Differential PERP Regulation by TP63 Mutants
Provides Insight Into AEC Pathogenesis
Veronica G. Beaudry,1Navneeta Pathak,1Maranke I. Koster,3and Laura D. Attardi1,2*
1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
2Department of Genetics, Stanford University School of Medicine, Stanford, California
3Department of Dermatology, Charles C. Gates Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver,
Received 24 August 2008; Accepted 31 December 2008
Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate
(AEC) or Hay–Wells Syndrome is an autosomal dominant dis-
order characterized by a variety of phenotypes in ectodermal
derivatives, including severe skin erosions, ankyloblepharon,
is caused by mutations in the gene encoding the TP63 transcrip-
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 associ-
ated with AEC. PERP is a TP63 target critical for cell–cell
adhesion due to its participation in desmosomal adhesion com-
plexes. 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
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.
protein; TP53 apoptosis effector related to PMP22; skin; biopsy;
knockout mice; Western blotting; immunohistochemistry
TP63 is a transcriptional activator critical for the development of
the skin and other ectodermal derivatives. This essential role was
originally revealed through studies of TP63-deficient mice, which
lack a variety of ectodermal appendages, including hair
follicles, teeth and mammary glands [Mills et al., 1999; Yang
et al., 1999]. TP63 mutations have also been associated with
several dominantly inherited human syndromes, including
Ectrodactyly-Ectodermal Dysplasia and Cleft Lip/Palate (EEC)
[Celli et al., 1999], Ankyloblepharon Ectodermal Dysplasia
Ungual-Lacrimal-Tooth Syndrome (ADULT) [Amiel et al., 2001],
Rapp–Hodgkin’s Syndrome (RHS) [Kantaputra et al., 2003], and
Limb–Mammary Syndrome (LMS) [van Bokhoven et al., 1999].
Each syndromeis associated with a spectrum of phenotypes affect-
ing the skin and various ectodermal derivatives, underscoring the
important role for TP63 in the development of these structures.
Although each syndrome is characterized by a unique set of
symptoms, there is overlap in phenotypes between the diseases.
Abbreviations: AEC, ankyloblepharon ectodermal dysplasia and cleft
lip/palate syndrome; EEC, ectrodactyly-ectodermal dysplasia and cleft
syndrome; RHS, Rapp–Hodgkin’s Syndrome; LMS, limb–mammary
Grant sponsor: NCI; Grant number: CA119944; Grant sponsor: NIH;
Grant numbers: CA093665 and AR054594; Grant sponsor: National
Foundation for Ectodermal Dysplasias (NFED).
Laura D. Attardi, CCSR-South, Room 1255, 269 Campus Drive, Stanford,
CA 94305-5152. E-mail: email@example.com
Published online 7 April 2009 in Wiley InterScience
How to Cite this Article:
Beaudry VG, Pathak N, Koster MI, Attardi
LD. 2009. Differential PERP regulation by
TP63 mutants provides insight into AEC
Am J Med Genet Part A 149A:1952–1957.
? 2009 Wiley-Liss, Inc.
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