Generation of two induced pluripotent stem cell lines from a patient with dominant PRPF31 mutation and a related non-penetrant carrier

McLenachan, Samuel; Zhang, Dan; Zhang, Xiao; Chen, Shang-Chih; Lamey, Tina M.; Thompson, Jennifer A.; McLaren, Terri L.; Roach, John N. De; Fletcher, Sue; Chen, Fred K.

doi:10.1016/j.scr.2018.11.018

Cited by 7 publications

(6 citation statements)

References 5 publications

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“…Although iPSC lines were established from patients with defects in RHO [ 31 ], MAK [ 74 ], PDE6A [ 75 ], PRPF31 [ 76 ], NR2E3 [ 77 ] and EYS [ 78 ], molecular mimicry of the iPSC-derived retina to the degenerative retina in human RP has not been confirmed. A high-throughput assay system for drug screening using human cellular models is necessary, although zebrafish model could complement such an assay [ 79 ].…”

Section: Discussionmentioning

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

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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.

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Section: Discussionmentioning

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

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“…In addition, gene expression and functional studies may provide additional information regarding the relationships between mutant and wild-type alleles and their role in the phenotypic expression of RP11. We recommend further investigation of tissue PRPF31 levels using patient-derived retinal tissue [51] that may provide additional clues towards a better understanding of these relationships and finding potential therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11

Roshandel

Thompson

Jeffery

et al. 2021

Genes

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PRPF31-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. PRPF31 mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression (N = 4), (B) adult-onset with rapid progression (N = 4), (C) adult-onset with slow progression (N = 4) and (D) non-penetrance (N = 2). Four different patterns were observed in a family harbouring c.267del; patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type PRPF31 allele rather than the type of mutation. Further studies that correlate in vitro wild-type PRPF31 allele expression level with the disease patterns are required to investigate this association.

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“…68 Mouse models with late-onset RP, 69 and induced pluripotent stem cells (iPSC) have been developed from a patient with PRPF31-RP and a related non-penetrant subject, to improve our understanding. 70 The latter have been used to create iPSC-RPE cells PRPF31 +/− and conduct a proof of concept AAV-mediated gene augmentation. Brydon et al reported a rescue in ciliogenesis, phagocytosis, and cell morphology.…”

Section: Prpf31mentioning

confidence: 99%

Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes

Varela

Georgiadis²,

Michaelides

2022

Br J Ophthalmol

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Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin (RHO)-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).Autosomal dominant RP represents 15%–25% of all RP, with RHO accounting for 20%–30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being BEST1. Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with RHO-adRP would typically become severely visually impaired at an age 2–3 times older than in X-linked RPGR-RP.Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes RHO, RP1 and PRPF31 among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here.

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Generation of two induced pluripotent stem cell lines from a patient with dominant PRPF31 mutation and a related non-penetrant carrier

Cited by 7 publications

References 5 publications

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

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

Clinical Evidence for the Importance of the Wild-Type PRPF31 Allele in the Phenotypic Expression of RP11

Genetic treatment for autosomal dominant inherited retinal dystrophies: approaches, challenges and targeted genotypes

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