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Developmental disorders: p53 and CHARGE syndrome

CHARGE syndrome is a developmental disorder presenting with many phenotypes such as heart defects and ear abnormalities. A recent study has found a role for p53 in the development of these phenotypes and provides a new mouse model to study the disease (Nature doi:10.1038/nature13585).

Jeanine L. Van Nostrand and her colleagues observed that mice expressing both wild-type p53 and a mutant form that is transcriptionally inactive but stabilized are embryonically lethal. These mice presented a wide range of developmental defects characteristic to CHARGE syndrome. Furthermore, in mouse embryonic fibroblasts derived from these mouse embryos, the mutant protein was itself found to stabilize the wild-type protein, resulting in its hyperactivation. This drove elevated expression of certain p53 targets, which most likely drives the increased apoptosis and reduced proliferation seen in affected tissues.

The transcriptional regulator CHD7 is known to be mutated in 70–90% of CHARGE syndrome cases. The authors found that CHD7 negatively regulated p53 expression in mice neural crest cells and that p53 was hyperactivated in these cells and in patient samples. Furthermore, the phenotypes of mice lacking Chd7 could be partially alleviated by p53 heterozygosity. Thus, the authors conclude that inappropriate activation of p53 has a crucial role in the development of CHARGE syndrome phenotypes.


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Stower, H. Developmental disorders: p53 and CHARGE syndrome. Nat Med 20, 991 (2014).

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