%0 Journal Article
%T De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome
%A Aiko Sato-Otsubo
%A Akira Ishiguro
%A Akira Ohara
%A Fumihiro Sugiyama
%A Hiroko Tanaka
%A Hirotoshi Sakaguchi
%A Hitoshi Kanno
%A Isao Hamaguchi
%A Kanji Sugita
%A Keisuke Kataoka
%A Kenichi Chiba
%A Kenichi Yoshida
%A Kiminori Terui
%A Koji Eto
%A Kumiko Goi
%A Madoka Kuramitsu
%A Masashi Sanada
%A Megumi C. Katoh
%A Naoya Kenmochi
%A Rika Kanezaki
%A RuNan Wang
%A Satoru Miyano
%A Satoru Takahashi
%A Seiji Kojima
%A Seishi Ogawa
%A Seiya Mizuno
%A Shouichi Ohga
%A Sou Nakamura
%A Takanobu Maekawa
%A Takuya Kamio
%A Tamayo Uechi
%A Tomohiko Sato
%A Tsutomu Toki
%A Yuichi Shiraishi
%A Yukari Nakajima
%A Yusuke Okuno
%A Yusuke Sato
%A Yusuke Shiozawa
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2018.07.020
%X 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
%K TP53
%K p53
%K the C-terminal domain
%K inherited bone marrow failure syndrome
%K Diamond-Blackfan anemia
%K dyskeratosis congenita
%K zebrafish
%K human-induced pluripotent stem cell
%K iPSC
%K gene editing
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128301/