Evidence map›Paper›PMID 42381704›Full record

ArticleMolecular therapy. Nucleic acids2026

Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.

Tristan N Samuels, Jenica H Kakadia, Cian Ward, Fatema Abdullatif, Marisa I Mendes, Desiree E Smith, Rachel Heilmann, Fanqi Wu, Jakub M Swiercz, Gajja S Salamons and 4 more

Abstract read
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In one paragraph

Article in Molecular therapy. Nucleic acids, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. Tyrosine Supplementation Rescues a Growth Defect in a HumanizedInternational journal of molecular sciences · 2026
    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

14 authors.

Tristan N SamuelsDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Jenica H KakadiaDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Cian WardDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Fatema AbdullatifDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Marisa I MendesLaboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Desiree E SmithLaboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Rachel HeilmannThe Rory Belle Foundation, Denver, CO, USA.
Fanqi WuDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Jakub M SwierczAlesta Therapeutics BV, Leiden, the Netherlands.
Gajja S SalamonsLaboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Kyle HoffmanBioinformatics Solutions Inc, Waterloo, ON, Canada.
Teklab GebregiworgisDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Patrick O'DonoghueDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.
Ilka U HeinemannDepartment of Biochemistry, The University of Western Ontario, London, ON, Canada.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aminoacyl-tRNA synthetase (ARS) alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the ISR. We also tested therapeutic cognate transfer RNA (tRNA) supplementation, which reduced the cytotoxicity of pathogenic NARS1 alleles but did not ameliorate activation of the ISR. A general control nonderepressible 2 (GCN2) inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by premature termination codons in NARS1 alleles. Our data also indicate asparagine supplementation as a feasible therapeutic approach to address the underlying cause of NARS1 disease, a rare disease for which currently no treatment is available.

Indexed as

amino acid supplementationaminoacyl-tRNA synthetaseARS diseaseintegrated stress responseMT: non-coding RNAsNARS1premature termination codontRNA

Identifiers

PMID42381704
PMCPMC13316625

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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.