Various combinations of limb anomalies, ectodermal dysplasias and orofacial clefts characterize heterozygous mutations in the transcription factor gene p63. The causative gene is crucial during embryonic ontogenesis, mostly in the development of limbs and other ectodermal derived tissues. The pattern of mutations in six different p63-related syndromes (EEC syndrome, AEC syndrome, ADULT syndrome, LMS syndrome, RHS syndrome, SHFM syndrome) shows genotype-phenotype correlations. The most frequent p63 mutation syndrome is the EEC syndrome, characterized by ectrodactyly, ectodermal dysplasia and cleft lip/palate. Ectodermal dysplasia is characterized by ectrodactyly often associated with syndactyly, sparse hair, dry skin, hypo-anodontia, dysplastic nails and alterations in sebaceous glands, mammary glands and nipples. The third hallmark of the EEC syndrome is orofacial clefting, in particular lip and palate. p63 mutations also cause the other five inherited syndromes: symptoms are overlapping, but each of these diseases has its own characteristic phenotypic features: for instance AEC syndrome (ankyloblepharon-ectodermal defects-cleft lip/palate) has as distinctive feature ankyloblepharon, while mammary glands and nipples hypoplasia are frequent findings in LMS syndrome and in ADULT syndrome (acro-dermato-ungual-lacrimal-tooth syndrome). The latter can be distinguished from other p63 syndromes by the absence of orofacial clefting and by prominent ectodermal signs. The narrowest genotype-phenotype correlation is in the EEC and AEC syndromes. All EEC missense mutations are clustered in the DNA binding domain and do not bind to DNA; in contrast, all missens mutations reported in AEC syndrome are localized in the α-motif domain, and it has been demonstrated that they disrupt interaction with other proteins. LMS and ADULT syndrome have their own unique mutated amino-acid residues. Only two amino-acid residues are known to be mutated amongst ADULT syndrome: asparagines 6 and arginine 298. Although R298 is in the DNA binding domain, it is functionally different from the EEC mutations, because its substitution by glutamine does not lead to a loss of DNA binding, but to a gain of transactivation activity of the ΔNp63γ isoform. In this paper we discuss the consistent phenotypic features associated with these gain of function mutations.
|Number of pages||6|
|Journal||Giornale Italiano di Dermatologia e Venereologia|
|Publication status||Published - 2013|
- Associated syndromes
- Ectodermal dysplasia
- p63 mutation
ASJC Scopus subject areas