Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue

Rodrigues, Amélie; Slembrouck-Brec, Amélie; Nanteau, Céline; Terray, Angélique; Tymoshenko, Yelyzaveta; Zagar, Yvrick; Reichman, Sacha; Xi, Zhouhuan; Sahel, José‐Alain; Fouquet, Stéphane; Orieux, Gaël; Nandrot, Emeline F.; Byrne, Leah C.; Audo, Isabelle; Roger, Jérôme E.; Goureau, Olivier

doi:10.1038/s41536-022-00235-6

Cited by 26 publications

(14 citation statements)

References 69 publications

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“…Moreover, the effect of PRPF31 mutation on the spliceosome impaired U4/U6.U5 tri-snRNP assembly and decreased splicing activity [ 43 ]. The mutant PRPF31 protein causes photoreceptor cell degeneration in organoids, with rods expiring first, followed by cones, which correspond to the results obtained in RP patients [ 44 ]. In contrast, some transgenic mice with prpf3 T494M/ + , prpf8 H2309P/ + , and prpf31 ± exhibited unsatisfactory performances in photoreceptor degeneration [ 9 , 45 ].…”

Section: Application Of Patient-derived Organoids In Irdssupporting

confidence: 81%

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Liang,

Sun,

Duan

et al. 2023

Stem Cell Res Ther

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Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic diseases have long been used as a primary research tool to decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, are considered a promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, and best vitelliform macular dystrophy. Here, this paper focuses on the status of patient-derived iPSCs and organoids in IRDs in recent years concerning disease modeling and therapeutic exploration, along with potential challenges for translating laboratory research to clinical application. Finally, the importance of human iPSCs and organoids in combination with emerging technologies such as multi-omics integration analysis, 3D bioprinting, or microfluidic chip platform are highlighted. Patient-derived retinal organoids may be a preferred choice for more accurately uncovering the mechanisms of human retinal diseases and will contribute to clinical practice.

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Section: Application Of Patient-derived Organoids In Irdssupporting

confidence: 81%

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Liang,

Sun,

Duan

et al. 2023

Stem Cell Res Ther

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“…Additionally, our analysis of the retina of mice expressing a GPATCH11 protein analogous to the human mutant variant, which faithfully recapitulated the retinal disease and neurological abnormalities associated with human GPATCH11 mutations, unveiled highly significant splicing abnormalities. Interestingly, we also detected dysregulation of gene expression, which, like splicing defects, impacted mainly photoreceptor light responses which dysregulation is known to trigger photoreceptor cell death, leading to visual loss 28 . Reduced mRNA abundance could be a direct consequence of splicing aberrations leading to the degradation of mRNA isoforms containing premature termination codons or an indirect result of splicing dysregulation.…”

Section: Discussionmentioning

confidence: 84%

GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

Zanetti,

Fares-Taie,

Amiel

et al. 2023

Preprint

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G-patch domain-containing proteins have emerged as pivotal regulators of RNA metabolism, and the dysfunction of these proteins has been linked to a large range of phenotypic traits. This study provides compelling evidence that biallelic mutations in GPATCH11 lead to severe early-onset photoreceptor degeneration, neurological issues, and skeletal abnormalities in humans. Analysis of exome datasets from affected individuals of four independent families identified variants in a new gene, GPATCH11. The aim of the study was to determine the genetic source of the patients symptoms and characterize the role of GPATCH11. Using engineered disease variants in mice, we showed abnormal levels of spliceosome components in mutant retinas and substantial splicing deregulation, indicating a role for GPATCH11 in spliceosome homeostasis and splicing activity. Additionally, we identified deregulated gene expression, partly independent of splicing abnormalities, suggesting the involvement of GPATCH11 in transcriptional regulation. The affected genes were found to be related to phototransduction and the transmission of visual messages, protein homeostasis, RNA homeostasis, and cilia metabolism. The presence of GPATCH11 in ciliary basal bodies further suggests a potential role in ciliary functions. Studying GPATCH11 dysfunction elucidates the complex roles of this protein in RNA metabolism, highlighting the significance of GPATCH11 in maintaining proper gene expression and its contributions to various aspects of retinal, neurological, and skeletal function or development. As demonstrated here, studying rare genetic disorders can help to define broader functions beyond the specific disease context, and study provides new insight into the broader roles of GPATCH11.

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“…These results indicate that the mutant transcript was unstable and may be subjected to the nonsense-mediated decay mechanism. Haploinsu ciency in PRPF31 is a well-established mechanism in the pathogenesis of RCD [20], [21] , [22]. The majority of PRPF31 mutations result in null alleles, leading to haploinsu ciency and subsequent photoreceptor death in the retina [20], [21].…”

Section: Discussionmentioning

confidence: 99%

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

Mousawi,

Choukeir,

Jaffal

et al. 2024

Preprint

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Background and Objectives: Rod-cone dystrophy (RCD), also known as Retinitis Pigmentosa, is the most common group of retinal dystrophies, affecting around 1:4,000 individuals worldwide. Herein, our objective was to identify the genetic cause of RCD in two Lebanese families with distinct inheritance patterns and explore the potential role of PRPF31 haploinsufficiency. Methods The study combined next-generation sequencing, real-time PCR (qPCR), and chromosomal microarray to identify, validate, and delineate the causative copy number variations (CNVs) identified in both families of this study. gene expression analysis using qPCR and Western Blot were conducted to assess the PRPF31 variant's impact on gene expression levels. Results A novel heterozygous deletion (701 bp) spanning exons 6 and 7 of PRPF31 was identified in the first family (F11), leading to autosomal dominant RCD through haploinsufficiency, evidenced by reduced mRNA and total absence of protein expression levels in the affected individuals (F11:III.2 and F11:II.1). A rare previously reported homozygous deletion in MERTK was found in the second family (F26), causing autosomal recessive RCD. These findings highlight the diversity of CNVs contributing to RCD and the critical role of haploinsufficiency in autosomal dominant RCD pathogenesis. Conclusion The current study expands the mutational spectrum associated with PRPF31 and MERTK genes in RCD, underscoring the importance of CNVs in its etiology. Identifying haploinsufficiency as a disease mechanism in PRPF31-related autosomal dominant RCD represents a stepping stone for future analyses regarding gene augmentation therapies.

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Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue

Cited by 26 publications

References 69 publications

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

GPATCH11variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment

A Novel Copy Number Variation in PRPF31 Causes Dominant Rod-Cone Dystrophy By Haploinsufficiency

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