Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia.
Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia.
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DOI：
10.1007/s00439-023-02589-3
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发表时间：
2023-09
期刊：
影响因子：
5.3
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中科院分区：
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编码酪氨酸- dna磷酸二酯酶2的TDP2突变与常染色体隐性遗传性脊髓小脑性共济失调23型（SCAR23）综合征有关。这是一种非常罕见的进行性神经退行性疾病，迄今为止只有9例患者被描述，由剪接位点或无义突变引起，导致TDP2蛋白大幅减少或缺失。TDP2是DNA拓扑异构酶II （TOP2）活性失活诱导的DNA双链断裂的快速修复所必需的，对有丝分裂后细胞（如神经元）的遗传稳定性很重要。在这里，我们描述了一个纯合的兄弟姐妹，该兄弟姐妹是第一个TDP2错义突变（p.g u152lys），其临床特征与SCAR23和范可尼贫血（FA）重叠。我们发现，与先前报道的SCAR23患者相反，来自当前患者的成纤维细胞保留了显著水平的TDP2蛋白。然而，该蛋白具有催化活性，导致TOP2诱导的DNA双链断裂修复率降低，细胞对TOP2毒素依托泊苷过敏。tdp2突变的患者源性成纤维细胞在DNA交联剂治疗后没有表现出增加的染色体断裂，但tdp2突变的细胞和FA细胞在对依托opo苷的反应中表现出增加的染色体断裂。这表明，在对top2诱导的DNA病变的反应中需要FA通路，这可能解释了FA与当前tdp2突变患者之间的临床重叠。在回顾已报道的相对较少的SCAR23患者时，很明显，这类患者的表型可以扩展到神经功能之外，这表明TDP2蛋白不仅影响神经稳态，还影响其他组织。
Mutations in TDP2, encoding tyrosyl-DNA phosphodiesterase 2, have been associated with a syndromal form of autosomal recessive spinocerebellar ataxia, type 23 (SCAR23). This is a very rare and progressive neurodegenerative disorder described in only nine patients to date, and caused by splice site or nonsense mutations that result in greatly reduced or absent TDP2 protein. TDP2 is required for the rapid repair of DNA double-strand breaks induced by abortive DNA topoisomerase II (TOP2) activity, important for genetic stability in post-mitotic cells such as neurons. Here, we describe a sibship that is homozygous for the first TDP2 missense mutation (p.Glu152Lys) and which presents with clinical features overlapping both SCAR23 and Fanconi anemia (FA). We show that in contrast to previously reported SCAR23 patients, fibroblasts derived from the current patient retain significant levels of TDP2 protein. However, this protein is catalytically inactive, resulting in reduced rates of repair of TOP2-induced DNA double-strand breaks and cellular hypersensitivity to the TOP2 poison, etoposide. The TDP2-mutated patient-derived fibroblasts do not display increased chromosome breakage following treatment with DNA crosslinking agents, but both TDP2-mutated and FA cells exhibit increased chromosome breakage in response to etoposide. This suggests that the FA pathway is required in response to TOP2-induced DNA lesions, providing a possible explanation for the clinical overlap between FA and the current TDP2-mutated patients. When reviewing the relatively small number of patients with SCAR23 that have been reported, it is clear that the phenotype of such patients can extend beyond neurological features, indicating that the TDP2 protein influences not only neural homeostasis but also other tissues as well.
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影响因子：
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