TP63 germ-line mutations are responsible for a group of human ectodermaldysplasia syndromes, underlining the key role of P63 in the development ofectoderm-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 identifiedG134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized inyeast, studied in a mammalian cell line and modeled based on the crystalstructure of the P63 DNA-binding domain. Although the p.Arg243Trp mutant showedboth complete loss of transactivation function and ability to interfere overwild-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 genesclosely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinctfunctional effect of each mutant. The present results highlight the importance ofintegrating different functional endpoints that take in account the features ofP63 proteins' target sequences to examine the impact of TP63 mutations and theassociated clinical variability.

EEC- and ADULT-AssociatedTP63Mutations Exhibit Functional Heterogeneity Toward P63 Responsive Sequences

BOCCIARDI, RENATA;FOGGETTI, GIORGIA;RAVAZZOLO, ROBERTO;
2013

Abstract

TP63 germ-line mutations are responsible for a group of human ectodermaldysplasia syndromes, underlining the key role of P63 in the development ofectoderm-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 identifiedG134D (p.Gly173Asp) and R204W (p.Arg243Trp), were functionally characterized inyeast, studied in a mammalian cell line and modeled based on the crystalstructure of the P63 DNA-binding domain. Although the p.Arg243Trp mutant showedboth complete loss of transactivation function and ability to interfere overwild-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 genesclosely related to the clinical manifestations of the TP63-associated syndromes, namely PERP and COL18A1. The modeling of the mutations supported the distinctfunctional effect of each mutant. The present results highlight the importance ofintegrating different functional endpoints that take in account the features ofP63 proteins' target sequences to examine the impact of TP63 mutations and theassociated clinical variability.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11567/587560
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