Evidence map›Paper›PMID 31257730›Full record

ArticleMolecular genetics & genomic medicine2019

Splicing dysregulation contributes to the pathogenicity of several F9 exonic point variants.

Upendra K Katneni, Aaron Liss, David Holcomb, Nobuko H Katagiri, Ryan Hunt, Haim Bar, Amra Ismail, Anton A Komar, Chava Kimchi-Sarfaty

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In one paragraph

Article in Molecular genetics & genomic medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing 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

8 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Review
  5. Article
  6. A Single Synonymous Variant (c.354G>A [p.P118P]) inInternational journal of molecular sciences · 2019
    Article
  7. Article
  8. Article
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

9 authors.

Upendra K KatneniHemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, Maryland.
Aaron LissHemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, Maryland.
David HolcombHemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, Maryland.
Nobuko H KatagiriHemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, Maryland.
Ryan HuntHemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, Maryland.
Haim BarDepartment of Statistics, University of Connecticut, Storrs, Connecticut.
Amra IsmailDepartment of Biological, Geological and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio.
Anton A KomarDepartment of Biological, Geological and Environmental Sciences, Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio.
Chava Kimchi-SarfatyHemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, Maryland.ORCID 0000-0002-9355-8585

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundPre-mRNA splicing is a complex process requiring the identification of donor site, acceptor site, and branch point site with an adjacent polypyrimidine tract sequence. Splicing is regulated by splicing regulatory elements (SREs) with both enhancer and suppressor functions. Variants located in exonic regions can impact splicing through dysregulation of native splice sites, SREs, and cryptic splice site activation. While splicing dysregulation is considered primary disease-inducing mechanism of synonymous variants, its contribution toward disease phenotype of non-synonymous variants is underappreciated.

methodsIn this study, we analyzed 415 disease-causing and 120 neutral F9 exonic point variants including both synonymous and non-synonymous for their effect on splicing using a series of in silico splice site prediction tools, SRE prediction tools, and in vitro minigene assays.

resultsThe use of splice site and SRE prediction tools in tandem provided better prediction but were not always in agreement with the minigene assays. The net effect of splicing dysregulation caused by variants was context dependent. Minigene assays revealed that perturbed splicing can be found.

conclusionSynonymous variants primarily cause disease phenotype via splicing dysregulation while additional mechanisms such as translation rate also play an important role. Splicing dysregulation is likely to contribute to the disease phenotype of several non-synonymous variants.

Indexed as

Computational BiologyExonsFactor IXFeasibility StudiesHemophilia BHumansPoint MutationRNA Splice SitesRNA SplicingFactor IXRNA Splice Siteshemophilia Bin silico splicing analysisin vitro minigene assaysplicing dysregulationsynonymous variants

Identifiers

PMID31257730
PMCPMC6687662

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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.