Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
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DOI：
10.1038/s41467-018-07067-3
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发表时间：
2019-02-12
影响因子：
16.6
通讯作者：
Gleeson, Joseph G.
中科院分区：
文献类型：
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作者：
Friedman, Jennifer;Smith, Desiree E.;Gleeson, Joseph G.
氨酰-tRNA合成酶（ARSs）的功能是将氨基酸转移到蛋白质翻译所需的同源tRNA分子。迄今为止，已知31个ARS基因中的双等位基因突变会导致隐性、早发性严重多器官疾病。VARS编码唯一已知的缬氨酸细胞质定位的氨酰-tRNA合成酶。在这里，我们报告7例患者来自五个无关的家庭与五个不同的双等位基因错义变异的VARS。受试者存在一系列全面发育迟缓、癫痫性脑病和原发性或进行性小头畸形。纵向评估显示进行性皮质萎缩和白色物质体积丢失。变体映射到VARS tRNA结合结构域和邻近反密码子结构域，并破坏高度保守的残基。患者原代细胞显示完整的VARS蛋白，但酶活性降低，表明部分功能丧失。VARS在小儿神经退行性变中的意义拓宽了由于tRNA合成酶基因突变引起的人类疾病的范围。
Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.