Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology
Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology
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DOI：
10.1111/j.1365-2133.2012.10888.x
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发表时间：
2012-07-01
影响因子：
10.3
通讯作者：
McGrath, J. A.
中科院分区：
文献类型：
--
作者：
Clements, S. E.;Techanukul, T.;McGrath, J. A.
AEC（强bleblepharon -ectodermal缺陷-cleft）综合征是一种常染色体显性外胚层发育不良疾病，由转录因子p63突变引起。临床上，皮肤干燥且易碎；其他特征包括部分眼睑融合（强直性眼睑）、下颌缺损、口面部裂、头发稀疏或脱发以及指甲营养不良。目的探讨p63基因突变对AEC综合征皮肤基因及蛋白表达的影响。方法对AEC综合征完整皮肤和侵蚀皮肤进行微阵列分析，并与对照皮肤进行比较。通过定量实时逆转录聚合酶链反应验证变化，并通过免疫组织化学和显微解剖皮肤分析验证基础角化细胞相关基因的变化。结果在AEC综合征皮肤中发现6个基因显著上调，69个基因显著下调，其中主要与表皮粘附、皮肤屏障形成和毛囊生物学相关的基因发生变化。基底膜蛋白FRAS1和胶原蛋白VII、皮肤屏障相关的富含脯氨酸的小蛋白1A和4、晚角化包膜蛋白5A、角蛋白和脂质转运蛋白ALOX15B的基因表达减少。头发相关角蛋白25、27、31、33B、34、35、81和85的表达也有所减少。我们还证实了侵蚀AEC头皮皮肤中75个基因中26个基因表达的类似变化。本研究确定了p63突变导致的皮肤结构生物学和信号通路的特异性变化，并为AEC综合征表型提供了新的分子见解。
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.Objectives 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.