Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology

St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK.
British Journal of Dermatology (Impact Factor: 4.28). 02/2012; 167(1):134-44. DOI: 10.1111/j.1365-2133.2012.10888.x
Source: PubMed


AEC (ankyloblepharon-ectodermal defects-clefting) syndrome is an autosomal dominant ectodermal dysplasia disorder caused by mutations in the transcription factor p63. Clinically, the skin is dry and often fragile; other features can include partial eyelid fusion (ankyloblepharon), hypodontia, orofacial clefting, sparse hair or alopecia, and nail dystrophy.
To investigate how p63 gene mutations affect gene and protein expression in AEC syndrome skin.
We performed microarray analysis on samples of intact and eroded AEC syndrome skin compared with control skin. Changes were verified by quantitative real-time reverse transcription-polymerase chain reaction and, for basal keratinocyte-associated genes, by immunohistochemistry and analysis of microdissected skin.
We identified significant upregulation of six genes and downregulation of 69 genes in AEC syndrome skin, with the main changes in genes implicated in epidermal adhesion, skin barrier formation and hair follicle biology. There was reduced expression of genes encoding the basement membrane proteins FRAS1 and collagen VII, as well as the skin barrier-associated small proline-rich proteins 1A and 4, late cornified envelope protein 5A, hornerin, and lipid transporters including ALOX15B. Reduced expression of the hair-associated keratins 25, 27, 31, 33B, 34, 35, 81 and 85 was also noted. We also confirmed similar alterations in gene expression for 26 of the 75 genes in eroded AEC scalp skin.
This study identifies specific changes in skin structural biology and signalling pathways that result from mutant p63 and provides new molecular insight into the AEC syndrome phenotype.

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    • "To gain insight into further pathways impacted, intact and eroded AEC syndrome skin and normal skin were compared by microarray analysis. The findings revealed changes in expression of genes associated with epidermal adhesion, skin barrier formation, and hair follicle biology, all consistent with the clinical presentation [48]. Thus, SAM domain mutations highlight the importance of p63 and in particular ΔNp63α to normal epidermal morphogenesis/homeostasis. "
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    • "During embryonic development, progenitor cell expansion is affected due to impairment of fibroblast growth factor signalling leading to a defective epidermal stem cell compartment (45). Despite epidermal hypoplasia, epidermal differentiation occurs normally in p63+/L514F newborn mice, and the impermeable epidermal barrier is established at the appropriate developmental time-point consistent with little or no alteration of terminal differentiation observed in the skin of AEC patients (18,46). Here, we demonstrate that in AEC syndrome skin fragility is associated with acantholysis and reduced desmosomes between the basal and suprabasal layers of the epidermis. "
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