scholarly journals Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1817
Author(s):  
Akio Oishi ◽  
Kaoru Fujinami ◽  
Go Mawatari ◽  
Nobuhisa Naoi ◽  
Yasuhiro Ikeda ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Age Of Onset ◽  
Phenotypic Variability ◽  
Retinal Dystrophy ◽  
Japanese Patients ◽  
Macular Dystrophy ◽  
Hand Motion ◽  
Pathogenic Variants ◽  
Inherited Retinal Dystrophy ◽  
Asian Cohort

Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

scholarly journals Retinitis Pigmentosa withEYSMutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Yuuki Arai ◽  
Akiko Maeda ◽  
Yasuhiko Hirami ◽  
Chie Ishigami ◽  
Shinji Kosugi ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Direct Sequencing ◽  
Retinal Dystrophy ◽  
In Silico Analysis ◽  
Japanese Patients ◽  
Sequence Variants ◽  
Stargardt Disease ◽  
Identification Rate ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy

The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is,ABCA4for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic.EYSmutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two majorEYSmutations identified in this cohort.EYSmutations are the most prevalent among Japanese patients with IRD.

scholarly journals Innate and Autoimmunity in the Pathogenesis of Inherited Retinal Dystrophy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 630 ◽  
Author(s):  
T. J. Hollingsworth ◽  
Alecia K. Gross
Keyword(s):  
Disease Progression ◽  
Age Of Onset ◽  
Retinal Dystrophy ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Major Player ◽  
Inherited Retinal Dystrophy ◽  
Rate Of Progression ◽  
Immunohistochemical Methods ◽  
Onset Rate

Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation.

Phenotypic variability of SLC7A14 mutations in patients with inherited retinal dystrophy

2019 ◽  
Vol 40 (2) ◽  
pp. 118-123 ◽  
Author(s):  
Li-Yun Guo ◽  
Sui-Lian Zheng ◽  
Jun Li ◽  
Qin Zhu ◽  
Wen-Hua Duan ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Retinal Dystrophy ◽  
Inherited Retinal Dystrophy

scholarly journals Targeting of the NRL Pathway as a Therapeutic Strategy to Treat Retinitis Pigmentosa

2020 ◽  
Vol 9 (7) ◽  
pp. 2224 ◽  
Author(s):  
Spencer M. Moore ◽  
Dorota Skowronska-Krawczyk ◽  
Daniel L. Chao
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Therapeutic Strategy ◽  
Leucine Zipper ◽  
Retinal Dystrophy ◽  
Rod Photoreceptor ◽  
Cone Photoreceptor ◽  
Future Directions ◽  
Inherited Retinal Dystrophy ◽  
Visual Acuity Loss

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

scholarly journals Antioxidant and Biological Properties of Mesenchymal Cells Used for Therapy in Retinitis Pigmentosa

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 983
Author(s):  
Paolo Giuseppe Limoli ◽  
Enzo Maria Vingolo ◽  
Celeste Limoli ◽  
Marcella Nebbioso
Keyword(s):  
Retinitis Pigmentosa ◽  
Tissue Repair ◽  
Therapeutic Option ◽  
Retinal Dystrophy ◽  
Retinal Disease ◽  
Biological Properties ◽  
Mesenchymal Cells ◽  
Cell Therapies ◽  
Tissue Repair And Regeneration ◽  
Inherited Retinal Dystrophy

Both tissue repair and regeneration are a priority in regenerative medicine. Retinitis pigmentosa (RP), a complex retinal disease characterized by the progressive loss of impaired photoreceptors, is currently lacking effective therapies: this represents one of the greatest challenges in the field of ophthalmological research. Although this inherited retinal dystrophy is still an incurable genetic disease, the oxidative damage is an important pathogenetic element that may represent a viable target of therapy. In this review, we summarize the current neuroscientific evidence regarding the effectiveness of cell therapies in RP, especially those based on mesenchymal cells, and we focus on their therapeutic action: limitation of both oxidative stress and apoptotic processes triggered by the disease and promotion of cell survival. Cell therapy could therefore represent a feasible therapeutic option in RP.

scholarly journals Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients

2019 ◽  
Vol 56 (10) ◽  
pp. 662-670 ◽  
Author(s):  
Yoshito Koyanagi ◽  
Masato Akiyama ◽  
Koji M Nishiguchi ◽  
Yukihide Momozawa ◽  
Yoichiro Kamatani ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Japanese Population ◽  
East Asian ◽  
Japanese Patients ◽  
Population Based ◽  
Genetic Profile ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Recessive Genes ◽  
Dominant Genes

BackgroundThe genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.MethodsA total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.ResultsWe successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

scholarly journals Genotype Profile of Global EYS-Associated Inherited Retinal Dystrophy and Clinical Findings in a Large Chinese Cohort

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke Xu ◽  
De-Fu Chen ◽  
Haoyu Chang ◽  
Ren-Juan Shen ◽  
Hua Gao ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Age Of Onset ◽  
Retinal Dystrophy ◽  
Clinical Findings ◽  
Pcr Analysis ◽  
Real Time Quantitative Pcr ◽  
Inherited Retinal Dystrophy ◽  
Chinese Cohort ◽  
Beijing Institute ◽  
Mutation Spectra

PurposeThe aim of this study was to probe the global profile of the EYS-associated genotype-phenotype trait in the worldwide reported IRD cases and to build a model for predicting disease progression as a reference for clinical consultation.MethodsThis retrospective study of 420 well-documented IRD cases with mutations in the EYS gene included 39 patients from a genotype-phenotype study of inherited retinal dystrophy (IRD) conducted at the Beijing Institute of Ophthalmology and 381 cases retrieved from global reports. All patients underwent ophthalmic evaluation. Mutations were revealed using next-generation sequencing, followed by Sanger DNA sequencing and real-time quantitative PCR analysis. Multiple regression models and statistical analysis were used to assess the genotype and phenotype characteristics and traits in this large cohort.ResultsA total of 420 well-defined patients with 841 identified mutations in the EYS gene were successfully obtained. The most common pathogenic variant was a frameshift c.4957dupA (p.S1653Kfs∗2) in exon 26, with an allele frequency of 12.7% (107/841), followed by c.8805C > A (p.Y2935X) in exon 43, with an allele frequency of 5.9% (50/841). Two new hot spots were identified in the Chinese cohort, c.1750G > T (p.E584X) and c.7492G > C (p.A2498P). Several EYS mutation types were identified, with CNV being relatively common. The mean age of onset was 20.54 ± 11.33 (4–46) years. Clinical examinations revealed a typical progression of RPE atrophy from the peripheral area to the macula.ConclusionThis large global cohort of 420 IRD cases, with 262 distinct variants, identified genotype-phenotype correlations and mutation spectra with hotspots in the EYS gene.

Expanding the retinal phenotype of RP1: from retinitis pigmentosa to a novel and singular macular dystrophy

2019 ◽  
Vol 104 (2) ◽  
pp. 173-181 ◽  
Author(s):  
Marina Riera ◽  
Víctor Abad-Morales ◽  
Rafael Navarro ◽  
Sheila Ruiz-Nogales ◽  
Pilar Méndez-Vendrell ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Retinitis Pigmentosa ◽  
Pigment Epithelium ◽  
Fundus Autofluorescence ◽  
Retinal Pigment ◽  
Retinal Dystrophy ◽  
Macular Dystrophy ◽  
Nucleotide Polymorphisms ◽  
Autofluorescence Imaging ◽  
New Genotype

PurposeThis study aimed to identify the underlying genetic cause(s) of inherited retinal dystrophy (IRD) in 12 families of Kuwaiti origin affected by macular dystrophy and four Spanish patients affected by retinitis pigmentosa (RP).MethodsClinical diagnoses were based on standard ophthalmic evaluations (best-corrected visual acuity, retinography, fundus autofluorescence imaging, optical coherence tomography, electroretinography and visual field tests). Panel-based whole exome sequencing was used to simultaneously analyse 224 IRD genes in one affected member of each family. The putative causative variants were confirmed by Sanger sequencing and cosegregation analyses. Haplotype analysis was performed using single nucleotide polymorphisms.ResultsA homozygous missense mutation c.606C>A (p.Asp202Glu) in RP1 was found to be the molecular cause of IRD in all 12 families from Kuwait. These patients exhibited comparable symptoms, including progressive decline in visual acuity since adolescence. Fundus autofluorescence images revealed bilateral macular retinal pigment epithelium disturbances, with neither perimacular flecks nor peripheral alterations. A shared haplotype spanning at least 1.1 Mb was identified in all families, suggesting a founder effect. Furthermore, RP1 variants involving nonsense and/or frameshifting mutations (three of them novel) were identified in three Spanish autosomal-recessive RP families and one dominant RP pedigree.ConclusionThis study describes, for the first time, a macular dystrophy phenotype caused by an RP1 mutation; establishing a new genotype-phenotype correlation in this gene, expanding its mutation spectrum and further highlighting the clinical heterogeneity associated with IRD.

Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa

2020 ◽  
pp. jmedgenet-2020-107150
Author(s):  
Guillaume Olivier ◽  
Marta Corton ◽  
Daniela Intartaglia ◽  
Sanne K Verbakel ◽  
Panagiotis I Sergouniotis ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Exome Sequencing ◽  
Autosomal Dominant ◽  
Macular Dystrophy ◽  
Common Disease ◽  
Medaka Fish ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing

BackgroundInherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.MethodsExome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.ResultsExome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.ConclusionThis study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

scholarly journals Truncating Variants Contribute to Hearing Loss and Severe Retinopathy in USH2A-Associated Retinitis Pigmentosa in Japanese Patients

2020 ◽  
Vol 21 (21) ◽  
pp. 7817
Author(s):  
Akira Inaba ◽  
Akiko Maeda ◽  
Akiko Yoshida ◽  
Kanako Kawai ◽  
Yasuhiko Hirami ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Usher Syndrome ◽  
Japanese Patients ◽  
Genetic Alterations ◽  
Causal Gene ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Genetic Features ◽  
Tissue Damages

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.

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