De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome

Tsutomu Toki, Kenichi Yoshida, Ru Nan Wang, Sou Nakamura, Takanobu Maekawa, Kumiko Goi, Megumi C. Katoh, Seiya Mizuno, Fumihiro Sugiyama, Rika Kanezaki, Tamayo Uechi, Yukari Nakajima, Yusuke Sato, Yusuke Okuno, Aiko Sato-Otsubo, Yusuke Shiozawa, Keisuke Kataoka, Yuichi Shiraishi, Masashi Sanada, Kenichi ChibaHiroko Tanaka, Kiminori Terui, Tomohiko Sato, Takuya Kamio, Hirotoshi Sakaguchi, Shouichi Ohga, Madoka Kuramitsu, Isao Hamaguchi, Akira Ohara, Hitoshi Kanno, Satoru Miyano, Seiji Kojima, Akira Ishiguro, Kanji Sugita, Naoya Kenmochi, Satoru Takahashi, Koji Eto, Seishi Ogawa, Etsuro Ito

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31 Citations (Scopus)


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 unique de novo TP53 germline variants found in two individuals with an IBMFS accompanied by hypogammaglobulinemia, growth retardation, and microcephaly mimicking DBA and DC. TP53 is 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 of TP53 lacking the CTD demonstrate that the CTD-truncation mutations of TP53 cause IBMFS, providing important insights into the previously postulated connection between p53 and IBMFSs.

Original languageEnglish
Pages (from-to)440-447
Number of pages8
JournalAmerican journal of human genetics
Issue number3
Publication statusPublished - Sept 6 2018

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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