Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.

1Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
European Journal of HumanGenetics (Impact Factor: 4.23). 09/2006; 14(8):904-10. DOI: 10.1038/sj.ejhg.5201640
Source: PubMed

ABSTRACT The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.

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    ABSTRACT: Mutations in the transcription factor gene p63 are causative for human developmental syndromes characterized by three main hallmarks: ectodermal dysplasia, limb malformations and orofacial clefting. Five different dominantly inherited human syndromes and two non-syndromic conditions have been linked to p63 gene defects. Ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC) is the most common p63-associated condition, since approximately 60 percent of all p63 mutations have been identified in EEC syndrome patients. Other p63-linked syndromes: AEC, LMS, ADULT and RHS, all show overlapping features of the three main disease characteristics. In contrast, isolated split hand/foot malformation (SHFM4) and non-syndromic cleft lip/palate (NSCL) only show one of the three main hallmarks. In this study I have tried to get more insight into the p63-associated diseases, their molecular disease mechanism and the role of p63 and its downstream signaling in these diseases.
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    ABSTRACT: Human Ectrodactyly, Ectodermal dysplasia, Clefting (EEC) syndrome is an autosomal dominant developmental disorder defined by limb deformities, skin defects, and craniofacial clefting. Although associated with heterozygous missense mutations in TP63, the genetic basis underlying the variable expressivity and incomplete penetrance of EEC is unknown. Here, we show that mice heterozygous for an allele encoding the Trp63 p.Arg318His mutation, which corresponds to the human TP63 p.Arg279His mutation found in patients with EEC, have features of human EEC. Using an allelic series, we discovered that whereas clefting and skin defects are caused by loss of Trp63 function, limb anomalies are due to gain- and/or dominant-negative effects of Trp63. Furthermore, we identify TAp63 as a strong modifier of EEC-associated phenotypes with regard to both penetrance and expressivity. © 2013 Wiley Periodicals, Inc.
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    ABSTRACT: TP63 germ-line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P63 in the development of ectoderm-derived tissues. Here we report the identification of two TP63 alleles, G134V (p.Gly173Val) and insR155 (p.Thr193_Tyr194insArg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized in yeast, studied in a mammalian cell line and modelled based on the crystal structure of the P63 DNA-binding domain. While the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild type P63, the impact of p.Gly173Asp, p.Gly173Val and p.Thr193_Tyr194insArg varied depending on the Response Element (RE) tested. Interestingly, p.Gly173Asp and p.Gly173Val mutants were characterized by a severe defect in transactivation along with interfering ability on two DN-P63α-specific REs derived from genes closely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modelling of the mutations supported the distinct functional effect of each mutant. The present results highlight the importance of integrating different functional endpoints that take in account the features of P63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.
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