Autosomal Dominant Retinitis Pigmentosa Secondary to Pre-mRNA Splicing-Factor Gene<i>PRPF31</i>(RP11): Review of Disease Mechanism and Report of a Family with a Novel 3-Base Pair Insertion

Utz, Virginia Miraldi; Beight, Craig D.; Marino, Meghan J; Hagstrom, Stephanie A.; Traboulsi, Elias I.

doi:10.3109/13816810.2012.762932

Cited by 25 publications

(12 citation statements)

References 37 publications

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“…The insertion mutant at amino acid 227 was especially intriguing because this is only one amino-acid away from a mutation of human PRP31 that occurs in retinitis pigmentosa ( 50 ), and which changes alanine 216 into a proline (corresponding to a.a 226 in yeast Prp31p). Retinitis pigmentosa is a group of inherited diseases characterized by the gradual degeneration of retina cells that lead to night blindness and visual field loss (for review, 51 ). Our results prompted us to test the A226P mutant of yeast Prp31p in our Y2H assays (the position homologous to A216P in the human protein).…”

Section: Resultsmentioning

confidence: 99%

NUFIP and the HSP90/R2TP chaperone bind the SMN complex and facilitate assembly of U4-specific proteins

et al. 2015

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The Sm proteins are loaded on snRNAs by the SMN complex, but how snRNP-specific proteins are assembled remains poorly characterized. U4 snRNP and box C/D snoRNPs have structural similarities. They both contain the 15.5K and proteins with NOP domains (PRP31 for U4, NOP56/58 for snoRNPs). Biogenesis of box C/D snoRNPs involves NUFIP and the HSP90/R2TP chaperone system and here, we explore the function of this machinery in U4 RNP assembly. We show that yeast Prp31 interacts with several components of the NUFIP/R2TP machinery, and that these interactions are separable from each other. In human cells, PRP31 mutants that fail to stably associate with U4 snRNA still interact with components of the NUFIP/R2TP system, indicating that these interactions precede binding of PRP31 to U4 snRNA. Knock-down of NUFIP leads to mislocalization of PRP31 and decreased association with U4. Moreover, NUFIP is associated with the SMN complex through direct interactions with Gemin3 and Gemin6. Altogether, our data suggest a model in which the NUFIP/R2TP system is connected with the SMN complex and facilitates assembly of U4 snRNP-specific proteins.

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Section: Resultsmentioning

confidence: 99%

NUFIP and the HSP90/R2TP chaperone bind the SMN complex and facilitate assembly of U4-specific proteins

et al. 2015

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“…Working in synergy, these proteins form the highly dynamic spliceosome and facilitate both constitutive and alternative splicing (Matera & Wang, 2014), the latter being fundamental to time- and tissue-specific gene expression. Dysregulation of splicing, which underlies many inherited and sporadic diseases (Paronetto, Passacantilli, & Sette, 2016), can be caused by mutations in spliceosome subunits (Boon et al, 2007; Utz, Beight, Marino, Hagstrom, & Traboulsi, 2013) or the target DNA sequence essential for spliceosome recognition and binding. The functional consequence includes exon skipping, intron retention and the formation of pseudo-exons (Baralle & Baralle, 2005; Dhir & Buratti, 2010).…”

Section: Introductionmentioning

confidence: 99%

Exonic mutations and exon skipping: Lessons learned from DFNA5

et al. 2018

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Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness-associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5-related deafness. In five families with postlingual progressive autosomal dominant non-syndromic hearing loss, we employed two next-generation sequencing platforms-OtoSCOPE and whole exome sequencing-followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini-genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5-related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing.

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“…Small nuclear ribonucleo proteins (snRNPs) U1, U2, U4, U5 and U6 contain specific small nuclear RNA sequences of around 150 nucletorides in length which recognize and interact with cis -acting sequences guiding the splicing process [33]. …”

Section: Figurementioning

confidence: 99%

Inherited Retinal Disease Therapies Targeting Precursor Messenger Ribonucleic Acid

Huang

Fletcher

Wilton

et al. 2017

Vision

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Inherited retinal diseases are an extremely diverse group of genetically and phenotypically heterogeneous conditions characterized by variable maturation of retinal development, impairment of photoreceptor cell function and gradual loss of photoreceptor cells and vision. Significant progress has been made over the last two decades in identifying the many genes implicated in inherited retinal diseases and developing novel therapies to address the underlying genetic defects. Approximately one-quarter of exonic mutations related to human inherited diseases are likely to induce aberrant splicing products, providing opportunities for the development of novel therapeutics that target splicing processes. The feasibility of antisense oligomer mediated splice intervention to treat inherited diseases has been demonstrated in vitro, in vivo and in clinical trials. In this review, we will discuss therapeutic approaches to treat inherited retinal disease, including strategies to correct splicing and modify exon selection at the level of pre-mRNA. The challenges of clinical translation of this class of emerging therapeutics will also be discussed.

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Autosomal Dominant Retinitis Pigmentosa Secondary to Pre-mRNA Splicing-Factor GenePRPF31(RP11): Review of Disease Mechanism and Report of a Family with a Novel 3-Base Pair Insertion

Cited by 25 publications

References 37 publications

NUFIP and the HSP90/R2TP chaperone bind the SMN complex and facilitate assembly of U4-specific proteins

NUFIP and the HSP90/R2TP chaperone bind the SMN complex and facilitate assembly of U4-specific proteins

Exonic mutations and exon skipping: Lessons learned from DFNA5

Inherited Retinal Disease Therapies Targeting Precursor Messenger Ribonucleic Acid

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