Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation.
Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation.
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DOI：
10.1002/humu.23287
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发表时间：
2017-10
期刊：
影响因子：
3.9
通讯作者：
Antonellis A
中科院分区：
文献类型：
--
作者：
Oprescu SN;Chepa-Lotrea X;Takase R;Golas G;Markello TC;Adams DR;Toro C;Gropman AL;Hou YM;Malicdan MCV;Gahl WA;Tifft CJ;Antonellis A
氨酰-tRNA合成酶（ARS）是广泛表达的将氨基酸连接到tRNA分子上的酶。编码ARS的基因与无数显性和隐性疾病表型有关。甘氨酰-tRNA合成酶（加尔斯）是一种双功能的ARS，它能在细胞质和线粒体中携带tRNA。加尔斯变异与显性腓骨肌萎缩症有关，但尚未令人信服地与隐性表型有关。在这里，我们描述了一个病人从美国国立卫生研究院未确诊的疾病计划与多系统，发育表型。全外显子序列分析显示，该患者是一个移码（p.Glu83Ilefs*6）和一个错义（p.Arg310Gln）加尔斯变异的复合杂合子。使用体外和体内功能研究，我们表明，这两个加尔斯变体引起功能丧失的影响：移码变体的结果在耗尽的蛋白质水平和错义变体减少加尔斯tRNA充电活动。为了支持加尔斯变异致病性，我们的患者表现出与其他患有ARS相关隐性疾病的患者惊人的表型重叠，包括与细胞质和线粒体ARS变异相关的特征;这一观察结果与加尔斯在两个细胞位置的基本功能一致。总之，我们的临床、遗传和功能分析扩展了与加尔斯变体相关的表型谱。
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in myriad dominant and recessive disease phenotypes. Glycyl-tRNA synthetase (GARS) is a bi-functional ARS that charges tRNAGly in the cytoplasm and mitochondria. GARS variants have been associated with dominant Charcot-Marie-Tooth disease but have not been convincingly implicated in recessive phenotypes. Here we describe a patient from the NIH Undiagnosed Diseases Program with a multi-system, developmental phenotype. Whole-exome sequence analysis revealed that the patient is compound heterozygous for one frameshift (p.Glu83Ilefs*6) and one missense (p.Arg310Gln) GARS variant. Using in vitro and in vivo functional studies, we show that both GARS variants cause a loss-of-function effect: the frameshift variant results in depleted protein levels and the missense variant reduces GARS tRNA charging activity. In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARS-related recessive diseases, including features associated with variants in both cytoplasmic and mitochondrial ARSs; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants.
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影响因子：
64.8
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
通讯作者：
Yang XL
影响因子：
2.9
作者：
SCHREIER, AA;SCHIMMEL, PR
通讯作者：
SCHIMMEL, PR
影响因子：
9.8
作者：
Antonellis, A;Ellsworth, RE;Green, ED
通讯作者：
Green, ED
影响因子：
5.3
作者：
Antonellis, Anthony;Lee-Lin, Shih-Queen;Green, Eric D.
通讯作者：
Green, Eric D.
DOI：
10.1073/pnas.0705055104
发表时间：
2007-07-03
影响因子：
11.1
作者：
Nangle, Leslie A.;Zhang, Wei;Schimmel, Paul
通讯作者：
Schimmel, Paul