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.

中文翻译：

---

酪氨酰-tRNA 合成酶基因 YARS2 相关新生儿表型中复合杂合致病性变异的动力学模型。


人类遗传疾病通常是由复合杂合性突变引起的，其中突变基因的每个等位基因都带有不同的遗传病变。然而，由于缺乏合适的模型，对此类突变的研究受到阻碍。在这里，我们描述了专性酶二聚体中化合物杂合变体的动力学模型，该二聚体在一个单体中包含一个突变，在第二个单体中包含另一个突变。该酶由人 YARS2 编码为线粒体酪氨酰-tRNA 合成酶 （mt-TyrRS），该酶将酪氨酸氨酰化为 mt-tRNATyr。YARS2 是 mt-氨酰基-tRNA 合成酶基因的成员，其中致病性突变在疾病严重程度和酶活性之间表现出有限的相关性。我们在 YARS2 中鉴定了一对与新生儿死亡相关的复合杂合变异。我们表明，虽然每个突变都会导致 mt-TyrRS 同型二聚体中氨酰化的轻微到中度缺陷，但反式突变协同降低酶活性以产生更大的效果。因此，该动力学模型准确地概括了疾病的严重程度，强调了其研究 YARS2 突变的效用及其推广到具有复合杂合突变的其他疾病的潜力。