Rhodopsin mutations in a Scottish retinitis pigmentosa population, including a novel splice site mutation in intron four.

Bell, Christine; Converse, Carolyn A.; Hammer, H M; Osborne, Aileen; Haites, Neva Elizabeth

doi:10.1136/bjo.78.12.933

Cited by 16 publications

(11 citation statements)

References 29 publications

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“…Most cases (9/29) were due to mutations affecting the genes SNRNP200 (7) and PRPF8 (2), which code for core spliceosomal proteins, although a splice site mutation in RHO23 was also detected (2/29).…”

Section: Resultsmentioning

confidence: 99%

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

Ezquerra-Inchausti

Barandika

Anasagasti

et al. 2017

Sci Rep

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Retinitis pigmentosa is the most frequent group of inherited retinal dystrophies. It is highly heterogeneous, with more than 80 disease-causing genes 27 of which are known to cause autosomal dominant RP (adRP), having been identified. In this study a total of 29 index cases were ascertained based on a family tree compatible with adRP. A custom panel of 31 adRP genes was analysed by targeted next-generation sequencing using the Ion PGM platform in combination with Sanger sequencing. This allowed us to detect putative disease-causing mutations in 14 out of the 29 (48.28%) families analysed. Remarkably, around 38% of all adRP cases analysed showed mutations affecting the splicing process, mainly due to mutations in genes coding for spliceosome factors (SNRNP200 and PRPF8) but also due to splice-site mutations in RHO. Twelve of the 14 mutations found had been reported previously and two were novel mutations found in PRPF8 in two unrelated patients. In conclusion, our results will lead to more accurate genetic counselling and will contribute to a better characterisation of the disease. In addition, they may have a therapeutic impact in the future given the large number of studies currently underway based on targeted RNA splicing for therapeutic purposes.

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Section: Resultsmentioning

confidence: 99%

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

Ezquerra-Inchausti

Barandika

Anasagasti

et al. 2017

Sci Rep

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“…Here, human rhodopsin, a protein that has been studied extensively for its relationship to retinitis pigmentosa (RP), was analyzed323334353637383940. Rhodopsin is a membrane protein found in retinal rods.…”

Section: Resultsmentioning

confidence: 99%

In silico Mapping of Protein Unfolding Mutations for Inherited Disease

McCafferty

Sergeev

2016

Sci Rep

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The effect of disease-causing missense mutations on protein folding is difficult to evaluate. To understand this relationship, we developed the unfolding mutation screen (UMS) for in silico evaluation of the severity of genetic perturbations at the atomic level of protein structure. The program takes into account the protein-unfolding curve and generates propensities using calculated free energy changes for every possible missense mutation at once. These results are presented in a series of unfolding heat maps and a colored protein 3D structure to show the residues critical to the protein folding and are available for quick reference. UMS was tested with 16 crystal structures to evaluate the unfolding for 1391 mutations from the ProTherm database. Our results showed that the computational accuracy of the unfolding calculations was similar to the accuracy of previously published free energy changes but provided a better scale. Our residue identity control helps to improve protein homology models. The unfolding predictions for proteins involved in age-related macular degeneration, retinitis pigmentosa, and Leber’s congenital amaurosis matched well with data from previous studies. These results suggest that UMS could be a useful tool in the analysis of genotype-to-phenotype associations and next-generation sequencing data for inherited diseases.

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“…One of these mutations also affects the DS, causes a G to T exchange at the first intronic position (c.93611G4T), and was predicted to activate a CS [Macke et al, 1993]. Additional mutations were reported to change the consensus sequence of the AS of exon 5 [Bell et al, 1994;Reig et al, 1996].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA

et al. 2009

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Retinitis pigmentosa (RP) is a degenerative retinopathy leading to visual impairment in more than 1.5 million patients worldwide. Splice site (SS) mutations cause various diseases including RP. Most exonic donor splice-site (DS) mutations are reported at the last nucleotide of an exon and over 95% of them are predicted to result in missplicing. A novel human mutation at the last nucleotide of exon 4 in rhodopsin (RHO, c.936G>A) is shown to generate two misspliced transcripts in COS 7 cells and retinal explants. One of these transcripts skips exon 4 whereas the other activates a cryptic DS. Both are predicted to result in truncated RHO, explaining the pathogenic mechanism underlying the patient's RP phenotype. U1 snRNA-mediated DS recognition is a key step in the splicing process. As a therapeutic strategy, U1 snRNAs were adapted to the novel RHO mutation and tested for its potential to reverse missplicing. The rescue efficiency for misspliced transcripts of RHO was examined by quantitative RT-PCR. Using mutation-adapted U1 snRNA, we observed significantly reduced exon skipping that reached wild-type levels. Nevertheless, activation of the cryptic splice site (CS) was still detected. To test the feasibility of the strategy for mutations that only cause exon skipping, we inactivated the CS. Indeed, adapted U1 snRNA was able to rescue almost 95% [corrected] of misspliced transcripts. This study shows that modified U1 snRNAs constitute a promising therapeutic strategy to treat DS mutations. Our findings have implications for various diseases caused by similar mutations.

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Rhodopsin mutations in a Scottish retinitis pigmentosa population, including a novel splice site mutation in intron four.

Abstract: (BrJ Ophthalmol 1994; 78: 933-938)

Cited by 16 publications

References 29 publications

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

In silico Mapping of Protein Unfolding Mutations for Inherited Disease

Therapeutic strategy to rescue mutation-induced exon skipping in rhodopsin by adaptation of U1 snRNA

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