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

Sci Adv. 2020 Apr 10;6(15):eaay3511. doi: 10.1126/sciadv.aay3511.

Eléonore Toufektchan ¹ ² ³ ⁴, Vincent Lejour ¹ ² ³ ⁴, Romane Durand ¹ ² ³ ⁴, Neelam Giri ⁵, Irena Draskovic ² ³ ⁴ ⁶, Boris Bardot ¹ ² ³ ⁴, Pierre Laplante ¹ ² ³ ⁴, Sara Jaber ¹ ² ³ ⁴, Blanche P Alter ⁵, José-Arturo Londono-Vallejo ² ³ ⁴ ⁶, Sharon A Savage ⁵, Franck Toledo ¹ ² ³ ⁴

Affiliations

1 Genetics of Tumor Suppression, Institut Curie, Paris, France.
2 CNRS UMR 3244, Paris, France.
3 Sorbonne Université, Paris, France.
4 PSL Research University, Paris, France.
5 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
6 Telomeres and Cancer, Institut Curie, Paris, France.

PMID: 32300648 DOI: 10.1126/sciadv.aay3511

Abstract

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.

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