| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.1 | Bone marrow failure syndrome 5 | 618165 | Autosomal dominant | 3 | TP53 | 191170 |
A number sign (#) is used with this entry because of evidence that bone marrow failure syndrome-5 (BMFS5) is caused by heterozygous mutation in the TP53 gene (191170) on chromosome 17p13.
Bone marrow failure syndrome-5 (BMFS5) is a hematologic disorder characterized by infantile onset of severe red cell anemia requiring transfusion. Additional features include hypogammaglobulinemia, poor growth with microcephaly, developmental delay, and seizures (summary by Toki et al., 2018)
For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).
Toki et al. (2018) reported 2 unrelated patients who presented in the first days or months of life with anemia and hypogammaglobulinemia. Both patients required blood transfusions and IgG replacement. Other blood parameters were normal. Bone marrow examination showed selective erythroid hypoplasia. Both patients had additional syndromic features. Patient 1 was a 20-year-old man who developed seizures at age 3 months, had poor growth with severe microcephaly (-6 SD), and global developmental delay with impaired cognition. He also had reticular skin pigmentation, tooth anomalies, hypogonadism, and delayed bone age. At age 13, his anemia showed spontaneous remission, suggesting a clonal genetic reversion event. However, his platelet counts gradually decreased, and bone marrow showed mild trilineage hypoplasia. The second patient was a 5-year-old boy who had an afebrile seizure at age 9 months. He also had severe growth retardation, microcephaly (-4.9 SD), and overall developmental delay. He died at age 5 after a bone marrow transplant. Telomere length in both patients was normal, neither patient developed cancer, and neither had recurrent infections.
The heterozygous mutations in the TP53 gene that were identified in patients with BMFS5 by Toki et al. (2018) occurred de novo.
In 2 unrelated patients with BMFS5, Toki et al. (2018) identified de novo heterozygous mutations in the TP53 gene (191170.0043 and 191170.0044) that resulted in the same truncation of the protein with a loss of 32 residues from the C-terminal end (Ser362AlafsTer8). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that both TP53 mutants had increased transcriptional activity compared to controls. Human induced pluripotent stem cells expressing a CRISPR/Cas9-derived C-terminal truncated TP53 showed significantly elevated expression of downstream TP53 targets, as well as impaired erythroid differentiation. Toki et al. (2018) postulated that the deletion may compromise binding of negative transcriptional regulators. The findings indicated that augmented p53 function, not loss of function, was responsible for the phenotype. Toki et al. (2018) noted that mouse models with animals lacking the C-terminal end of Tp53 show similar abnormalities (Simeonova et al., 2013, Hamard et al., 2013).
Toki et al. (2018) found that expression of a C-terminal truncated tp53 in zebrafish resulted in developmental defects with severe morphologic abnormalities, reduced erythrocyte production, and increased lethality.
Hamard, P.-J., Barthelery, N., Hogstad, B., Mungamuri, S. K., Tonnessen, C. A., Carvajal, L. A., Senturk, E., Gillespie, V., Aaronson, S. A., Merad, M., Manfredi, J. J. The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo. Genes Dev. 27: 1868-1885, 2013. [PubMed: 24013501] [Full Text: https://doi.org/10.1101/gad.224386.113]
Simeonova, I., Jaber, S., Draskovic, I., Bardot, B., Fang, M., Bouarich-Bourimi, R., Lejour, V., Charbonnier, L., Soudais, C., Bourdon, J.-C., Huerre, M., Londono-Vallejo, A., Toledo, F. Mutant mice lacking the p53 C-terminal domain model telomere syndromes. Cell Rep. 3: 2046-2058, 2013. [PubMed: 23770245] [Full Text: https://doi.org/10.1016/j.celrep.2013.05.028]
Toki, T., Yoshida, K., Wang, R., Nakamura, S., Maekawa, T., Goi, K., Katoh, M. C., Mizuno, S., Sugiyama, F., Kanezaki, R., Uechi, T., Nakajima, Y., and 27 others. De novo mutations activating germline TP53 in an inherited bone-marrow-failure syndrome. Am. J. Hum. Genet. 103: 440-447, 2018. [PubMed: 30146126] [Full Text: https://doi.org/10.1016/j.ajhg.2018.07.020]