EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences

Hum Mutat. 2013 Jun;34(6):894-904. doi: 10.1002/humu.22304. Epub 2013 Apr 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acid Substitution
  • Anodontia / genetics*
  • Anodontia / metabolism
  • Apoptosis Regulatory Proteins / genetics
  • Breast / abnormalities*
  • Breast / metabolism
  • Cell Line
  • Cleft Lip / genetics*
  • Cleft Lip / metabolism
  • Cleft Palate / genetics*
  • Cleft Palate / metabolism
  • Ectodermal Dysplasia / genetics*
  • Ectodermal Dysplasia / metabolism
  • Gene Expression Regulation
  • Genetic Association Studies
  • Germ-Line Mutation
  • HCT116 Cells
  • Humans
  • Lacrimal Duct Obstruction / genetics*
  • Lacrimal Duct Obstruction / metabolism
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / metabolism
  • Mutation*
  • Nails, Malformed / genetics*
  • Nails, Malformed / metabolism
  • Phenotype
  • Pigmentation Disorders / genetics*
  • Pigmentation Disorders / metabolism
  • Protein Isoforms
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Response Elements*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Yeasts / genetics
  • Yeasts / metabolism
  • bcl-2-Associated X Protein / genetics

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • Proto-Oncogene Proteins c-mdm2

Supplementary concepts

  • Ectrodactyly-cleft lip-palate syndrome
  • Propping Zerres syndrome