ADP ribosylation is a reversible posttranslational modification mediated by poly(ADP-ribose)transferases (e.g., PARP1) and (ADP-ribosyl)hydrolases (e.g., ARH3 and PARG), ensuring synthesis and removal of mono-ADP-ribose or poly-ADP-ribose chains on protein substrates. Dysregulation of ADP ribosylation signaling has been associated with several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Recessive ADPRHL2/ARH3 mutations are described to cause a stress-induced epileptic ataxia syndrome with developmental delay and axonal neuropathy (CONDSIAS). Here, we present two families with a neuropathy predominant disorder and homozygous mutations in ADPRHL2 We characterized a novel C26F mutation, demonstrating protein instability and reduced protein function. Characterization of the recurrent V335G mutant demonstrated mild loss of expression with retained enzymatic activity. Although the V335G mutation retains its mitochondrial localization, it has altered cytosolic/nuclear localization. This minimally affects basal ADP ribosylation but results in elevated nuclear ADP ribosylation during stress, demonstrating the vital role of ADP ribosylation reversal by ARH3 in DNA damage control.

中文翻译：

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复杂神经病中的双等位基因 ADPRHL2 突变影响 ADP 核糖基化和 DNA 损伤反应。


ADP 核糖基化是由聚（ADP-核糖）转移酶（例如 PARP1）和（ADP-核糖基）水解酶（例如 ARH3 和 PARG）介导的可逆翻译后修饰，确保单 ADP 核糖或多聚 ADP 的合成和去除-蛋白质底物上的核糖链。 ADP 核糖基化信号传导失调与多种神经退行性疾病有关，包括帕金森病、肌萎缩侧索硬化症和亨廷顿病。据描述，隐性ADPRHL2/ ARH3 突变会导致应激诱发的癫痫性共济失调综合征，伴有发育迟缓和轴突神经病变 (CONDSIAS)。在这里，我们介绍了两个以神经病为主的疾病和ADPRHL2纯合突变的家族。我们表征了一种新的 C26F 突变，证明了蛋白质不稳定和蛋白质功能降低。复发性 V335G 突变体的表征表明，表达轻度丧失，但酶活性保留。尽管 V335G 突变保留了其线粒体定位，但它改变了细胞质/核定位。这对基础 ADP 核糖基化的影响最小，但会导致应激期间核 ADP 核糖基化升高，证明 ARH3 逆转 ADP 核糖基化在 DNA 损伤控制中的重要作用。