Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification.

IF 3.3 Q2 GENETICS & HEREDITY HGG Advances Pub Date : 2024-10-31 DOI:10.1016/j.xhgg.2024.100377
Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu
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Abstract

Epileptic encephalopathies are severe epilepsy syndromes characterized by early onset and progressive cerebral dysfunction. A nonsense variant in the DALR anticodon binding domain containing 3 (DALRD3) gene has been implicated in epileptic encephalopathy, but no other disease-associated variants in DALRD3 have been described. In human cells, the DALRD3 protein forms a complex with the METTL2 methyltransferase to generate the 3-methylcytosine (m3C) modification in specific arginine tRNAs. Here, we identify an individual with a homozygous missense variant in DALRD3 who displays developmental delay, cognitive deficiencies, and multifocal epilepsy. The missense variant substitutes an arginine residue to cysteine (R517C) within the DALR domain of the DALRD3 protein that is required for binding tRNAs. Cells derived from the individual homozygous for the DALRD3-R517C variant exhibit reduced levels of m3C modification in arginine tRNAs, indicating that the R517C variant impairs DALRD3 function. Notably, the DALRD3-R517C protein displays reduced association with METTL2 and loss of interaction with substrate tRNAs. Our results uncover another loss-of-function variant in DALRD3 linked to epileptic encephalopathy disorders. Importantly, these findings underscore DALRD3-dependent tRNA modification as a key contributor to proper brain development and function.

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癫痫性脑病与影响 tRNA 修饰的 DALRD3 错义变体有关。
癫痫性脑病是一种严重的癫痫综合征,其特点是发病较早,并伴有进行性脑功能障碍。DALR 反密码子结合域包含 3(DALRD3)基因中的一个无义变异与癫痫性脑病有关,但尚未发现其他与疾病相关的 DALRD3 变异。在人体细胞中,DALRD3 蛋白与 METTL2 甲基转移酶形成复合物,在特定的精氨酸 tRNA 中产生 3-甲基胞嘧啶(m3C)修饰。在这里,我们发现了一个患有 DALRD3 同源错义变异的个体,他表现出发育迟缓、认知缺陷和多灶性癫痫。该错义变异将 DALRD3 蛋白质的 DALR 结构域中的一个精氨酸残基置换为半胱氨酸(R517C),而该结构域是结合 tRNA 所必需的。来自同源 DALRD3-R517C 变异个体的细胞显示精氨酸 tRNA 的 m3C 修饰水平降低,这表明 R517C 变异损害了 DALRD3 的功能。值得注意的是,DALRD3-R517C 蛋白与 METTL2 的结合减少,并失去了与底物 tRNA 的相互作用。我们的研究结果发现了另一个与癫痫性脑病有关的 DALRD3 功能缺失变异。重要的是,这些发现强调了 DALRD3 依赖性 tRNA 修饰是大脑正常发育和功能的关键因素。
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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
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