Evidence map›Paper›PMID 39002681›Full record

ArticleThe Journal of biological chemistry2024

Modulation of prion protein expression through cryptic splice site manipulation.

Juliana E Gentile, Taylor L Corridon, Meredith A Mortberg, Elston Neil D'Souza, Nicola Whiffin, Eric Vallabh Minikel, Sonia M Vallabh

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of biological chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Divalent siRNA for prion disease.Nucleic acids research · 2026
    Article
  2. Divalent siRNA for prion disease.bioRxiv : the preprint server for biology · 2026
    Article
  3. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors.

Juliana E GentileMcCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Taylor L CorridonMcCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Meredith A MortbergMcCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Elston Neil D'SouzaBig Data Institute and Centre for Human Genetics, University of Oxford, Oxford, UK.
Nicola WhiffinBig Data Institute and Centre for Human Genetics, University of Oxford, Oxford, UK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Eric Vallabh MinikelMcCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Sonia M VallabhMcCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Electronic address: svallabh@broadinstitute.org.

Funding

How Substrate Dosage Drives Prion Disease KineticsR01NS125255 · NINDS · BROAD INSTITUTE, INC. · PI Sonia Minikel Vallabh · 2022 to 2026
$2.7M
NINDS NIH HHS R01 NS125255Wellcome Trust
6 · The paper itself

Abstract

Lowering expression of prion protein (PrP) is a well-validated therapeutic strategy in prion disease, but additional modalities are urgently needed. In other diseases, small molecules have proven capable of modulating pre-mRNA splicing, sometimes by forcing inclusion of cryptic exons that reduce gene expression. Here, we characterize a cryptic exon located in human PRNP's sole intron and evaluate its potential to reduce PrP expression through incorporation into the 5' untranslated region. This exon is homologous to exon 2 in nonprimate species but contains a start codon that would yield an upstream open reading frame with a stop codon prior to a splice site if included in PRNP mRNA, potentially downregulating PrP expression through translational repression or nonsense-mediated decay. We establish a minigene transfection system and test a panel of splice site alterations, identifying mutants that reduce PrP expression by as much as 78%. Our findings nominate a new therapeutic target for lowering PrP.

Indexed as

ExonsPrion ProteinsRNA Splice Sites5' Untranslated RegionsAnimalsGene Expression RegulationHumansIntronsPrion DiseasesPrionsRNA Splicing5' Untranslated RegionsPrion ProteinsPrionsPRNP protein, humanRNA Splice Sitescryptic exonminigeneprion proteinsplice modulationupstream open reading frame

Identifiers

PMID39002681
PMCPMC11342779

What OpenQuestion holds

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LicenceCC BY
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Registered trials

None linked

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.