由FARSA基因双等位基因变异引起的苯丙氨酰-tRNA合成酶缺乏症及文献综述

Phenylalanyl-tRNA synthetase deficiency caused by biallelic variants in FARSA gene and literature review.

作者信息

Guo Ruolan, Chen Yuanying, Hu Xuyun, Qi Zhan, Guo Jun, Li Yuchuan, Hao Chanjuan

机构信息

Beijing Key Laboratory for Genetics of Birth Defects, MOE Key Laboratory of Major Diseases in Children, National Center for Children's Health, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.

Outpatient Department, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.

出版信息

BMC Med Genomics. 2023 Oct 13;16(1):245. doi: 10.1186/s12920-023-01662-0.

DOI:10.1186/s12920-023-01662-0

PMID:37833669

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10571242/

Abstract

BACKGROUND

Aminoacyl-tRNA synthetases (ARSs) are indispensable enzymes for protein biosynthesis in cells. The phenylalanyl-tRNA synthetase (FARS1) located in cytoplasm which consists of two FARS alpha subunits (FARSA) and two FARS beta subunits (FARSB). Autosomal recessive inheritance of pathogenic variants of FARSA or FARSB can result in defective FARS1 which are characterized by interstitial lung disease, liver disease, brain abnormalities, facial dysmorphism and growth restriction.

METHODS

Exome sequencing was used to detect the candidate variants. The in silico prediction and expressional level analysis were performed to evaluate the pathogenicity of the variations. Additionally, we presented the patient's detailed clinical information and compared the clinical feature with other previously reported patients with FARSA-deficiency.

RESULTS

We identified compound heterozygous rare missense variants (c.1172 T > C/ p.Leu391Pro and c.1211G > A/ p.Arg404His) in FARSA gene in a Chinese male patient. The protein structure prediction and the analysis of levels of FARSA and FARSB subunits indicated both variants pathogenic. Clinical feature review indicated inflammatory symptoms in young infants may be an additional key feature. Thyroid dysfunction should be considered as a phenotype with variable penetrance.

CONCLUSIONS

Our results expanded the current phenotypic and genetic spectrum of FARSA-deficiency.

摘要

背景

氨酰-tRNA合成酶（ARSs）是细胞中蛋白质生物合成所必需的酶。位于细胞质中的苯丙氨酰-tRNA合成酶（FARS1）由两个FARSα亚基（FARSA）和两个FARSβ亚基（FARSB）组成。FARSA或FARSB的致病变异的常染色体隐性遗传可导致FARS1缺陷，其特征为间质性肺病、肝病、脑异常、面部畸形和生长受限。

方法

采用外显子组测序检测候选变异。进行计算机预测和表达水平分析以评估变异的致病性。此外，我们展示了患者的详细临床信息，并将临床特征与其他先前报道的FARSA缺陷患者进行了比较。

结果

我们在中国一名男性患者的FARSA基因中鉴定出复合杂合罕见错义变异（c.1172 T＞C/p.Leu391Pro和c.1211G＞A/p.Arg404His）。蛋白质结构预测以及FARSA和FARSB亚基水平分析表明这两个变异均具有致病性。临床特征回顾表明，幼儿期的炎症症状可能是另一个关键特征。甲状腺功能障碍应被视为一种具有可变外显率的表型。