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

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.

Increased p53 signaling impairs neural differentiation causing HUWE1-promoted intellectual disabilities

“…Only very few of the JMS organoids that did develop had decreased size, which is in line with the microcephaly observed in JMS patients (4), and were characterized by reduced cellularity and lack of the laminar patterning, features reported previously in the mouse Huwe1 mouse models (9,10). Interestingly, the observation that elevated p53 activity accompanies neurodevelopmental impairments in JMS is supported by 11 recent studies showing that patients with germline TP53 mutations present with microcephaly (27), as well as that microcephaly and neurodevelopmental defects in several human neurodevelopmental disorders are p53-dependent (13). This supports the idea that deregulation of p53 activity could have central role in the onset of various neurological conditions.…”

Germline mutation of MDM4 , a major p53 regulator, in a familial syndrome of defective telomere maintenance

“…In that regard, our finding that increased p53 activity correlates with short telomeres appears relevant because telomere attrition is a primary hallmark of aging, well known to trigger cellular senescence (41). Furthermore, germline TP53 frameshift mutations were recently reported in two patients diagnosed with pure red blood cell aplasia and hypogammaglobulinemia, resembling but not entirely consistent with Diamond Blackfan anemia (DBA) (42). In addition to the pure red cell aplasia diagnostic of DBA, those patients were found to exhibit relatively short telomeres (although not as short as telomeres from patients with DC), which may also seem consistent with our results.…”

The role of p53 in developmental syndromes

“…While the analysis of various mouse strains carrying mutations in Trp53 or Mdm2 clearly indicates that inappropriate p53 activation can cause developmental defects and premature aging phenotypes in mice (Figure 1C), recent reports indicate that TP53 and MDM2 mutations can cause similar phenotypes in humans. Indeed, germline TP53 mutations were recently identified in two unrelated patients presenting with bone marrow failure, growth retardation, microcephaly, abnormal skin pigmentation, hypogonadism, and tooth anomalies (Toki et al, 2018). These patients carried heterozygous frameshift mutations that were predicted to lead to the truncation of the final 32 amino acids of the C-terminal domain of p53.…”