of genetic variants identified in inherited retinal dystrophy (IRD) patients, which were located in non-canonical splice sites (NCSS). Methods: After next generation sequencing (NGS) analysis (target gene panels or whole exome sequencing (WES)), NCSS variants were prioritized according to in silico predictions. In vivo and in vitro functional tests were used to validate their pathogenicity. Results: Four novel NCSS variants have been identified. They are located in intron 33 and 34 of ABCA4 (c.4774-9G>A and c.4849-8C>G, respectively), intron 2 of POC1B (c.101-3T>G) and intron 3 of RP2 (c.884-14G>A). Functional analysis detected different aberrant splicing events, including intron retention, exon skipping and intronic nucleotide addition, whose molecular effect was either the disruption or the elongation of the open reading frame of the corresponding gene. Conclusions: Our data increase the genetic diagnostic yield of IRD patients and expand the landscape of pathogenic variants, which will have an impact on the genotype–phenotype correlations and allow patients to opt for the emerging gene and cell therapies. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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10 pages, 1280 KiB

Open AccessArticle

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

by Johannes Birtel, Martin Gliem, Kristina Hess, Theresa H. Birtel, Frank G. Holz, Ulrich Zechner, Hanno J. Bolz and Philipp Herrmann

Genes 2020, 11(2), 137; https://doi.org/10.3390/genes11020137 - 28 Jan 2020

Cited by 12 | Viewed by 3642

Abstract

Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and [...] Read more.

Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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17 pages, 2542 KiB

Open AccessArticle

The Expression of Decidual Protein Induced by Progesterone (DEPP) Is Controlled by Three Distal Consensus Hypoxia Responsive Element (HRE) in Hypoxic Retinal Epithelial Cells

by Katrin Klee, Federica Storti, Jordi Maggi, Vyara Todorova, Duygu Karademir, Wolfgang Berger, Marijana Samardzija and Christian Grimm

Genes 2020, 11(1), 111; https://doi.org/10.3390/genes11010111 - 18 Jan 2020

Cited by 4 | Viewed by 3589

Abstract

Hypoxia affects the development and/or progression of several retinopathies. Decidual protein induced by progesterone (DEPP) has been identified as a hypoxia-responsive gene that may be part of cellular pathways such as autophagy and connected to retinal diseases. To increase our understanding [...] Read more.

Hypoxia affects the development and/or progression of several retinopathies. Decidual protein induced by progesterone (DEPP) has been identified as a hypoxia-responsive gene that may be part of cellular pathways such as autophagy and connected to retinal diseases. To increase our understanding of DEPP regulation in the eye, we defined its expression pattern in mouse and human retina and retinal pigment epithelium (RPE). Interestingly, DEPP expression was increased in an age-dependent way in the central human RPE. We showed that DEPP was regulated by hypoxia in the mouse retina and eyecup and that this regulation was controlled by hypoxia-inducible transcription factors 1 and 2 (HIF1 and HIF2). Furthermore, we identified three hypoxia response elements (HREs) about 3.5 kb proximal to the transcriptional start site that were responsible for hypoxic induction of DEPP in a human RPE cell line. Comparative genomics analysis suggested that one of the three HREs resides in a highly conserved genomic region. Collectively, we defined the molecular elements controlling hypoxic induction of DEPP in an RPE cell line, and provided evidence for an enrichment of DEPP in the aged RPE of human donors. This makes DEPP an interesting gene to study with respect to aging and age-related retinal pathologies. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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16 pages, 3058 KiB

Open AccessArticle

Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

by Lama Jaffal, Wissam H Joumaa, Alexandre Assi, Charles Helou, George Cherfan, Kazem Zibara, Isabelle Audo, Christina Zeitz and Said El Shamieh

Genes 2019, 10(12), 1047; https://doi.org/10.3390/genes10121047 - 16 Dec 2019

Cited by 8 | Viewed by 3315

Abstract

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two [...] Read more.

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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Review

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25 pages, 725 KiB

Open AccessReview

Application of CRISPR Tools for Variant Interpretation and Disease Modeling in Inherited Retinal Dystrophies

by Carla Fuster-García, Belén García-Bohórquez, Ana Rodríguez-Muñoz, José M. Millán and Gema García-García

Genes 2020, 11(5), 473; https://doi.org/10.3390/genes11050473 - 27 Apr 2020

Cited by 4 | Viewed by 3604

Abstract

Inherited retinal dystrophies are an assorted group of rare diseases that collectively account for the major cause of visual impairment of genetic origin worldwide. Besides clinically, these vision loss disorders present a high genetic and allelic heterogeneity. To date, over 250 genes have [...] Read more.

Inherited retinal dystrophies are an assorted group of rare diseases that collectively account for the major cause of visual impairment of genetic origin worldwide. Besides clinically, these vision loss disorders present a high genetic and allelic heterogeneity. To date, over 250 genes have been associated to retinal dystrophies with reported causative variants of every nature (nonsense, missense, frameshift, splice-site, large rearrangements, and so forth). Except for a fistful of mutations, most of them are private and affect one or few families, making it a challenge to ratify the newly identified candidate genes or the pathogenicity of dubious variants in disease-associated loci. A recurrent option involves altering the gene in in vitro or in vivo systems to contrast the resulting phenotype and molecular imprint. To validate specific mutations, the process must rely on simulating the precise genetic change, which, until recently, proved to be a difficult endeavor. The rise of the CRISPR/Cas9 technology and its adaptation for genetic engineering now offers a resourceful suite of tools to alleviate the process of functional studies. Here we review the implementation of these RNA-programmable Cas9 nucleases in culture-based and animal models to elucidate the role of novel genes and variants in retinal dystrophies. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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5 pages, 203 KiB

Open AccessComment

An Assessment of GUCA1C Variants in Primary Congenital Glaucoma

by Emmanuelle Souzeau, Nicole Weisschuh, Jamie E. Craig, Francesca Pasutto and Karl-Wilhelm Koch

Genes 2021, 12(3), 359; https://doi.org/10.3390/genes12030359 - 02 Mar 2021

Cited by 2 | Viewed by 1403

Abstract

In the special issue “Molecular Genetics of Retinal Dystrophies”, Morales–Cámara and colleagues reported the association of a new candidate gene with primary congenital glaucoma (PCG) [...] Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

7 pages, 3730 KiB

Open AccessCase Report

A Mild Phenotype Caused by Two Novel Compound Heterozygous Mutations in CEP290

by Agnieszka Rafalska, Anna M. Tracewska, Anna Turno-Kręcicka, Milena J. Szafraniec and Marta Misiuk-Hojło

Genes 2020, 11(11), 1240; https://doi.org/10.3390/genes11111240 - 22 Oct 2020

Cited by 7 | Viewed by 2398

Abstract

CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss [...] Read more.

CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss due to cone-rod dystrophy, as in Leber congenital amaurosis. In this case report, we describe two novel loss-of-function heterozygous alterations in the CEP290 gene, discovered in a patient suffering from retinitis pigmentosa using massive parallel sequencing of a molecular inversion probes library constructed for 108 genes involved in IRDs. A milder phenotype than expected was found in the individual, which serves to prove that some CEP290-associated disorders may display preserved cone function. Full article

(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)

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