title: EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.
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 modeled based on the crystal structure of the P63 DNA-binding domain. Although 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 modeling 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.
authors: Molecular Mutagenesis and DNA Repair Unit, Istituto di Ricerca e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Paola
authors: P
authors: Monti
authors: Debora
authors: D
authors: Russo
authors: Renata
authors: R
authors: Bocciardi
authors: Giorgia
authors: G
authors: Foggetti
authors: Paola
authors: P
authors: Menichini
authors: Maria T
authors: MT
authors: Divizia
authors: Margherita
authors: M
authors: Lerone
authors: Claudio
authors: C
authors: Graziano
authors: Anita
authors: A
authors: Wischmeijer
authors: Hector
authors: H
authors: Viadiu
authors: Roberto
authors: R
authors: Ravazzolo
authors: Alberto
authors: A
authors: Inga
authors: Gilberto
authors: G
authors: Fronza
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000848:Anodontia / Q000235:genetics* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001940:Breast / Q000002:abnormalities* / Q000378:metabolism; D002460:Cell Line; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D045325:HCT116 Cells; D006801:Humans; D007767:Lacrimal Duct Obstruction / Q000235:genetics* / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009264:Nails, Malformed / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010859:Pigmentation Disorders / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015003:Yeasts / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051736:Proto-Oncogene Proteins c-mdm2