Isoform-Specific Roles of Mutant p63 in Human Diseases

SIMPLE SUMMARY: The protein p63 belongs to the family of the p53 tumor suppressor. Mouse models have, however, shown that it is not a classical tumor suppressor but instead involved in developmental processes. Mutations in the p63 gene cause several developmental defects in human patients characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia due to p63’s role as a master regulator of epidermal development. In addition, p63 plays a key role as a quality control factor in oocytes and p63 mutations can result either in compromised genetic quality control or premature cell death of all oocytes. ABSTRACT: The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.