Document Type
Article
Publication Date
12-13-2024
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.
Recommended Citation
Christian, Thomas W; Maharjan, Sunita; Yin, Sitao; Yamaki, Yuka; Masuda, Isao; Li, Fenglin; Muraresku, Colleen; Clever, Sheila; Ganetzky, Rebecca; and Hou, Ya-Ming, "A Kinetic Model for Compound Heterozygous Pathogenic Variants in Tyrosyl-tRNA Synthetase Gene YARS2-Associated Neonatal Phenotype" (2024). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 275.
https://jdc.jefferson.edu/bmpfp/275
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
39675712
Language
English
Included in
Biochemistry Commons, Genetic Phenomena Commons, Genetics and Genomics Commons, Molecular Biology Commons
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