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Functional dissection of core spliceosomal mutations causing Retinitis Pigmentosa.

Objective

More than 95% of human genes undergo pre-mRNA splicing, and alternative splicing of mRNA precursors represents a prevalent mode of gene regulation. Errors in this process are often the origin of of disorders. Most of splicing-related diseases are caused by perturbation in pre-mRNA transcripts which lead to their aberrant processing. Interestingly, a fraction of mutations affecting directly splicing factors, including core spliceosomal components, has been linked to a group of pathologies. Particularly intriguing are variants of the key spliceosomal subcomplex U4/5/6 tri-snRNP, associated with Retinitis Pigmentosa. Why these mutations lead to highly tissue-specific phenotypes, rather than general toxicity cause by a global block in splicing, remain unexplained. The proposed research aims to increase our understanding of the molecular mechanisms underlying the effects of these mutations and shed light on the basis of the disease. To functionally dissect these variants, I will combine spliceosomal network approaches (I) with genome-wide transcriptome analysis (II) and detailed biochemical and structural studies (III). Mechanistic insights derived from these analyses will help to identify transcripts that are predominantly sensitive to these mutations and that could be behind their pathogenic effects (IV). This work will allow us to better understand the function of key splicing factors, as well as the basis for their effects on splice site selection and their contributions to Retinitis Pigmentosa pathology.

Fields of science (EuroSciVoc)

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Programme(s)

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Topic(s)

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Funding Scheme

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MSCA-IF-EF-ST - Standard EF

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2016

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Coordinator

FUNDACIO CENTRE DE REGULACIO GENOMICA
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 158 121,60
Address
CARRER DOCTOR AIGUADER 88
08003 Barcelona
Spain

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Region
Este Cataluña Barcelona
Activity type
Research Organisations
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 158 121,60
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