Evidence map›Paper›PMID 35708503›Full record

ArticleHuman molecular genetics2022

Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich's ataxia.

Yanjie Li, Jixue Li, Jun Wang, Siyuan Zhang, Keith Giles, Thazha P Prakash, Frank Rigo, Jill S Napierala, Marek Napierala

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

Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
1.7field-weighted citation impact, top 17% 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

15 citing papers in PubMed, 17 citations in OpenAlex.

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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

9 authors at 2 institutions in 1 country.

Yanjie LiDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
Jixue LiDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
Jun WangDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
Siyuan ZhangDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
Keith GilesDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
Thazha P PrakashIonis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Frank RigoIonis Pharmaceuticals Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Jill S NapieralaDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.
Marek NapieralaDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA.ORCID 0000-0002-9987-0641
University of Alabama at Birmingham · USIonis Pharmaceuticals (United States) · US

Funding

GAA REPEATS INDUCED EPIGENETIC SILENCING IN FRIEDREICH'S ATAXIAR01NS081366 · NINDS · UT SOUTHWESTERN MEDICAL CENTER · PI NAPIERALA, MAREK · 2012 to 2021
$3.7M
Defining the impact of Frataxin point mutations on Friedreich's ataxia pathogenesisR01NS121038 · NINDS · UT SOUTHWESTERN MEDICAL CENTER · PI NAPIERALA, MAREK · 2021 to 2025
$2.0M
NINDS NIH HHS R01 NS081366NINDS NIH HHS R01 NS121038
6 · The paper itself

Abstract

Frataxin deficiency in Friedreich's ataxia results from transcriptional downregulation of the FXN gene caused by expansion of the intronic trinucleotide guanine-adenine-adenine (GAA) repeats. We used multiple transcriptomic approaches to determine the molecular mechanism of transcription inhibition caused by long GAAs. We uncovered that transcription of FXN in patient cells is prematurely terminated upstream of the expanded repeats leading to the formation of a novel, truncated and stable RNA. This FXN early terminated transcript (FXN-ett) undergoes alternative, non-productive splicing and does not contribute to the synthesis of functional frataxin. The level the FXN-ett RNA directly correlates with the length of the longer of the two expanded GAA tracts. Targeting GAAs with antisense oligonucleotides or excision of the repeats eliminates the transcription impediment, diminishes expression of the aberrant FXN-ett, while increasing levels of FXN mRNA and frataxin. Non-productive transcription may represent a common phenomenon and attractive therapeutic target in diseases caused by repeat-mediated transcription aberrations.

Indexed as

Friedreich AtaxiaAdenineArsenicalsFrataxinGalliumGuanineHumansIron-Binding ProteinsOligonucleotides, AntisensePolyadenylationRNA, MessengerTranscription, GeneticTrinucleotide Repeat ExpansionAdenineArsenicalsFrataxinGalliumgallium arsenideGuanineIron-Binding ProteinsOligonucleotides, AntisenseRNA, Messenger

Identifiers

PMID35708503
PMCPMC9558844
OpenAlexW4283025248

What OpenQuestion holds

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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.