Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease.
Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease.
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DOI：
10.1002/humu.23424
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发表时间：
2018-06
期刊：
影响因子：
3.9
通讯作者：
Innis JW
中科院分区：
文献类型：
--
作者：
Antonellis A;Oprescu SN;Griffin LB;Heider A;Amalfitano A;Innis JW
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的基因与表型多样的显性和隐性人类疾病有关。用苯丙氨酸对tRNAPHE进行充电是通过含有两个α（FARSA）和两个β（FARSB）亚基的四聚体酶进行的。迄今为止，编码这些亚基（FARSA和FARSB）的基因突变尚未涉及任何人类疾病。在这里，我们描述了一个严重的，致命的，多系统，发育表型谁是复合杂合子FARSB变异：p.Thr256Met和p.His496Lysfs*14的患者。使用从先证者分离的成纤维细胞的表达研究揭示了FARSB和FARSA蛋白水平的严重耗竭。这些数据表明，FARSB变体使总苯丙氨酰-tRNA合成酶水平不稳定，从而引起功能丧失效应。重要的是，我们的患者与患有与其他ARS基因座相关的隐性疾病的患者表现出强烈的表型重叠;这些观察结果强烈支持所鉴定的FARSB变体的致病性，并且与人体细胞中苯丙氨酰-tRNA合成酶的基本功能一致。总之，我们的临床、遗传和功能分析揭示了第一个与人类疾病表型相关的FARSB变异体，并扩大了与ARS相关的人类疾病的基因座异质性。
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in phenotypically diverse dominant and recessive human diseases. The charging of tRNAPHE with phenylalanine is performed by a tetrameric enzyme that contains two alpha (FARSA) and two beta (FARSB) subunits. To date, mutations in the genes encoding these subunits (FARSA and FARSB) have not been implicated in any human disease. Here, we describe a patient with a severe, lethal, multisystem, developmental phenotype who was compound heterozygous for FARSB variants: p.Thr256Met and p.His496Lysfs*14. Expression studies using fibroblasts isolated from the proband revealed a severe depletion of both FARSB and FARSA protein levels. These data indicate that the FARSB variants destabilize total phenylalanyl-tRNA synthetase levels, thus causing a loss-of-function effect. Importantly, our patient shows strong phenotypic overlap with patients that have recessive diseases associated with other ARS loci; these observations strongly support the pathogenicity of the identified FARSB variants and are consistent with the essential function of phenylalanyl-tRNA synthetase in human cells. In sum, our clinical, genetic, and functional analyses revealed the first FARSB variants associated with a human disease phenotype and expand the locus heterogeneity of ARS-related human disease.
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影响因子：
4.8
作者：
Raina, Medha;Moghal, Adil;Ibba, Michael
通讯作者：
Ibba, Michael
影响因子：
3.5
作者：
Tracewska-Siemiątkowska A;Haer-Wigman L;Bosch DGM;Nickerson D;Bamshad MJ;University of Washington Center for Mendelian Genomics;van de Vorst M;Rendtorff ND;Möller C;Kjellström U;Andréasson S;Cremers FPM;Tranebjærg L
通讯作者：
Tranebjærg L
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3.5
作者：
HENDRICKX, J;COUCKE, P;WILLEMS, PJ
通讯作者：
WILLEMS, PJ
影响因子：
2
作者：
Nowaczyk, Malgorzata J. M.;Huang, Lijia;Boycott, Kym M.
通讯作者：
Boycott, Kym M.