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

Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family ...
with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.
Mesh Terms:
Alleles, Amino Acid Substitution, Animals, Bone Marrow, Cell Cycle Proteins, Disease Models, Animal, Family, Female, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Mice, Mice, Knockout, Pedigree, Phenotype, Proto-Oncogene Proteins, Signal Transduction, Syndrome, Telomere, Telomere Homeostasis, Telomere Shortening, Tumor Suppressor Protein p53
Sci Adv
Date: Dec. 01, 2019
Download Curated Data For This Publication
230477
Switch View:
  • Interactions 1