A MOLECULAR AND FUNCTIONAL STUDY OF P63 MUTANT PROTEINS OCCURRING IN EEC, AEC AND OTHER HUMAN HEREDITARY ECTODERMAL SYNDROMES

Molecular lesions of the p63 gene are the major cause of several human hereditary syndromes characterized by ectodermal dysplasia, facial clefts and limb defects (EEC, AEC, SFHM and others). Clinical distinction among these syndromes is sustained by both the occurrence of unique characteristics and the different degree of expressivity. For instance, in EEC patients the extensive ectodermal dysplasia is associated with ectrodactyly while AEC patients do not show limb defects but have fused eyelids, cleft lip/palate and severe scalp dermatitis. The p63 gene encodes a transcription factor, it has a very complex pattern of expression giving raise to at least six different proteins with widely different activities. All six different proteins share a DNA binding domain but only two of them (the p63alpha isoforms) possess a sterile alpha motif (SAM), an evolutionary conserved domain which characterize proteins involved in developmental processes. Mutational analysis on the p63 gene from EEC and AEC patients revealed that the majority of EEC mutations are in residues predicted to contact DNA while AEC mutations are all located in the SAM domain. At present, the knowledge of the mechanisms through which individual p63 proteins modulate ephitelial differentiation is still rudimentary. We will use molecular, cellular and bioinformatic approaches in order to shed light on the different outcomes of p63 molecular lesions in human hereditary skin pathologies. Moreover we will focus on the identification of proteins which physically interact with the p63 SAM domain, where AEC mutations are clustered, to investigate their importance in AEC syndrome. We expect our studies to shed light on cellular pathways in which p63 proteins are involved and to be helpful in devising strategies for therapies that alleviate symptoms of human hereditary skin pathologies.