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Achromatopsia: From Genetics to Therapy

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 15053

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Prof. Dr. Francesca Simonelli

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Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
Interests: inherited retinal distrophies; retinitis pigmentosa; Leber congenital amaurosis; choroideremia; Stargardt disease; best disease; achromatopsia; gene therapy

Prof. Dr. Fracesco Testa

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Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
Interests: retinitis pigmentosa

Dr. Marianthi Karali

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Telethon Institute of Genetics and MedicineVia Campi Flegrei, 34, 80078 Pozzuoli NA, Italy

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Dear Colleagues,

Achromatopsia (rod monochromatism) is a rare (1 in 30,000–50,000) autosomal recessive disorder affecting cone photoreceptors. Pathogenic variants in six genes (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6) have been associated with achromatopsia to date. Currently, gene therapy trials are ongoing to correct the defects of CNGA3 and CNGB3 that account for almost 70% of cases. Novel therapeutic approaches can greatly benefit from a better understanding of the molecular basis of achromatopsia. Defining the genetic components and the mechanisms underlying disease progression has implications for patient selection and intervention timing.

This Special Issue aims to offer novel insights into the molecular pathogenesis of achromatopsia, the mechanistic role of the genetic components, and relevant genotype–phenotype correlations. We welcome contributions on new gene targets and mechanisms that improve our understanding of the disease. Topics also include novel molecular therapeutic strategies.

Dr. Marianthi Karali
Prof. Dr. Fracesco Testa
Prof. Dr. Francesca Simonelli
Guest Editors

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Keywords

achromatopsia
photoreceptors
molecular genetics
retina
genotype–phenotype correlations
molecular therapy

Published Papers (6 papers)

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10 pages, 1644 KiB

Open AccessArticle

Oscillatory Potentials in Achromatopsia as a Tool for Understanding Cone Retinal Functions

by Giulia Righetti, Melanie Kempf, Christoph Braun, Ronja Jung, Susanne Kohl, Bernd Wissinger, Eberhart Zrenner, Katarina Stingl and Krunoslav Stingl

Int. J. Mol. Sci. 2021, 22(23), 12717; https://doi.org/10.3390/ijms222312717 - 24 Nov 2021

Cited by 3 | Viewed by 1607

Abstract

Achromatopsia (ACHM) is an inherited autosomal recessive disease lacking cone photoreceptors functions. In this study, we characterize the time-frequency representation of the full-field electroretinogram (ffERG) component oscillatory potentials (OPs), to investigate the connections between photoreceptors and the inner retinal network using ACHM as a model. Time-frequency characterization of OPs was extracted from 52 controls and 41 achromat individuals. The stimulation via ffERG was delivered under dark-adaptation (DA, 3.0 and 10.0 cd·s·m⁻²) to assess mixed rod-cone responses. The ffERG signal was subsequently analyzed using a continuous complex Morlet transform. Time-frequency maps of both DA conditions show the characterization of OPs, disclosing in both groups two distinct time-frequency windows (~70–100 Hz and >100 Hz) within 50 ms. Our main result indicates a significant cluster (p < 0.05) in both conditions of reduced relative power (dB) in ACHM people compared to controls, mainly at the time-frequency window >100 Hz. These results suggest that the strongly reduced but not absent activity of OPs above 100 Hz is mostly driven by cones and only in small part by rods. Thus, the lack of cone modulation of OPs gives important insights into interactions between photoreceptors and the inner retinal network and can be used as a biomarker for monitoring cone connection to the inner retina. Full article

(This article belongs to the Special Issue Achromatopsia: From Genetics to Therapy)

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13 pages, 2954 KiB

Open AccessArticle

CNGB3 Missense Variant Causes Recessive Achromatopsia in Original Braunvieh Cattle

by Irene M. Häfliger, Emma Marchionatti, Michele Stengård, Sonja Wolf-Hofstetter, Julia M. Paris, Joana G. P. Jacinto, Christine Watté, Katrin Voelter, Laurence M. Occelli, András M. Komáromy, Anna Oevermann, Christine Goepfert, Angelica Borgo, Raphaël Roduit, Mirjam Spengeler, Franz R. Seefried and Cord Drögemüller

Int. J. Mol. Sci. 2021, 22(22), 12440; https://doi.org/10.3390/ijms222212440 - 18 Nov 2021

Cited by 4 | Viewed by 2936

Abstract

Sporadic occurrence of inherited eye disorders has been reported in cattle but so far pathogenic variants were found only for rare forms of cataract but not for retinopathies. The aim of this study was to characterize the phenotype and the genetic aetiology of a recessive form of congenital day-blindness observed in several cases of purebred Original Braunvieh cattle. Electroretinography in an affected calf revealed absent cone-mediated function, whereas the rods continue to function normally. Brain areas involved in vision were morphologically normal. When targeting cones by immunofluorescence, a decrease in cone number and an accumulation of beta subunits of cone cyclic-nucleotide gated channel (CNGB3) in the outer plexiform layer of affected animals was obvious. Achromatopsia is a monogenic Mendelian disease characterized by the loss of cone photoreceptor function resulting in day-blindness, total color-blindness, and decreased central visual acuity. After SNP genotyping and subsequent homozygosity mapping with twelve affected cattle, we performed whole-genome sequencing and variant calling of three cases. We identified a single missense variant in the bovine CNGB3 gene situated in a ~2.5 Mb homozygous genome region on chromosome 14 shared between all cases. All affected cattle were homozygous carriers of the p.Asp251Asn mutation that was predicted to be deleterious, affecting an evolutionary conserved residue. In conclusion, we have evidence for the occurrence of a breed-specific novel CNGB3-related form of recessively inherited achromatopsia in Original Braunvieh cattle which we have designated OH1 showing an allele frequency of the deleterious allele of ~8%. The identification of carriers will enable selection against this inherited disorder. The studied cattle might serve as an animal model to further elucidate the function of CNGB3 in mammals. Full article

(This article belongs to the Special Issue Achromatopsia: From Genetics to Therapy)

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17 pages, 2521 KiB

Open AccessArticle

Mouse Models of Achromatopsia in Addressing Temporal “Point of No Return” in Gene-Therapy

by Nan-Kai Wang, Pei-Kang Liu, Yang Kong, Sarah R. Levi, Wan-Chun Huang, Chun-Wei Hsu, Hung-Hsi Wang, Nelson Chen, Yun-Ju Tseng, Peter M. J. Quinn, Ming-Hong Tai, Chyuan-Sheng Lin and Stephen H. Tsang

Int. J. Mol. Sci. 2021, 22(15), 8069; https://doi.org/10.3390/ijms22158069 - 28 Jul 2021

Cited by 3 | Viewed by 2709

Abstract

Achromatopsia is characterized by amblyopia, photophobia, nystagmus, and color blindness. Previous animal models of achromatopsia have shown promising results using gene augmentation to restore cone function. However, the optimal therapeutic window to elicit recovery remains unknown. Here, we attempted two rounds of gene augmentation to generate recoverable mouse models of achromatopsia including a Cnga3 model with a knock-in stop cassette in intron 5 using Easi-CRISPR (Efficient additions with ssDNA inserts-CRISPR) and targeted embryonic stem (ES) cells. This model demonstrated that only 20% of CNGA3 levels in homozygotes derived from target ES cells remained, as compared to normal CNGA3 levels. Despite the low percentage of remaining protein, the knock-in mouse model continued to generate normal cone phototransduction. Our results showed that a small amount of normal CNGA3 protein is sufficient to form “functional” CNG channels and achieve physiological demand for proper cone phototransduction. Thus, it can be concluded that mutating the Cnga3 locus to disrupt the functional tetrameric CNG channels may ultimately require more potent STOP cassettes to generate a reversible achromatopsia mouse model. Our data also possess implications for future CNGA3-associated achromatopsia clinical trials, whereby restoration of only 20% functional CNGA3 protein may be sufficient to form functional CNG channels and thus rescue cone response. Full article

(This article belongs to the Special Issue Achromatopsia: From Genetics to Therapy)

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10 pages, 1706 KiB

Open AccessArticle

Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with CNGA3-Associated Autosomal Recessive Achromatopsia

by Susanne Kohl, Britta Baumann, Francesca Dassie, Anja K. Mayer, Maria Solaki, Peggy Reuter, Laura Kühlewein, Bernd Wissinger and Pietro Maffei

Int. J. Mol. Sci. 2021, 22(15), 7842; https://doi.org/10.3390/ijms22157842 - 22 Jul 2021

Cited by 4 | Viewed by 2071

Abstract

Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families. Full article

(This article belongs to the Special Issue Achromatopsia: From Genetics to Therapy)

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16 pages, 2065 KiB

Open AccessArticle

Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study

by Raffaella Brunetti-Pierri, Marianthi Karali, Paolo Melillo, Valentina Di Iorio, Antonella De Benedictis, Gennarfrancesco Iaccarino, Francesco Testa, Sandro Banfi and Francesca Simonelli

Int. J. Mol. Sci. 2021, 22(4), 1681; https://doi.org/10.3390/ijms22041681 - 7 Feb 2021

Cited by 19 | Viewed by 2518

Abstract

Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (−0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies. Full article

(This article belongs to the Special Issue Achromatopsia: From Genetics to Therapy)

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13 pages, 2311 KiB

Open AccessCase Report

Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes

by Giancarlo Iarossi, Andrea Maria Coppè, Chiara Passarelli, Paolo Enrico Maltese, Lorenzo Sinibaldi, Alessandro Cappelli, Sarah Cetola, Antonio Novelli and Luca Buzzonetti

Int. J. Mol. Sci. 2021, 22(16), 8617; https://doi.org/10.3390/ijms22168617 - 10 Aug 2021

Cited by 3 | Viewed by 2161

Abstract

Blue cone monochromatism (BCM) is an X-linked recessive cone dysfunction disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength-sensitive cone opsins. Here, we report on the unusual clinical presentation of BCM caused by a novel mutation in the OPN1LW gene in a young man. We describe in detail the phenotype of the proband, and the subclinical morpho-functional anomalies shown by his carrier mother. At a clinical level, the extensive functional evaluation demonstrated in the proband the M/L cone affection and the sparing of S-cone function, distinctive findings of BCM. Interestingly, spectral-domain optical coherence tomography showed the presence of foveal hypoplasia with focal irregularities of the ellipsoid layer in the foveal area, reported to be associated with some cases of cone-rod dystrophy and achromatopsia. At a molecular level, we identified the novel mutation c.427T > C p.(Ser143Pro) in the OPN1LW gene and the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene. In addition, we discovered the c.768-2_769delAGTT splicing variant in the GPR143 gene. To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects. Full article

(This article belongs to the Special Issue Achromatopsia: From Genetics to Therapy)

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