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Dominant-negative NARS1 R534∗ mutation causes wild-type subunit poisoning and heterodimer predominance in cells.

Ingrid Vallee¹, Ryan Shapiro¹, Leo Qi¹

¹Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA.

The Journal of Biological Chemistry

|September 6, 2025

Summary

A mutation in asparaginyl-tRNA synthetase (AsnRS) causes severe neurodevelopmental issues by forming defective heterodimers with wild-type AsnRS, impairing protein synthesis.

Keywords:

AsnRS NARS1 aminoacyl-tRNA synthetase asparaginyl-tRNA synthetase enzyme heterodimer mutation

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Area of Science:

Biochemistry
Molecular Biology
Genetics

Background:

Aminoacyl-tRNA synthetases (aaRSs) are crucial for protein biosynthesis.
Mutations in aaRSs can lead to various diseases, with monoallelic mutations often causing milder symptoms than biallelic ones.

Purpose of the Study:

To investigate the mechanism behind severe neurodevelopmental symptoms caused by a monoallelic AsnRS mutation (R534*).
To understand how this mutation leads to cellular dysfunction and disease.

Main Methods:

Analysis of patient-derived lymphoblasts expressing wild-type (WT) and mutant AsnRS (R534*).
Structural analysis of AsnRS dimerization and tRNA binding.
Enzymatic activity assays.
Exogenous expression studies in human cells.

Main Results:

The AsnRS R534* mutation results in a truncated protein that forms weaker homodimers and has impaired tRNA binding and enzymatic activity.
The mutant AsnRS R534* preferentially heterodimerizes with WT AsnRS.
These heterodimers exhibit severely defective enzymatic function, leading to a dominant-negative effect.

Conclusions:

The monoallelic AsnRS R534* mutation causes severe neurodevelopmental disease through a dominant-negative loss-of-function mechanism via heterodimerization.
This study provides insights into aaRS-associated pathologies and potential therapeutic targets.