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"p53 and p63 share extensive sequence and structure homology  p53 is frequently mutated in cancer  whereas mutations in p63 cause developmental disorders manifested in ectodermal dysplasia  limb defects  and orofacial clefting  We have established primary adult skin keratinocytes from ectrodactyly  ectodermal dysplasia  and cleft lip palate  EEC  syndrome patients with p63 mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients  We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification  Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246 PRIMA-1 MET  p53 reactivation and induction of massive apoptosis  that has been successfully tested in a phase I  II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models  This rescue coincides with restoration of p63 target-gene expression  Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant p63-associated developmental abnormalities "
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