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Published on: August 15, 2019
A kinetic model for compound heterozygous pathogenic variants in Tyrosyl-tRNA synthetase gene YARS2-Associated
Thomas Christian1, Sunita Maharjan1, Sitao Yin1
1Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, USA.
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.
Insights
Compound heterozygous mutations in the YARS2 gene cause severe mitochondrial tyrosyl-tRNA synthetase (mt-TyrRS) defects. A new kinetic model explains how these variants synergistically reduce enzyme activity, leading to neonatal fatality.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Compound heterozygosity, with distinct mutations on each allele, underlies many genetic disorders.
- Studying compound heterozygous mutations is challenging due to the lack of suitable models.
- Mitochondrial aminoacyl-tRNA synthetases, including YARS2, show poor genotype-phenotype correlation in disease.
Purpose of the Study:
- To develop and validate a kinetic model for compound heterozygous variants in the obligate enzyme dimer of human mitochondrial tyrosyl-tRNA synthetase (mt-TyrRS).
- To investigate the synergistic effects of compound heterozygous mutations in YARS2 on enzyme activity and disease severity.
- To provide a model for studying YARS2 mutations and other compound heterozygous disorders.
Main Methods:
- Developed a kinetic model for an obligate enzyme dimer with mutations in separate monomers.
- Analyzed compound heterozygous variants in the human YARS2 gene, encoding mt-TyrRS.
- Assessed the impact of individual and combined mutations on mt-TyrRS aminoacylation activity in vitro.
Main Results:
- Identified compound heterozygous YARS2 variants linked to neonatal fatality.
- Demonstrated that individual mutations cause minor-to-modest aminoacylation defects in homodimers.
- Showed that trans-acting mutations synergistically decrease enzyme activity more than additive effects.
Conclusions:
- The kinetic model accurately recapitulates disease severity associated with compound heterozygous YARS2 variants.
- This model is valuable for studying YARS2 mutations and can be generalized to other compound heterozygous genetic disorders.
- Understanding synergistic effects in compound heterozygotes is crucial for predicting disease outcomes.
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