title: Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To investigate how p63 gene mutations affect gene and protein expression in AEC syndrome skin.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: St John's Institute of Dermatology, King's College London (Guy's Campus), London SE1 9RT, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Clements
authors.forename: T
authors.initials: T
authors.lastname: Techanukul
authors.forename: J E
authors.initials: JE
authors.lastname: Lai-Cheong
authors.forename: J B
authors.initials: JB
authors.lastname: Mee
authors.forename: A P
authors.initials: AP
authors.lastname: South
authors.forename: C
authors.initials: C
authors.lastname: Pourreyron
authors.forename: N P
authors.initials: NP
authors.lastname: Burrows
authors.forename: J E
authors.initials: JE
authors.lastname: Mellerio
authors.forename: J A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D000328:Adult; D001485:Basement Membrane / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D005143:Eyelids / Q000002:abnormalities / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006197:Hair / Q000378:metabolism; D006801:Humans; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D046228:Microarray Analysis; D009154:Mutation / Q000235:genetics*; D009262:Nails / Q000378:metabolism
chemical_list: C081876:CKAP4 protein, human; D016326:Extracellular Matrix Proteins; C475145:FRAS1 protein, human; C507540:KRT14 protein, human; D053547:Keratin-14; D008565:Membrane Proteins