PRPF31 reduction causes mis-splicing of the phototransduction genes in human organotypic retinal culture

Pormehr, Leila Azizzadeh; Ahmadian, Shahin; Daftarian, Narsis; Mousavi, Seyed Ahmad; Shafiezadeh, Mahshid

doi:10.1038/s41431-019-0531-1

Cited by 18 publications

(13 citation statements)

References 35 publications

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“…Aberrant mRNA splicing of phototransduction and ciliary genes have been implicated in the pathogenesis of PRPF31-associated RP ( 22 , 24 , 61 , 62 ). In this study, we detected no obvious mis-splicing of phototransduction genes, likely because the early differentiation defects of RPCs lead to limited expression of these genes in prpf31 knockout retinas.…”

Section: Discussionmentioning

confidence: 99%

“…Pre-mRNAs processing factor 31 ( PRPF31 ) is a constitutive component of spliceosomes, which participates in the assembly and stabilization of U4/U6/U5 tri-snRNP ( 21–23 ). Mutations in PRPF31 have been determined to be loss-of-function, resulting in reduced levels of activated snRNPs and decreased splicing efficiency ( 14 , 22 , 24 ). Remarkably, in patient-derived lymphocytes or siRNA-treated human organotypic retinal cultures, the insufficiency of PRPF31 only impaired the splicing of a subset of genes ( 22 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in PRPF31 have been determined to be loss-of-function, resulting in reduced levels of activated snRNPs and decreased splicing efficiency ( 14 , 22 , 24 ). Remarkably, in patient-derived lymphocytes or siRNA-treated human organotypic retinal cultures, the insufficiency of PRPF31 only impaired the splicing of a subset of genes ( 22 , 25 ). In vivo studies in prpf31 transient knockdown zebrafish or Prpf31 +/− mice also showed that the global transcriptome is mildly affected by Prpf31 deficiency, while the retinal-specific gene expression is more severely disturbed ( 26–28 ).…”

Section: Introductionmentioning

confidence: 99%

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Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing

Liu

et al. 2021

Nucleic Acids Research

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Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5′ splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing

Liu

et al. 2021

Nucleic Acids Research

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“…Interestingly, over-expression of PRPF6 rescues the mutant phenotype and, consequently, PRPF6 expression may represent an additional factor accounting for some cases of PRPF31 adRP incomplete penetrance [ 85 ]. Regarding the retinal phenotype, studies using induced pluripotent stem cell (iPSC)-derived organoids, revealed that impaired splicing is restricted to retinal cells only and it affects genes involved in RNA processing as well as genes involved in phototransduction and ciliogenesis, which have been associated with progressive degeneration and cellular stress [ 86 , 87 ]. In fact, mis-splicing of ciliary genes was associated with severe defects in the retinal pigmented epithelium (RPE) cells, which are typically affected (together with photoreceptors) in the RP disease [ 87 ].…”

Section: The Role Of Alternative Splicing In Retinal Diseasementioning

confidence: 99%

The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

Aísa-Marín

García-Arroyo

Mirra

et al. 2021

IJMS

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Alternative splicing of mRNA is an essential mechanism to regulate and increase the diversity of the transcriptome and proteome. Alternative splicing frequently occurs in a tissue- or time-specific manner, contributing to differential gene expression between cell types during development. Neural tissues present extremely complex splicing programs and display the highest number of alternative splicing events. As an extension of the central nervous system, the retina constitutes an excellent system to illustrate the high diversity of neural transcripts. The retina expresses retinal specific splicing factors and produces a large number of alternative transcripts, including exclusive tissue-specific exons, which require an exquisite regulation. In fact, a current challenge in the genetic diagnosis of inherited retinal diseases stems from the lack of information regarding alternative splicing of retinal genes, as a considerable percentage of mutations alter splicing or the relative production of alternative transcripts. Modulation of alternative splicing in the retina is also instrumental in the design of novel therapeutic approaches for retinal dystrophies, since it enables precision medicine for specific mutations.

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“…The enzyme is responsible for catalysing the release of C-terminal amino acids and have functions ranging from digestion to selective biosynthesis of neuroendocrine peptides [23]. On the other hand, pre-mRNA processing factor 31 (PRPF31) encodes a ubiquitously expressed mRNA splicing factor [24]. Furthermore, Rotroff et al (2018) demonstrated that rs254271 (PRPF31) was associated with decreased metformin response among patients of European and African origin.…”

Section: Introductionmentioning

confidence: 99%

Single Nucleotide Polymorphisms Associated with Metformin and Sulphonylureas’ Glycaemic Response among South African Adults with Type 2 Diabetes Mellitus

Masilela

Pearce

Ongole

et al. 2021

JPM

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Aims: To examine the association of polymorphisms belonging to SLC22A1, SP1, PRPF31, NBEA, SCNN1B, CPA6 and CAPN10 genes with glycaemic response to metformin and sulphonylureas (SU) combination therapy among South African adults with diabetes mellitus type 2 (T2DM). Methods: A total of 128 individuals of Swati (n = 22) and Zulu (n = 106) origin attending chronic care for T2DM were recruited. Nine SNPs previously associated with metformin and SUs were selected and genotyped using MassArray. Uncontrolled T2DM was defined as HbA1c > 7%. The association between genotypes, alleles and glycaemic response to treatment was determined using multivariate logistic regression model analysis. Results: About 85.93% (n = 110) of the study participants were female and 77.34% (n = 99) had uncontrolled T2DM (HbA1c > 7%). In the multivariate (adjusted) logistic regression model analysis, the CC genotype of rs2162145 (CPA6), GG and GA genotypes of rs889299 (SCNN1B) were significantly associated with uncontrolled T2DM. On the other hand, the C allele of rs254271 (PRPF31) and the GA genotype of rs3792269 (CAPN10) were associated with controlled T2DM. A significant interaction between rs2162145 and rs889299 in response to metformin and SU combination therapy was observed. Conclusions: In this study, we reported the association of rs2162145 (CC) and rs889299 (GG and GA) with uncontrolled T2DM. We also reported the association of rs254271 (C) and rs3792269 (GA) with controlled T2DM in response to metformin and SU combination therapy. Furthermore, an interaction between rs2162145 and rs889299 was established, where the genotype combination GA (rs889299) and TT (rs2162145) was associated with uncontrolled T2DM.

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PRPF31 reduction causes mis-splicing of the phototransduction genes in human organotypic retinal culture

Cited by 18 publications

References 35 publications

Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing

Prpf31 is essential for the survival and differentiation of retinal progenitor cells by modulating alternative splicing

The Alter Retina: Alternative Splicing of Retinal Genes in Health and Disease

Single Nucleotide Polymorphisms Associated with Metformin and Sulphonylureas’ Glycaemic Response among South African Adults with Type 2 Diabetes Mellitus

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