Heterozygous Mutation in the SAM Domain of p63 Underlies Rapp-Hodgkin Ectodermal Dysplasia

Abstract

Several ectodermal dysplasia syndromes, including Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) and Ankyloblepharon-Ectodermal Dysplasia-Clefting (AEC) syndromes, are known to result from mutations in the p63 gene. We investigated whether Rapp-Hodgkin syndrome (RHS) is also caused by mutations in the p63 gene. We identified a heterozygous de novo germline missense mutation, S545P, in the sterile-alpha-motif (SAM) domain of p63, in a Thai patient affected with RHS. This is the first genetic abnormality to be described in RHS. The amino acid substitution is the most downstream missense mutation in p63 reported thus far. Histological assessment of a skin biopsy from the patient's palm showed hyperkeratosis and keratinocyte cell-cell detachment in the upper layers of the epidermis, along with numerous apoptotic keratinocytes. Collectively, these investigations demonstrate that RHS is also caused by mutations in p63 and that the clinical similarities to AEC syndrome are paralleled by the nature of the inherent mutation.

p63-Associated Disorders

“…AEC and RHS syndromes share three mutations: I510, S541 and 1859 Del A. 24,25,28,29,31,33 Often the clinical distinction between RHS and AEC syndrome is solely based on the presence or absence of ankyloblepharon, which in fact is not the discriminating feature between these two conditions. 11 Also LMS and ADULT syndrome seem to be caused by the same mutation G134D (authors' unpublished data), 23 as well as EEC syndrome and non-syndromic cleft lip/palate due to the R313G mutation (authors' unpublished data).…”

“…They are either point mutations in the SAM domain or deletions in the SAM or TI domains (Table 1). 7,11,12,[24][25][26][27][28][29][30][31][32][33][34][35] The SAM domain is known to be involved in protein-protein interactions and therefore mutations in this domain are most probably hampering the binding to interacting proteins. One known interactor of p63 SAM domain is the Apobec-1-binding protein-1 (ABBP1), which is a member of RNA processing machinery and known to regulate the alternative splicing of the Fibroblast-growth-factor-receptor-2 (FGFR2) towards the epithelial specific isoform.…”

Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

“…[5][6][7][8] The p63 gene, the evolutionary progenitor and homolog of the TP53 gene, is responsible for several disorders known as ectodermal dysplasias. [9][10][11][12][13][14][15] p63 proteins have important functions in epithelial development and tumorigenesis as regulators of the proliferation potential of epithelial stem cells, as well as of cell death, reviewed in. [6][7][8][9][10][11][12][13][14][15][16][17][18] Thanks to two specific promoters, the TP63 gene is expressed as ΔNp63 and TAp63 proteins that have distinct functions in transcription control.…”

AEC-Associated p63 Mutations Lead to Alternative Splicing/Protein Stabilization of p63 and Modulation of Notch Signaling

“…[1][2][3][4] More than forty naturally occurred p63 mutations were mapped to different domains of p63 and were found to be associated with several developmental disorders, such as ankyloblepharon, ectodermal dysplasia and clefting (AEC or Hay-Wells), ectodermal dysplasia, facial clefting (EEC), split hand/foot malformation (SHFM), limb-mammary syndrome (LMS) acrodermato-ungual-lacrimal-tooth syndrome (ADULT) and Rapp-Hodgkin's syndrome. [5][6][7][8][9][10] All these mutations were sought to disrupt specific p63 protein-protein complexes therefore affecting its transcriptional function toward specific target genes.…”