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Am J Hum Genet. 2018 Sep 6;103(3):440-447. doi: 10.1016/j.ajhg.2018.07.020. Epub 2018 Aug 23.

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

Author information

1
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
2
Cancer Genomics Project, Graduate School of Medicine, the University of Tokyo, Tokyo 113-00333, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
3
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China.
4
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
5
Department of General Pediatric and Interdisciplinary Medicine, National Center for Child Health and Development, Tokyo 157-8535, Japan.
6
Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
7
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba 305-8575, Japan.
8
Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba 305-8575, Japan.
9
Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan.
10
Cancer Genomics Project, Graduate School of Medicine, the University of Tokyo, Tokyo 113-00333, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
11
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
12
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan.
13
Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan.
14
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
15
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
16
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
17
Department of Pediatrics, Omori Medical Center, Toho University, Tokyo 143-8540, Japan.
18
Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
19
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo 108-8639, Japan.
20
Division of Hematology, National Center for Child Health and Development, Tokyo 157-8535, Japan.
21
Cancer Genomics Project, Graduate School of Medicine, the University of Tokyo, Tokyo 113-00333, Japan; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Medicine, Karolinska Institute, Center for Hematology and Regenerative Medicine, SE-171 76 Stockholm, Sweden. Electronic address: sogawa-tky@umin.ac.jp.
22
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: eturou@hirosaki-u.ac.jp.

Abstract

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.

KEYWORDS:

Diamond-Blackfan anemia; TP53; dyskeratosis congenita; gene editing; human-induced pluripotent stem cell; iPSC; inherited bone marrow failure syndrome; p53; the C-terminal domain; zebrafish

PMID:
30146126
PMCID:
PMC6128301
DOI:
10.1016/j.ajhg.2018.07.020
[Indexed for MEDLINE]
Free PMC Article

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