Evidence map›Paper›PMID 32479602›Full record

ArticleNucleic acids research2020

FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention.

Jack Humphrey, Nicol Birsa, Carmelo Milioto, Martha McLaughlin, Agnieszka M Ule, David Robaldo, Andrea B Eberle, Rahel Kräuchi, Matthew Bentham, Anna-Leigh Brown and 14 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.

0numbers the graph read from it
0cells of the map it votes in
58citing papers in PubMed
6.8field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

58 citing papers in PubMed, 113 citations in OpenAlex.

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  15. Coding relationship links RNA G-quadruplexes and protein RGG motifs in RNA-binding protein autoregulation.Proceedings of the National Academy of Sciences of the United States of America · 2025
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors at 8 institutions in 3 countries.

Jack HumphreyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Nicol BirsaDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Carmelo MiliotoUK Dementia Research Institute.
Martha McLaughlinDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Agnieszka M UleDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
David RobaldoUK Dementia Research Institute.
Andrea B EberleDepartment of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, Bern 3012, Switzerland.
Rahel KräuchiDepartment of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, Bern 3012, Switzerland.
Matthew BenthamDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Anna-Leigh BrownDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Seth JarvisDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Cristian BodoDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Maria G GaroneSapienza University of Rome, Rome 00185, Italy.
Anny DevoyDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Gianni SoraruDepartment of Neurosciences, Università degli Studi di Padova, Padova 35121, Italy.
Alessandro RosaSapienza University of Rome, Rome 00185, Italy.
Irene BozzoniSapienza University of Rome, Rome 00185, Italy.
Elizabeth M C FisherDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Oliver MühlemannDepartment of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, Bern 3012, Switzerland.
Giampietro SchiavoDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Marc-David RueppUK Dementia Research Institute.
Adrian M IsaacsUK Dementia Research Institute.
Vincent PlagnolUCL Genetics Institute, University College London, London WC1E 6BT, UK.
Pietro FrattaDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
National Hospital for Neurology and Neurosurgery · GBUK Dementia Research Institute · GBUniversity of Bern · CHItalian Institute of Technology · ITKing's College London · GBSapienza University of Rome · ITUniversity College London · GBUniversity of Padua · IT

Funding

Department of HealthMedical Research Council MR/M008606/1Medical Research Council MR/S006508/1Medical Research Council MR/S022708/1Motor Neurone Disease Association FISHER/APR14/874-792Motor Neurone Disease Association FRATTA/JAN15/946-795Motor Neurone Disease Association ISAACS/APR15/834-791Motor Neurone Disease Association PLAGNOL/OCT15/885-792Wellcome TrustWellcome Trust 107116/Z/15/Z
6 · The paper itself

Abstract

Mutations in the RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease. FUS plays a role in numerous aspects of RNA metabolism, including mRNA splicing. However, the impact of ALS-causative mutations on splicing has not been fully characterized, as most disease models have been based on overexpressing mutant FUS, which will alter RNA processing due to FUS autoregulation. We and others have recently created knockin models that overcome the overexpression problem, and have generated high depth RNA-sequencing on FUS mutants in parallel to FUS knockout, allowing us to compare mutation-induced changes to genuine loss of function. We find that FUS-ALS mutations induce a widespread loss of function on expression and splicing. Specifically, we find that mutant FUS directly alters intron retention levels in RNA-binding proteins. Moreover, we identify an intron retention event in FUS itself that is associated with its autoregulation. Altered FUS levels have been linked to disease, and we show here that this novel autoregulation mechanism is altered by FUS mutations. Crucially, we also observe this phenomenon in other genetic forms of ALS, including those caused by TDP-43, VCP and SOD1 mutations, supporting the concept that multiple ALS genes interact in a regulatory network.

Indexed as

Amyotrophic Lateral SclerosisAnimalsCytoplasmDisease Models, AnimalDNA-Binding ProteinsGene Expression RegulationHomeostasisHumansIntronsLoss of Function MutationMiceMice, KnockoutMutationRNA-Binding Protein FUSRNA SplicingSuperoxide Dismutase-1DNA-Binding ProteinsFUS protein, humanRNA-Binding Protein FUSSOD1 protein, humanSuperoxide Dismutase-1TARDBP protein, humanValosin Containing ProteinVCP protein, human

Identifiers

PMID32479602
PMCPMC7337901
OpenAlexW3031465586

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.