氨酰基-tRNA合成酶基因变异10例分析

吴腾辉, 彭镜, 张慈柳, 吴丽文, 杨丽芬, 彭盼, 庞楠, 尹飞, 何芳

中国当代儿科杂志 ›› 2020, Vol. 22 ›› Issue (6) : 595-601.

PDF(2071 KB)
HTML
PDF(2071 KB)
HTML
中国当代儿科杂志 ›› 2020, Vol. 22 ›› Issue (6) : 595-601. DOI: 10.7499/j.issn.1008-8830.1912040
论著·临床研究

氨酰基-tRNA合成酶基因变异10例分析

  • 吴腾辉1,2, 彭镜1,2, 张慈柳1,2, 吴丽文1,2, 杨丽芬1,2, 彭盼1,2, 庞楠1,2, 尹飞1,2, 何芳1,2
作者信息 +

Mutations in aminoacyl-tRNA synthetase genes: an analysis of 10 cases

  • WU Teng-Hui1,2, PENG Jing1,2, ZHANG Ci-Liu1,2, WU Li-Wen1,2, YANG Li-Fen1,2, PENG Pan1,2, PANG Nan1,2, YIN Fei1,2, HE Fang1,2
Author information +
文章历史 +

摘要

目的 研究氨酰基-tRNA合成酶(ARS)缺陷相关疾病的临床特征。方法 回顾性分析2016年1月至2019年10月通过二代测序诊断的10例ARS基因变异患儿的临床资料及基因突变类型。结果 10例ARS基因变异患儿中,起病年龄为0~9岁,首发症状多为抽搐(7例)。临床表现为共济失调为主而智力轻度落后或正常,伴或不伴有癫痫(4例);或儿童期起病的癫痫,后出现发育倒退(2例);也可表现为新生儿期起病,严重癫痫脑病,出现肌阵挛、全面强直及痉挛发作(4例),伴有严重发育落后(3例)、喂养困难(2例)、听力损害(1例)等。10例患儿中,共检测出5种基因突变,包括AARS2(c.331G > C、c.2682+5G > A、c.2164C > T、c.761G > A,均为新突变)3例,DARS2(c.228-16C > A、c.536G > A,均为已报道突变)2例,CARS2(c.1036C > T、c.323T > G,均为新突变)1例,RARS2(c.1210A > G、c.622C > T,均为新突变)1例,AARS(c.1901T > A、c.229C > T、c.244C > T、c.961G > C、Chr16:70298860-70316687del、c.2248C > T,均为新突变)3例。结论 ARS基因缺陷相关疾病临床表型异质性高。该研究共发现5种ARS基因的14个未报道的变异,丰富了ARS缺陷相关疾病的临床表型及基因型。

Abstract

Objective To study the clinical features of the diseases associated with aminoacyl-tRNA synthetases (ARS) deficiency. Methods A retrospective analysis was performed of the clinical and gene mutation data of 10 children who were diagnosed with ARS gene mutations, based on next-generation sequencing from January 2016 to October 2019. Results The age of onset ranged from 0 to 9 years among the 10 children. Convulsion was the most common initial symptom (7 children). Clinical manifestations included ataxia and normal or mildly retarded intellectual development (with or without epilepsy; n=4) and onset of epilepsy in childhood with developmental regression later (n=2). Some children experienced disease onset in the neonatal period and had severe epileptic encephalopathy, with myoclonus, generalized tonic-clonic seizure, and convulsive seizure (n=4); 3 had severe delayed development, 2 had feeding difficulty, and 1 had hearing impairment. Mutations were found in five genes:3 had novel mutations in the AARS2 gene (c.331G > C, c.2682+5G > A, c.2164C > T, and c.761G > A), 2 had known mutations in the DARS2 gene (c.228-16C > A and c.536G > A), 1 had novel mutations in the CARS2 gene (c.1036C > T and c.323T > G), 1 had novel mutations in the RARS2 gene (c.1210A > G and c.622C > T), and 3 had novel mutations in the AARS gene (c.1901T > A, c.229C > T, c.244C > T, c.961G > C, c.2248C > T, and Chr16:70298860-70316687del). Conclusions A high heterogeneity is observed in the clinical phenotypes of the diseases associated with the ARS deficiency. A total of 14 novel mutations in 5 genes are reported in this study, which enriches the clinical phenotypes and genotypes of the diseases associated with ARS deficiency.

关键词

氨酰基-tRNA合成酶缺陷 / ARS2/ARS基因 / 儿童

Key words

Aminoacyl-tRNA synthetases deficiency / ARS/ARS2 gene / Child

引用本文

导出引用
吴腾辉, 彭镜, 张慈柳, 吴丽文, 杨丽芬, 彭盼, 庞楠, 尹飞, 何芳. 氨酰基-tRNA合成酶基因变异10例分析[J]. 中国当代儿科杂志. 2020, 22(6): 595-601 https://doi.org/10.7499/j.issn.1008-8830.1912040
WU Teng-Hui, PENG Jing, ZHANG Ci-Liu, WU Li-Wen, YANG Li-Fen, PENG Pan, PANG Nan, YIN Fei, HE Fang. Mutations in aminoacyl-tRNA synthetase genes: an analysis of 10 cases[J]. Chinese Journal of Contemporary Pediatrics. 2020, 22(6): 595-601 https://doi.org/10.7499/j.issn.1008-8830.1912040

参考文献

[1] Bonnefond L, Fender A, Rudinger-Thirion J, et al. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases:characterization of AspRS and TyrRS[J]. Biochemistry, 2005, 44(12):4805-4816.
[2] Antonellis A, Green ED. The role of aminoacyl-tRNA synthetases in genetic diseases[J]. Annu Rev Genomics Hum Genet, 2008, 9:87-107.
[3] 刘方方, 张康庆, 刘亢丁, 等. AARS2基因突变相关的脑白质营养不良1例并文献分析[J]. 中风与神经疾病杂志, 2018, 35(6):557-558.
[4] 彭方, 俞海, 陈向军, 等. 线粒体病(卵巢-脑白质营养不良)1例报道及文献复习[J]. 中国临床神经科学, 2016, 24(5):505-513.
[5] 黄琼辉, 肖江喜, 王静敏, 等. 一个伴脊髓与脑干受累以及脑白质乳酸升高的脑白质病家系临床及DARS2基因突变分析[J]. 中华儿科杂志, 2012, 50(1):50-55.
[6] 张捷, 刘明, 周玲, 等. DARS基因突变致髓鞘化低下伴脑干、脊髓受累及下肢痉挛的白质脑病二例并文献复习[J]. 中华儿科杂志, 2018, 56(3):211-215.
[7] Scheper GC, van der Klok T, van Andel RJ, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation[J]. Nat Genet, 2007, 39(4):534-539.
[8] Tzoulis C, Tran GT, Gjerde IO, et al. Leukoencephalopathy with brainstem and spinal cord involvement caused by a novel mutation in the DARS2 gene[J]. J Neurol, 2012, 259(2):292-296.
[9] van Berge L, Hamilton EM, Linnankivi T, et al. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation:clinical and genetic characterization and target for therapy[J]. Brain, 2014, 137(Pt 4):1019-1029.
[10] Steenweg ME, van Berge L, van Berkel CG, et al. Early-onset LBSL:how severe does it get?[J]. Neuropediatrics, 2012, 43(6):332-338.
[11] Dogan SA, Pujol C, Maiti P, et al. Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart[J]. Cell Metab, 2014, 19(3):458-469.
[12] Euro L, Konovalova S, Asin-Cayuela J, et al. Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation[J]. Front Genet, 2015, 6:21.
[13] Dallabona C, Diodato D, Kevelam SH, et al. Novel (ovario) leukodystrophy related to AARS2 mutations[J]. Neurology, 2014, 82(23):2063-2071.
[14] Raini G, Sharet R, Herrero M, et al. Mutant eIF2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease[J]. J Neurochem, 2017, 141(5):694-707.
[15] Woo CW, Kutzler L, Kimball SR, et al. Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B[J]. Nat Cell Biol, 2012, 14(2):192-200.
[16] Ognjenovi? J, Simonovi? M. Human aminoacyl-tRNA synthetases in diseases of the nervous system[J]. RNA Biol, 2018, 15(4-5):623-634.
[17] Hallmann K, Zsurka G, Moskau-Hartmann S, et al. A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy[J]. Neurology, 2014, 83(23):2183-2187.
[18] Coughlin CR 2nd, Scharer GH, Friederich MW, et al. Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder[J]. J Med Genet, 2015, 52(8):532-540.
[19] Samanta D, Gokden M, Willis E. Clinicopathologic findings of CARS2 mutation[J]. Pediatr Neurol, 2018, 87:65-69.
[20] van Dijk T, van Ruissen F, Jaeger B, et al. RARS2 mutations:is pontocerebellar hypoplasia type 6 a mitochondrial encephalopathy?[J]. JIMD Rep, 2017, 33:87-92.
[21] Nishri D, Goldberg-Stern H, Noyman I, et al. RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia[J]. Eur J Paediatr Neurol, 2016, 20(3):412-417.
[22] Simons C, Griffin LB, Helman G, et al. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect[J]. Am J Hum Genet, 2015, 96(4):675-681.
[23] Krey I, Krois-Neudenberger J, Hentschel J, et al. Genotype-phenotype correlation on 45 individuals with West syndrome[J]. Eur J Paediatr Neurol, 2020, 25:134-138.
[24] Nakayama T, Wu J, Galvin-Parton P, et al. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy[J]. Hum Mutat, 2017, 38(10):1348-1354.
[25] Blocquel D, Sun L, Matuszek Z, et al. CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells[J]. Proc Natl Acad Sci U S A, 2019, 116(39):19440-19448.
[26] Blocquel D, Li S, Wei N, et al. Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy[J]. Nucleic Acids Res, 2017, 45(13):8091-8104.
[27] He W, Bai G, Zhou H, et al. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase[J]. Nature, 2015, 526(7575):710-714.
[28] Wei N, Zhang Q, Yang XL. Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases[J]. J Biol Chem, 2019, 294(14):5321-5339.
[29] Wolf NI, Toro C, Kister I, et al. DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder[J]. Neurology, 2015, 84(3):226-230.


PDF(2071 KB)
HTML

Accesses

Citation

Detail

段落导航
相关文章

/