CDKN1C (also known as P57 (kip2) ) is a cyclin-dependent kinase inhibitor that 
functions as a negative regulator of cell proliferation through G1 phase cell 
cycle arrest. Recently, our group described gain-of-function mutations in the 
PCNA-binding site of CDKN1C that result in an undergrowth syndrome called IMAGe 
Syndrome (Intrauterine Growth Restriction, Metaphyseal dysplasia, Adrenal 
hypoplasia, and Genital anomalies), with life-threatening consequences. 
Loss-of-function mutations in CDKN1C have been identified in 5-10% of 
individuals with Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder with 
features that are the opposite of IMAGe syndrome. Here, we investigate the 
effects of IMAGe-associated mutations on protein stability, cell cycle 
progression and cell proliferation. Mutations in the PCNA-binding site of CDKN1C 
significantly increase CDKN1C protein stability and prevent cell cycle 
progression into the S phase. Overexpression of either wild-type or BWS-mutant 
CDKN1C inhibited cell proliferation. However, the IMAGe-mutant CDKN1C protein 
decreased cell growth significantly more than both the wild-type or BWS protein. 
These findings bring new insights into the molecular events underlying IMAGe 
syndrome.