A heterozygous mutation in the SAM domain of p63 underlies a mild form of ectodermal dysplasia

p63 is a major transcription factor which plays crucial roles in development of various epithelial tissues including skin [ ]. In humans, p63 is encoded by TP63 gene and mutations in the TP63 gene are known to underlie at least five distinct ectodermal dysplasia (ED) syndromes: Rapp-Hodgkin syndrome (OMIM 129400), ankyloblepharon, ectodermal defects and cleft lip/palate (AEC) syndrome (OMIM 106260), ectrodactyly, ectodermal dysplasia and cleft lip/palate (EEC) syndrome (OMIM 604292), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; OMIM 103285), and limb mammary syndrome (OMIM 603543) [ , ]. The human TP63 gene has several isoforms, of which only TAp63α and ΔNp63α isoforms contain a sterile alpha motif (SAM) domain at the C-terminal region, while all the isoforms have a DNA-binding domain. The SAM domain is believed to be essential for protein–protein interaction [ ]. Importantly, there is a clear genotype-phenotype correlation, i.e. mutations in the DNA binding domain cause ectorodactyly or syndactyly, whereas those in the SAM domain do not. In contrast, most cases with TP63 mutations show cleft lip/palate regardless of position of the mutations. Recently, a case of mild ED caused by TP63 gene was reported [ ]. We herein report a case of ED associated with a mutation in the SAM domain of p63, who showed a unique and mild clinical manifestations. We predicted structural changes of the mutant protein using crystal structure models. Moreover, we demonstrated that the mutant protein affected both expression and function of the wild-type protein through a dominant-negative effect. The detailed materials and methods are given elsewhere (Supplementary information online).