Document Type

Article

Publication Date

12-13-2024

Comments

This article is the author's final published version in Journal of Biological Chemistry, Volume 301, Issue 1, January 2025, Article number 108092.

The published version is available at https://doi.org/10.1016/j.jbc.2024.108092.

Copyright © 2024 THE AUTHORS

Abstract

Human genetic disorders are often caused by mutations of compound heterozygosity, where each allele of the mutant gene harbors a different genetic lesion. However, studies of such mutations are hampered due to the lack of an appropriate model. Here we describe a kinetic model of compound heterozygous variants in an obligate enzyme dimer that contains one mutation in one monomer and the other mutation in the second monomer. This enzyme is encoded by human YARS2 for mitochondrial tyrosyl-tRNA synthetase (mt-TyrRS), which aminoacylates tyrosine to mt-tRNATyr. YARS2 is a member of the genes for mt-aminoacyl-tRNA synthetases, where pathogenic mutations present limited correlation between disease severity and enzyme activity. We identify a pair of compound heterozygous variants in YARS2 that is associated with neonatal fatality. We show that, while each mutation causes a minor-to-modest defect in aminoacylation in the homodimer of mt-TyrRS, the two mutations in trans synergistically reduce the enzyme activity to a greater effect. This kinetic model thus accurately recapitulates the disease severity, emphasizing its utility to study YARS2 mutations and its potential for generalization to other diseases with compound heterozygous mutations.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

39675712

Language

English

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