ONLINE MUTATION REPORT Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene

I ncreases in the number of allelic malformation syndromes (due to mutations in a single gene) have led to their classification according to their pathogenesis rather than their clinical specific phenotype. TP63 mutations have been identified in several such syndromes characterised by autosomal dominant transmission and various combinations of ectodermal dysplasia, limb malformations, and orofacial clefting. The TP63 gene is a TP53 homologue, part of a family composed of only three members. The third member (TP73) is more similar to TP63 than to TP53 in both structure and function. Like p53, p63 has a transactivating (TA), a DNA binding (DB), and a polymerisation domain; it exerts p53like activities in various contexts, such as binding canonical p53 sites, transactivating p53 target genes, and inducing apoptosis. 2 Unlike TP53, which expresses one major transcript, TP63 contains four separate transcription initiation sites that direct expression of two fundamentally different isotypes that retain (TA products) or lack (DN products) the TA domain. Alternative splicing generates additional complexity at the C terminus. DN isoforms lack TA activity and may also suppress the TA isoforms, either by simple competition for the DNA target sites or by acting as dominant negatives through oligomerisation. By contrast to p53, the C terminus in p63 is longer and contains a SAM domain and a TID (transactivation inhibitory domain). SAM domains are involved in protein-protein interactions and probably have regulatory functions in p63, since its TA-a isoform shows a lower TA activity than the c form, which lacks the SAM but retains the TA domain. The TID has been mapped within the a tail downstream to the SAM domain. The differences at the C terminus identify three transcripts which have different properties and functions: a, b, and c isoforms. The a isoforms have the SAM and the TID, and lack the region corresponding to exon 15, which is shown by the c isoforms. The latter are formed by splicing out the regions encoded by exons 11–14. The b isoforms lack the region corresponding to exon 13 and use a different frame that finds a stop codon at the beginning of exon 14: they lack both the SAM and the TID. Lastly, p53 is conditionally expressed, whereas p63 is constitutively present. It is expressed mainly in the stem cell compartment of epithelial tissues. DN products are the most abundant isoforms, and highlight a role for repressive versions in epithelial stem cell identity. TP63 is rarely mutated in cancer, and its main role is in embryo development. 19 In fact, TP63 mutations have been identified in the following malformation syndromes: ectodermal dysplasia, ectrodactyly, cleft lip / palate (EEC: MIM 604292); split-hand / foot malformation (SHFM: MIM 183600); ankyloblepharon-ectodermal dysplasia-cleft (AEC: MIM 106260); limb-mammary syndrome (LM: MIM 603543); and acro-dermato-ungual-lacrimal-tooth syndrome (ADULT: MIM 103285). Patients do not show an increased susceptibility to cancer. An apparently conclusive genotype-phenotype correlation has been deduced to explain the development of different syndromes (with some exceptions). All but one of the EEC mutations affect the TP63 DNA binding domain, whereas all but one of the AEC mutations are caused by missense mutations affecting the SAM domain. SHFM patients have either missense mutations in the DNA binding domain or nonsense mutations within the C terminus. Three mutations have been found in LMS patients: two frameshift mutations in exon 13 or 14, and a missense mutation in exon 4. ADULT syndrome mutants include one missense mutation in the TA2 domain located at the N terminal region of the DN isoform, and a specific missense mutation in the DNA binding domain. EEC and SHFM missense mutations are expected to lose TA functions; AEC and LMS mutants maintain TA functions, but lose the regulatory functions ascribed to the SAM domain and the TID, respectively. 17 28 ADULT mutations are mutations that gain function, because they both activate the TA2 domain. These hypotheses have been supported by expression of mutant proteins and analysis of their function in the laboratory or by analogy with p73 and p53 mutants. SHFM is genetically heterogeneous: only 10% of SHFM are due to TP63. 24 Rapp-Hodgkin syndrome (RHS: MIM 129400) is autosomal dominant and shares two cardinal symptoms with