Novel variant in BRAT1 with the lethal neonatal rigidity and multifocal seizure syndrome
Novel variant in BRAT1 with the lethal neonatal rigidity and multifocal seizure syndrome
复制标题
BRAT1 的新变异导致致命的新生儿强直和多灶性癫痫综合征
DOI：
10.1038/s41390-021-01468-9
复制
发表时间：
2021-03-31
影响因子：
3.6
通讯作者：
Liu, Ying
中科院分区：
文献类型：
--
作者：
Li, Weixi;Wu, Shuiyan;Liu, Ying
致命性新生儿强直和多灶性癫痫发作综合征（RMFSL）是由BRAT 1（ATM激活所需的BRCA 1相关蛋白-1）变异引起的。然而，RMFSL的分子机制仍不清楚。招募了一名RMFSL婴儿，并从他的三人家庭收集外周血样本。提取基因组DNA，进行全外显子组测序。Western blotting检测BRAT 1的表达。通过共聚焦显微镜研究BRAT 1和MitoSOX的亚细胞定位（线粒体超氧化物水平）。从转染的细胞中获得RNA样品，然后进行RNA测序。在这项研究中，一个新的纯合子BRAT 1变异体c.233G C与氨基酸的变化与P在残基78（R78 P）。该变体改变了肽结构和亚细胞定位以及体外表达。然而，R78 P并没有改变BRAT 1下调线粒体中MitoSOX的能力。同时，R78 P BRAT 1与颞叶癫痫、常染色体隐性遗传原发性小头畸形、水平自主眼球运动缺陷/缺失和神经元凋亡过程正相关，如基因集富集分析（GSEA）所示。BRAT 1变异谱得到扩大，这将有助于遗传咨询。我们还探讨了R78 P改变RMFSL的分子机制，这将为RMFSL的发病机制提供更好的理解。详细的过程中，一个婴儿与致命的新生儿RMFSL描述。鉴定了BRAT 1中致死性新生儿RMFSL的新致病变体R78 P。R78 P导致体外BRAT 1表达和核定位降低。R78 P没有改变BRAT 1下调线粒体中MitoSOX的能力。BRAT 1基因R78 P变异与颞叶癫痫、常染色体隐性遗传原发性小头畸形、水平随意眼球运动缺陷/缺失和神经元凋亡过程正相关。详细的过程中，一个婴儿与致命的新生儿RMFSL描述。鉴定了BRAT 1中致死性新生儿RMFSL的新致病变体R78 P。R78 P导致体外BRAT 1表达和核定位降低。R78 P没有改变BRAT 1下调线粒体中MitoSOX的能力。BRAT 1基因R78 P变异与颞叶癫痫、常染色体隐性遗传原发性小头畸形、水平随意眼球运动缺陷/缺失和神经元凋亡过程正相关。
Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is caused by variants in BRAT1 (BRCA1-associated protein required for ATM activation-1). However, the molecular mechanism of RMFSL is still unclear. An RMFSL infant was recruited and the peripheral blood samples from his trio-family were collected. The genomic DNA was extracted, and then the whole-exome sequencing was performed. The expression of BRAT1 was analyzed by Western blotting. The subcellular localization of BRAT1 and MitoSOX (mitochondrial superoxide level) was investigated by confocal microscopy. The RNA samples were obtained from transfected cells, and then the RNA sequencing was performed. In this study, a novel homozygous BRAT1 variant c.233G > C with amino acid change of R with P at residue 78 (R78P) was identified. This variant altered the peptide structure and subcellular localization, as well as the expression in vitro. However, R78P did not alter the ability of BRAT1 to downregulate MitoSOX in mitochondria. Meanwhile, R78P BRAT1 was positively correlated with temporal lobe epilepsy, autosomal recessive primary microcephaly, defective/absent horizontal voluntary eye movements, and neuron apoptotic process as indicated by gene set enrichment analysis (GSEA). The BRAT1 variant spectrum has been expanded, which will be helpful for genetic counseling. We also explored the molecular mechanism altered by R78P, which will provide a better understanding of the pathogenesis of RMFSL. The detailed course of an infant with lethal neonatal RMFSL was depicted. A novel disease-causing variant R78P in BRAT1 for lethal neonatal RMFSL was identified. R78P led to reduced BRAT1 expression and nuclear localization in vitro. R78P did not alter the ability of BRAT1 to downregulate MitoSOX in the mitochondria. The variant R78P in BRAT1 was positively correlated with temporal lobe epilepsy, autosomal recessive primary microcephaly, defective/absent horizontal voluntary eye movements, and neuron apoptotic process as indicated by GSEA. The detailed course of an infant with lethal neonatal RMFSL was depicted. A novel disease-causing variant R78P in BRAT1 for lethal neonatal RMFSL was identified. R78P led to reduced BRAT1 expression and nuclear localization in vitro. R78P did not alter the ability of BRAT1 to downregulate MitoSOX in the mitochondria. The variant R78P in BRAT1 was positively correlated with temporal lobe epilepsy, autosomal recessive primary microcephaly, defective/absent horizontal voluntary eye movements, and neuron apoptotic process as indicated by GSEA.