Tumor protein p63 (TP63)-related disorders can be divided into at least six categories, including ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC syndrome 3), ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome), acro-dermo-ungual-lacrimal-tooth syndrome (ADULT syndrome), limb-mammary syndrome (LMS), Rapp-Hodgkin syndrome (RHS) and split-hand/foot malformation 4 (SHFM4), and are all a result of heterozygous mutations of TP63.
Gain of function mutations of TP63 are known to be responsible for a group of conditions with distal limb and ectodermal involvement, such as ADULT, EEC, LMS, and SHFM4 syndromes.
Using a set of p63 deletion mutants, we have identified a region and two critical lysine residues of p63, associated to human Split-Hand and Foot Malformation-4 (SHFM-4) syndrome, which are involved in the mechanism of Itch-mediated p63 degradation.
Natural p63 mutants, associated to the AEC syndrome, show a partial or complete lack of transactivation potential of the p57Kip2 promoter, while three other natural p63 mutants, associated to the EEC, LMS and SHFM-4 syndromes, were less affected.