A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa

Nishiguchi, Koji M.; Miya, Fuyuki; Mori, Yoshiyuki; Fujita, Kosuke; Akiyama, Masato; Kamatani, Takashi; Koyanagi, Yoshito; Sato, Kota; Takigawa, Toru; Ueno, Shinji; Tsugita, Misato; Kunikata, Hiroshi; Cisarova, Katarina; Nishino, Junichi; Murakami, Akira; Abe, Toshiaki; Momozawa, Yukihide; Terasaki, Hiroko; Wada, Yuko; Sonoda, Koh Hei; Rivolta, Carlo; Tsunoda, Tatsuhiko; Tsujikawa, Motokazu; Ikeda, Yasuhiro; Nakazawa, Toru

doi:10.1038/s42003-021-01662-9

Cited by 13 publications

(14 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, carrier frequencies of homozygous (4.13 × 10 −3 , 5/1210) and compound heterozygous (2.23 × 10 −2 , 27/1210) p.G843E in our IRD cohort were significantly higher than their expected frequencies in the general Japanese population (homozygous p.G843E: 3.57 × 10 −4 by 8.3KJPN, p = 8.73 × 10 −5 ; compound heterozygous p.G843E: 1.38 × 10 −4 by 8.3KJPN, p < 2.2 × 10 −16 ) (Supporting Information: Table ). Together with previous reports showing p.G843E variant enrichment in Japanese RP patients (Nishiguchi et al, 2021; Numa et al, 2020), and functional data showing a reduced rescue efficiency of a p.G843E mutant construct in zebrafish (Nishiguchi et al, 2021), our data suggested that p.G843E may contribute to the IRD phenotype either in trans with other EYS mutations or as a homozygous variant. Therefore, we propose that the p.G843E variant is pathogenic.…”

Section: Discussionsupporting

confidence: 88%

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole‐exome sequencing

et al. 2022

Self Cite

View full text Add to dashboard Cite

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone-or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees.The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively.Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

show abstract

Section: Discussionsupporting

confidence: 88%

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole‐exome sequencing

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our cohort, and those reported elsewhere, 14–20 may represent the more severe end of the disease spectrum that involves C2139Y. Hypomorphic EYS alleles have been reported in a Japanese RP cohort recently, 27 and their high population frequency makes it likely that they do not cause clinical disease when present homozygously. The C2139Y variant does appear to cause clinically relevant disease homozygously, and thus it should not be considered hypomorphic.…”

Section: Discussionsupporting

confidence: 62%

Retinitis pigmentosa associated with the EYS C2139Y variant: an important cause of blindness in East Asian populations.

Chan,

Tan,

Jain

et al. 2023

Retina

View full text Add to dashboard Cite

Purpose: The study aimed to describe the phenotypic features of retinitis pigmentosa (RP) associated with the previously described EYS C2139Y variant in Singaporeans and establish the importance of this variant as a prevalent cause of RP among East Asians. Methods: A clinical phenotyping and exome sequencing study was conducted on consecutive patients with non-syndromic RP. Epidemiological analysis was performed using Singaporean and global population-based genetic data. Results: A study of 150 consecutive unrelated individuals with non-syndromic RP found that 87 (58%) of cases had plausible genotypes. A previously described missense variant in the EYS gene, 6416G>A (C2139Y), occurred heterozygously or homozygously in 17 of 150 families (11.3%), all with autosomal recessive RP. Symptom onset in EYS C2139Y-related RP ranged from 6 to 45 years, with visual acuity (VA) ranging from 20/20 at 21 years to no light perception by 48 years. C2139Y-related RP had typical findings, including sectoral RP in cases with EYS E2703X in trans. The median age at presentation was 45 and visual fields declined to less than 20° (Goldmann V4e isopter) by age 65. Inter-eye correlation for VA, fields, and ellipsoid band width was high (r-squared 0.77 to 0.95). Carrier prevalence was 0.66% (allele frequency of 0.33%) in Singaporean Chinese and 0.34% in East Asians, suggesting a global disease burden exceeding ten thousand individuals. Conclusions: The EYS C2139Y variant is common in Singaporean RP patients and other ethnic Chinese populations. Targeted molecular therapy for this single variant could potentially treat a significant proportion of RP cases worldwide.

show abstract

“…Therefore, it is an urgent global issue to develop a strategy to delay progressive retinal dystrophy. Although gene therapy has been reported to be safe and effective for one type of inherited retinal dystrophy [ 10 – 13 ], and several drugs are promising [ 14 – 17 ], no established treatments are available for EYS-RP to date.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of photoreceptor-directed fibroblasts derived from retinitis pigmentosa patients with defects in the EYS gene: a possible cost-effective cellular model for mechanism-oriented drug

et al. 2022

View full text Add to dashboard Cite

Background The most common gene responsible for autosomal recessive retinitis pigmentosa (RP) is EYS. The manner of decay of genetically defective EYS gene transcripts varies depending on the type of mutation using our cellular model, which consists of induced photoreceptor-directed fibroblasts from EYS-RP patients (EYS-RP cells). However, disease-specific profiles have not been clarified in EYS-RP cells. Herein we investigated comprehensive gene expression patterns and restoration of altered expression by low molecular weight molecules in EYS-RP cells. Methods Using induced photoreceptor-like cells by CRX, RAX, NeuroD, and OTX2, we employed qRT-PCR and DNA microarray analysis to compare expression levels of disease-related genes in EYS-RP cells. We investigated the effect of antiapoptotic or anti-endoplasmic reticulum (ER) stress/antioxidant reagents on the restoration of altered gene expression. Results Expression levels of phototransduction-related genes (blue opsin, rhodopsin, S-antigen, GNAT1, GNAT2) were lower in EYS-RP cells. CRYGD was extracted by global gene expression analysis, as a downregulated, retina-related and apoptosis-, endoplasmic reticulum (ER) stress- or aging-related gene. Pathway enrichment analysis suggested that “complement and coagulation cascades,” “ECM-receptor interaction” and “PI3K-Akt signaling pathway” could be involved in EYS-RP-associated pathogenesis. Among the matching/overlapping genes involved in those pathways, F2R was suggested as an EYS-RP-associated gene. The downregulation of CRYGD and F2R was completely restored by additional 4-PBA, an inhibitor of ER stress, and partially restored by metformin or NAC. In addition, 4-PBA normalized the expression level of cleaved caspase-3. Conclusions Our cellular model may reflect the ER stress-mediated degenerative retina and serve as a pathogenesis-oriented cost-effective rescue strategy for RP patients.

show abstract

A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa

Cited by 13 publications

References 58 publications

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole‐exome sequencing

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole‐exome sequencing

Retinitis pigmentosa associated with the EYS C2139Y variant: an important cause of blindness in East Asian populations.

Evaluation of photoreceptor-directed fibroblasts derived from retinitis pigmentosa patients with defects in the EYS gene: a possible cost-effective cellular model for mechanism-oriented drug

Contact Info

Product

Resources

About