AI Article Synopsis

  • Inherited bone-marrow-failure syndromes (IBMFSs) are a group of genetic disorders linked to bone marrow failure, congenital issues, and a higher cancer risk, with p53 activation thought to play a key role in their development.
  • Recent findings revealed specific mutations in the TP53 gene in two patients exhibiting symptoms like low antibody levels, growth delays, and small head size, which resemble conditions such as Diamond-Blackfan anemia and dyskeratosis congenita.
  • Interestingly, these mutations led to a loss of part of the p53 protein but resulted in increased transcriptional activity, which was unusual; further experiments in zebrafish and stem cells showed disrupted red blood cell production, highlighting a new connection between p

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128301PMC
http://dx.doi.org/10.1016/j.ajhg.2018.07.020DOI Listing

Publication Analysis

Top Keywords

inherited bone-marrow-failure
8
p53 activation
8
germline variants
8
variants individuals
8
transcriptional activities
8
tp53
5
novo mutations
4
mutations activating
4
activating germline
4
germline tp53
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!