VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain.

Semra Hiz, Seval Kiliç, Güney Bademci, Tülay Karakulak, Aybike Erdoğan, Burcu Özden, Çiğdem Eresen, Esra Erdal, Uluç Yiş, Mustafa Tekin, Gökhan Karakülah, Ezgi Karaca, Mehmet Öztürk
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引用次数: 1

Abstract

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations.

Abstract Image

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与神经发育障碍相关的VARS1突变位于抗密码子结合域的短氨基酸延伸上。
37种人类氨基酰基tRNA合成酶中的大多数与多种主要是隐性的遗传疾病有关。据此,我们发现了一个新的纯合子valyl-tRNA合成酶1 (VARS1)基因变异,导致p.T1068M突变。与先前报道的VARS1突变一样,携带p.T1068M的受影响个体经历了顽固性癫痫、精神运动迟缓和小头畸形等神经发育障碍。为了将这种表型结果与观察到的基因型联系起来,我们在结构上模拟了人类VARS1,并在先前报道的VARS1变异的空间分布中解释了p.T1068M。结果,我们发现p.T1068M与其他三个致病突变聚集在VARS1反密码子结合域的15个氨基酸长链上。当在反密码子结合区域形成螺旋-转-螺旋基序时,这一延伸包含了四分之一的已报道的VARS1突变。在这里,我们提出这些簇状突变可以破坏抗密码子结合和tRNA合成酶结构域之间的相互作用,从而阻碍VARS1的最佳酶活性。我们期望这种突变簇的描述将为药物的开发铺平道路,能够减轻这些突变的功能影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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