A Novel Multisystem Disease Associated with Recessive Mutations in the Tyrosyl-tRNA Synthetase (YARS) Gene
A Novel Multisystem Disease Associated with Recessive Mutations in the Tyrosyl-tRNA Synthetase (YARS) Gene
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DOI：
10.1002/ajmg.a.37973
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发表时间：
2017-01-01
影响因子：
2
通讯作者：
Boycott, Kym M.
中科院分区：
文献类型：
--
作者：
Nowaczyk, Malgorzata J. M.;Huang, Lijia;Boycott, Kym M.
氨酰-tRNA合成酶（ARSs）是一组广泛表达的酶，其在蛋白质翻译的第一步中的功能是众所周知的，但已经越来越多地与包括转录和翻译控制以及细胞外信号传导的次级功能相关。许多ARS的突变与越来越多的常染色体显性和常染色体隐性人类疾病有关。酪氨酰-tRNA合成酶（YARS）将氨基酸酪氨酸连接到其同源tRNA。我们报告了两个兄弟姐妹出现发育迟缓（FTT）、高甘油三酯血症、发育迟缓、肝功能障碍、肺囊肿和皮质下白色物质异常。使用外显子组测序，发现兄弟姐妹在YARS基因（NM_003680.3）内具有双等位基因致病性外观变体：c.638C> Tp。（Pro213Leu）和c.1573G>A p.（Gly525Arg）。这些YARS变体分别发生在催化结构域和C-末端结构域中。YARS突变以前与Charcot-Marie-Tooth（CMT）的常染色体显性形式相关;我们的研究结果表明，与YARS失调相关的疾病谱比周围神经病变更广泛。(C)2016 Wiley Periodicals，Inc.
Aminoacyl-tRNA synthetases (ARSs) are a group of ubiquitously expressed enzymes that are best known for their function in the first step of protein translation but have been increasingly associated with secondary functions including transcription and translation control and extracellular signaling. Mutations in numerous ARSs have been linked to a growing number of both autosomal dominant and autosomal recessive human diseases. The tyrosyl-tRNA synthetase (YARS) links the amino acid tyrosine to its cognate tRNA. We report two siblings who presented with failure to thrive (FTT), hypertriglyceridemia, developmental delay, liver dysfunction, lung cysts, and abnormal subcortical white matter. Using exome sequencing the siblings were found to harbor bi-allelic pathogenic-appearing variants within the YARS gene (NM_003680.3): c.638C>T p.(Pro213Leu) and c.1573G>A p.(Gly525Arg). These YARS variants occur in the catalytic domain and the C-terminal domain, respectively. Mutations in YARS have been previously associated with an autosomal dominant form of Charcot-Marie-Tooth (CMT); our findings suggest the disease spectrum associated with YARS dysregulation is broader than peripheral neuropathy. (C) 2016 Wiley Periodicals, Inc.