We confirmed that three Chinese pedigrees affected with EEC or AEC harboring a distinct TP63 mutation, and described novel clinical phenotypes of EEC and AEC, including the presence of cubitus valgus deformity and taurodontism, which were discordant to their classical disease features.
The truncated p63failed to associate with the C-terminal domain of RNA polymerase II through SRA4 protein and, therefore affected keratinocyte proliferation, differentiation and survival and may strongly contribute to AEC phenotype.
Mutations in TP63, mainly missense in exons 13 and 14 encoding the sterile alpha motif (SAM) and the transactivation inhibitory (TI) domains, account for 99% of mutations in individuals with AEC syndrome.
Missense mutations in the 3' end of the p63 gene are associated with either RHS (Rapp-Hodgkin syndrome) or AEC (Ankyloblepharon Ectodermal defects Cleft lip/palate) syndrome.
The expanding p63 mutation database demonstrates that there is considerable overlap between the molecular pathology of RHS and Hay-Wells syndrome, with identical mutations in some cases, and that these two disorders may in fact be synonymous.
Since DeltaNp63alpha is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant DeltaNp63alpha proteins are primarily responsible for skin fragility in AEC patients.
Collectively, advancement in understanding the molecular mechanisms by which epidermal cell junctions precisely exert their functions and how p63 orchestrates their coordinated expression, will ultimately lead to insight into developing future strategies for the treatment of AEC syndrome and more in generally for diseases that share an overlapping phenotype.
These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients.
Here, we characterize the transcriptional activity and protein stability of ΔNp63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly-ectodermal dysplasia-cleft syndrome (EEC), ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC) and nonsyndromic split-hand/split-foot malformation (SHFM).
Several missense and heterozygous frame shift mutations, encoded within exon 13 and 14 of the p63 gene, have been identified in the p63α SAM domain in patients suffering from ankyloblepharon-ectodermal dysplasia-clefting syndrome.
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.
We report a new point mutation in the p63 gene in a family in which the mother was initially diagnosed with Rapp-Hodgkin syndrome and her two offspring manifested ankyloblepharon, ectodermal defects, cleft lip and palate, syndrome.
However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Wells syndrome) were found in the p63 carboxyl-terminal region with a sterile alpha-motif.
Collectively, these investigations demonstrate that RHS is also caused by mutations in p63 and that the clinical similarities to AEC syndrome are paralleled by the nature of the inherent mutation.