Deng Jiong, Zhou Ling, Zhang Jie, Chang Xuting, Jiang Yuwu, Wang Jingmin, Wu Ye
Department of Pediatrics, Peking University First Hospital, Beijing, China.
Front Genet. 2021 Oct 20;12:729777. doi: 10.3389/fgene.2021.729777. eCollection 2021.
Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive leukoencephalopathy caused by mutations in any of the five genes encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). The severity of the disease varies considerably, and its genotypic-phenotypic correlation is still unclear. Age of onset is the only independent clinical predictor for VWM severity. In this study, the correlation between genotype and age at onset of patients was investigated. Data were collected from patients with VWM in the available literature reports and from those diagnosed in Peking University First Hospital. The age of onset was divided into early-onset (≤4 years) and late-onset type (>4 years) for the analysis of the correlation between genotype and age of onset in patients with VWM. A total of 341 patients were included, 281 were reported in 87 available articles and 60 were diagnosed in our center. A total of 180 different mutations were found, among which 86.1% were missense. The gene () in which the mutation located, and the number of null alleles were not associated with age of onset in these patients. Certain mutations such as eIF2Bε[Arg195His] and eIF2Bε[Arg269Gln] that were predicted to have a serious influence on eIF2B structure were related to earlier age of onset. EIF2Bγ[Ala87Val] which was predicted to have a minimal influence on eIF2B structure, was related to later age of onset. Whereas eIF2Bβ[Glu213Gly], eIF2Bβ[Gly200Val] and eIF2Bε[Thr91Ala], also predicted having a small effect on the structure of eIF2B, did not show correlation with the age of onset. The onset age of patients with one or biallelic missense mutations located in the catalytic domain or other homologous domains in catalytic subunits (eIF2Bγ, ε) was earlier than that of patients with biallelic mutations located in the NT domain. The onset age of patients with different genotypes varied greatly. The degree of influence in protein structure of some missense mutations was correlated with phenotypic severity, but the results were not completely consistent. The combined effect of biallelic mutations, the role of regulatory genes, environmental stress and other potential factors on phenotypes need to be further explored.
伴脑白质消失的脑白质病（VWM）是一种常染色体隐性脑白质病，由编码真核生物翻译起始因子2B（eIF2B）亚基的五个基因中任何一个发生突变引起。该病严重程度差异很大，其基因型与表型的相关性仍不清楚。发病年龄是VWM严重程度唯一的独立临床预测指标。在本研究中，对患者的基因型与发病年龄之间的相关性进行了调查。数据收集自现有文献报道的VWM患者以及北京大学第一医院确诊的患者。将发病年龄分为早发型（≤4岁）和晚发型（>4岁），以分析VWM患者基因型与发病年龄之间的相关性。共纳入341例患者，其中87篇现有文章报道了281例，本中心确诊60例。共发现180种不同突变，其中86.1%为错义突变。这些患者中，突变所在基因（）以及无效等位基因数量与发病年龄无关。某些预测对eIF2B结构有严重影响的突变，如eIF2Bε[Arg195His]和eIF2Bε[Arg269Gln]，与较早发病年龄相关。预测对eIF2B结构影响最小的EIF2Bγ[Ala87Val]与较晚发病年龄相关。而预测对eIF2B结构影响也较小的eIF2Bβ[Glu213Gly]、eIF2Bβ[Gly200Val]和eIF2Bε[Thr91Ala]与发病年龄无相关性。催化亚基（eIF2Bγ、ε）催化结构域或其他同源结构域中存在一个或两个错义突变的患者发病年龄早于NT结构域中存在两个等位基因突变的患者。不同基因型患者的发病年龄差异很大。一些错义突变对蛋白质结构的影响程度与表型严重程度相关，但结果并不完全一致。双等位基因突变的联合效应、调控基因的作用、环境应激及其他潜在因素对表型的影响有待进一步探索。
