How to cite this article: Beaudry VG, Pathak N, Koster MI, Attardi LD. 2009. Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis. Am J Med Genet Part A 149A:1952–1957.
Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis†
Article first published online: 7 APR 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Special Issue: Ankyloblepharon-Ectodermal Defects-Cleft Lip and/or Palate Syndrome and Ectodermal Dysplasias
Volume 149A, Issue 9, pages 1952–1957, September 2009
How to Cite
Beaudry, V. G., Pathak, N., Koster, M. I. and Attardi, L. D. (2009), Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis. Am. J. Med. Genet., 149A: 1952–1957. doi: 10.1002/ajmg.a.32760
- Issue published online: 20 AUG 2009
- Article first published online: 7 APR 2009
- Manuscript Accepted: 31 DEC 2008
- Manuscript Received: 24 AUG 2008
- NCI. Grant Number: CA119944
- NIH. Grant Numbers: CA093665, AR054594
- National Foundation for Ectodermal Dysplasias (NFED)
- ectodermal dysplasia;
- PERP protein;
- TP53 apoptosis effector related to PMP22;
- knockout mice;
- Western blotting;
Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay–Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell–cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC-patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC. © 2009 Wiley-Liss, Inc.