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EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.
Hum Mutat. 2013 Jun; 34(6):894-904.HM

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23463580

Citation

Monti, Paola, et al. "EEC- and ADULT-associated TP63 Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences." Human Mutation, vol. 34, no. 6, 2013, pp. 894-904.
Monti P, Russo D, Bocciardi R, et al. EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences. Hum Mutat. 2013;34(6):894-904.
Monti, P., Russo, D., Bocciardi, R., Foggetti, G., Menichini, P., Divizia, M. T., Lerone, M., Graziano, C., Wischmeijer, A., Viadiu, H., Ravazzolo, R., Inga, A., & Fronza, G. (2013). EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences. Human Mutation, 34(6), 894-904. https://doi.org/10.1002/humu.22304
Monti P, et al. EEC- and ADULT-associated TP63 Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences. Hum Mutat. 2013;34(6):894-904. PubMed PMID: 23463580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences. AU - Monti,Paola, AU - Russo,Debora, AU - Bocciardi,Renata, AU - Foggetti,Giorgia, AU - Menichini,Paola, AU - Divizia,Maria T, AU - Lerone,Margherita, AU - Graziano,Claudio, AU - Wischmeijer,Anita, AU - Viadiu,Hector, AU - Ravazzolo,Roberto, AU - Inga,Alberto, AU - Fronza,Gilberto, Y1 - 2013/04/02/ PY - 2012/11/09/received PY - 2013/02/22/accepted PY - 2013/3/7/entrez PY - 2013/3/7/pubmed PY - 2014/1/1/medline SP - 894 EP - 904 JF - Human mutation JO - Hum Mutat VL - 34 IS - 6 N2 - 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. SN - 1098-1004 UR - https://wwww.unboundmedicine.com/medline/citation/23463580/EEC__and_ADULT_associated_TP63_mutations_exhibit_functional_heterogeneity_toward_P63_responsive_sequences_ L2 - https://doi.org/10.1002/humu.22304 DB - PRIME DP - Unbound Medicine ER -