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RNA-binding proteins in human genetic disease

Abstract

RNA-binding proteins (RBPs) are critical effectors of gene expression, and as such their malfunction underlies the origin of many diseases. RBPs can recognize hundreds of transcripts and form extensive regulatory networks that help to maintain cell homeostasis. System-wide unbiased identification of RBPs has increased the number of recognized RBPs into the four-digit range and revealed new paradigms: from the prevalence of structurally disordered RNA-binding regions with roles in the formation of membraneless organelles to unsuspected and potentially pervasive connections between intermediary metabolism and RNA regulation. Together with an increasingly detailed understanding of molecular mechanisms of RBP function, these insights are facilitating the development of new therapies to treat malignancies. Here, we provide an overview of RBPs involved in human genetic disorders, both Mendelian and somatic, and discuss emerging aspects in the field with emphasis on molecular mechanisms of disease and therapeutic interventions.

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Fig. 1: RNA-binding proteins control RNA life.
Fig. 2: High-throughput approaches to identify RNA-binding proteins and their binding sites on RNA.
Fig. 3: Human RNA-binding proteins involved in Mendelian and somatic genetic diseases.
Fig. 4: Potential effects of mutations in RBP genes.
Fig. 5: Location and networks of disease-associated mutations.
Fig. 6: RNA-binding proteins and phase transitions.
Fig. 7: Mechanisms of disease in fragile X syndrome and FXTAS.

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Data availability

The data that support the findings of this study are available as Supplementary Tables and in RBPbase: https://rbpbase.shiny.embl.de/.

Code availability

The source code used in this paper and written by T.S. is publicly available at http://www.hentze.embl.de/public/hRBPdiseases/.

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Acknowledgements

The authors thank J. Guillén-Boixet for insightful comments and suggestions on the manuscript and S. Sahadevan for help with parsing Open Targets data. The authors acknowledge funding from the Spanish Ministry of Science and Innovation (MICINN; PGC2018-099697-B-I00 to F.G. and BFU2017-89308-P to J.V.), ‘la Caixa’ Foundation (ID 100010434 under the agreement LCF/PR/HR17/52150016 to F.G.), the Catalan Government (2017SGR534 to F.G. and J.V.) and the ERC (AdvG 670146 to J.V.) as well as the EMBL Partnership, the Severo Ochoa and CERCA Programs.

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T.S. performed the bioinformatics analyses. All authors contributed to all other aspects of the article.

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Correspondence to Fátima Gebauer or Matthias W. Hentze.

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Nature Reviews Genetics thanks S. Blagden, J. Ule and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

OMIM #223900: https://omim.org/entry/223900

OMIM #300438: https://omim.org/entry/300438

OMIM #311900: https://omim.org/entry/311900

OMIM #600886: https://omim.org/entry/600886

OMIM #603896: https://omim.org/entry/603896

Open Targets: https://www.opentargets.org/

RBPbase: http://rbpbase.shiny.embl.de

Supplementary information

Glossary

RNA interactome

The group of proteins that interact with RNA.

Intrinsically disordered regions

Protein regions that lack a stable secondary or tertiary structure.

Genetic disease

A disease that is caused by mutations in a gene or a group of genes.

Somatic mutations

Mutations that occur in somatic cells and, therefore, are not transmitted to the next generation.

Mendelian disorders

Diseases caused by gene mutations in the germline and inherited either in a dominant or recessive manner according to Mendelian laws.

Germline mutation

A mutation that occurs in the germline and, therefore, is inherited by the next generation.

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Gebauer, F., Schwarzl, T., Valcárcel, J. et al. RNA-binding proteins in human genetic disease. Nat Rev Genet 22, 185–198 (2021). https://doi.org/10.1038/s41576-020-00302-y

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