Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
复制标题
DOI：
10.1038/s41467-018-07953-w
复制
发表时间：
2019-02-12
影响因子：
16.6
通讯作者：
De Jonghe, Peter
中科院分区：
文献类型：
--
作者：
Siekierska, Aleksandra;Stamberger, Hannah;De Jonghe, Peter
氨酰tRNA合成酶（ARSs）在蛋白质翻译的关键早期步骤中将特定氨基酸与其同源转移RNA连接起来。ARS突变已成为隐性的，通常是复杂的神经系统疾病特征的原因。在这里，我们报告了一个等位基因系列，包括7个新的和两个以前报道的双等位基因变异缬氨酰-tRNA合成酶（VARS）在10例发育性脑病与小头畸形，往往与早发性癫痫。计算机模拟、体外和酵母互补试验表明，这些突变的潜在病理机制很可能是蛋白质功能丧失。斑马鱼模型准确地概括了一些关键的神经系统疾病特征。这些结果为神经发育疾病提供了遗传学和生物学方面的见解，并为进一步深入研究ARS相关隐性疾病和精确治疗铺平了道路。
Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.