De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome
De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome
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遗传性骨髓衰竭综合征中种系 TP53 的从头突变激活
DOI：
10.1016/j.ajhg.2018.07.020
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
O
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作者：
Toki Tsutomu;Yoshida Kenichi;Wang RuNan;Okuno Yusuke;Kataoka Keisuke;Shiraishi Yuichi;Ohga Shouichi;Kuramitsu Madoka;Hamaguchi Isao;Ohara Akira;Kanno Hitoshi;Miyano Satoru;Kojima Seiji;Ishiguro Akira;Sugita Kanji;Kenmochi Naoya;Takahashi Satoru;Eto Koji;O
遗传性骨髓衰竭综合征(IBMFS)包括以骨髓衰竭、先天性异常和恶性风险增加为特征的异质性遗传疾病。许多证据表明，P53的激活可能在IBMFSS的发病机制中起中心作用，包括钻石-布莱克凡贫血(DBA)和先天性角化不良(DC)。然而，P53激活在每个临床特征中的确切作用仍不清楚。在这里，我们报告了在两名IBMFS伴低丙种球蛋白血症、生长迟缓和模仿DBA和DC的小头畸形患者中发现的独特的新的TP53胚系变异。TP53是一种肿瘤抑制基因，在人类癌症中最常见的突变，在Li-Fraumeni癌症易感综合征中偶尔会发生胚系变异。这些突变大多影响核心DNA结合域，导致转录活性受损。相反，在这里研究的两个个体中发现的变异导致了相同的蛋白质截断，导致C-末端结构域(CTD)的32个残基丢失。出乎意料的是，p53突变体增强了转录活性，这是以前在人类中没有描述过的观察结果。当我们在斑马鱼和人类诱导的多能干细胞中表达该突变体时，我们观察到红细胞生成受损。这些发现，加上与已发表的缺失CTD的TP53敲入小鼠模型的密切相似性，表明TP53的CTD截断突变导致IBMFS，为先前假设的P53和IBMFS之间的联系提供了重要的见解。
Inherited bone-marrow-failure syndromes (IBMFSs) include heterogeneous genetic disorders characterized by bone-marrow failure, congenital anomalies, and an increased risk of malignancy. Many lines of evidence have suggested that p53 activation might be central to the pathogenesis of IBMFSs, including Diamond-Blackfan anemia (DBA) and dyskeratosis congenita (DC). However, the exact role of p53 activation in each clinical feature remains unknown. Here, we report uniquede novo TP53germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC.TP53is a tumor-suppressor gene most frequently mutated in human cancers, and occasional germline variants occur in Li-Fraumeni cancer-predisposition syndrome. Most of these mutations affect the core DNA-binding domain, leading to compromised transcriptional activities. In contrast, the variants found in the two individuals studied here caused the same truncation of the protein, resulting in the loss of 32 residues from the C-terminal domain (CTD). Unexpectedly, the p53 mutant had augmented transcriptional activities, an observation not previously described in humans. When we expressed this mutant in zebrafish and human-induced pluripotent stem cells, we observed impaired erythrocyte production. These findings together with close similarities to published knock-in mouse models ofTP53lacking the CTD demonstrate that the CTD-truncation mutations ofTP53cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.