ArticleHuman molecular genetics2023
A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.
Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 11 citations in OpenAlex.
- Phenotypic dominance emerges from activity fitness functions and molecular interactions.Genetics · 2026Article
- Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.Nature communications · 2025Article
- AARS1 and AARS2: From Protein Synthesis to Lactylation-Driven Oncogenesis.Biomolecules · 2025Review
- Recessive, pathogenic AARS1 variants display variable loss-of-function and dominant-negative effects.Disease models & mechanisms · 2025Article
- Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.IUBMB life · 2025Review
- Purification and validation of asparaginyl-tRNA synthetase heterodimer with indistinguishable subunits.IUBMB life · 2025Article
- A previously unreported NARS1 variant causes dominant distal hereditary motor neuropathy in a French family.Journal of the peripheral nervous system : JPNS · 2024Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Aminoacyl-tRNA synthetases (ARSs) are essential enzymes that ligate tRNA molecules to cognate amino acids. Heterozygosity for missense variants or small in-frame deletions in six ARS genes causes dominant axonal peripheral neuropathy. These pathogenic variants reduce enzyme activity without significantly decreasing protein levels and reside in genes encoding homo-dimeric enzymes. These observations raise the possibility that neuropathy-associated ARS variants exert a dominant-negative effect, reducing overall ARS activity below a threshold required for peripheral nerve function. To test such variants for dominant-negative properties, we developed a humanized yeast assay to co-express pathogenic human alanyl-tRNA synthetase (AARS1) mutations with wild-type human AARS1. We show that multiple loss-of-function AARS1 mutations impair yeast growth through an interaction with wild-type AARS1, but that reducing this interaction rescues yeast growth. This suggests that neuropathy-associated AARS1 variants exert a dominant-negative effect, which supports a common, loss-of-function mechanism for ARS-mediated dominant peripheral neuropathy.
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Registered trials
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