Premium
EEC ‐ and ADULT ‐Associated TP63 Mutations Exhibit Functional Heterogeneity Toward P 63 Responsive Sequences
Author(s) -
Monti Paola,
Russo Debora,
Bocciardi Renata,
Foggetti Giorgia,
Menichini Paola,
Divizia Maria T.,
Lerone Margherita,
Graziano Claudio,
Wischmeijer Anita,
Viadiu Hector,
Ravazzolo Roberto,
Inga Alberto,
Fronza Gilberto
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22304
Subject(s) - biology , transactivation , mutant , ectodermal dysplasia , mutation , genetics , allele , phenotype , gene , microbiology and biotechnology , transcription factor
TP63 germ‐line mutations are responsible for a group of human ectodermal dysplasia syndromes, underlining the key role of P 63 in the development of ectoderm‐derived tissues. Here, we report the identification of two TP63 alleles, G 134 V (p. G ly173 V al) and ins R 155 (p. T hr193_ T yr194ins A rg), associated to ADULT and EEC syndromes, respectively. These alleles, along with previously identified G 134 D (p. G ly173 A sp) and R 204 W (p. A rg243 T rp), were functionally characterized in yeast, studied in a mammalian cell line and modeled based on the crystal structure of the P 63 DNA ‐binding domain. Although the p.Arg243Trp mutant showed both complete loss of transactivation function and ability to interfere over wild‐type P 63, the impact of p. G ly173 A sp, p. G ly173 V al, and p. T hr193_ T yr194ins A rg varied depending on the response element (RE) tested. Interestingly, p. G ly173 A sp and p. G ly173 V al mutants were characterized by a severe defect in transactivation along with interfering ability on two DN ‐ P 63α‐specific RE s derived from genes closely related to the clinical manifestations of the TP63 ‐associated syndromes, namely PERP and COL 18 A 1. 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 P 63 proteins' target sequences to examine the impact of TP63 mutations and the associated clinical variability.