TY - JOUR AU - Lessel, Davor AU - Wu, Danyi AU - Trujillo, Carlos AU - Ramezani, Thomas AU - Lessel, Ivana AU - Alwasiyah, Mohammad K. AU - Saha, Bidisha AU - Hisama, Fuki M. AU - Rading, Katrin AU - Goebel, Ingrid AU - Schütz, Petra AU - Speit, Günter AU - Högel, Josef AU - Thiele, Holger AU - Nürnberg, Gudrun AU - Nürnberg, Peter AU - Hammerschmidt, Matthias AU - Zhu, Yan AU - Tong, David R. AU - Katz, Chen AU - Martin, George M. AU - Oshima, Junko AU - Prives, Carol AU - Kubisch, Christian T1 - Dysfunction of the MDM2/p53 axis is linked to premature aging PY - 2017/10/02/ AB - The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient’s primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation’s aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI92171 VL - 127 IS - 10 UR - https://doi.org/10.1172/JCI92171 SP - 3598 EP - 3608 PB - The American Society for Clinical Investigation ER -