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IR@PKUHSC  > 北京大学第一临床医学院  > 皮肤性病科  > 期刊论文
学科主题: 临床医学
题名:
Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads
作者: Lin, Zhimiao1,2; Zhao, Jiahui1,2; Nitoiu, Daniela3; Scott, Claire A.3; Plagnol, Vincent4; Smith, Frances J. D.5,6,7; Wilson, Neil J.5,6,7; Cole, Christian5,6,7,8; Schwartz, Mary E.9; McLean, W. H. Irwin5,6,7; Wang, Huijun1,2,10; Feng, Cheng1,2; Duo, Lina1,2,10; Zhou, Eray Yihui1,2; Ren, Yali11; Dai, Lanlan12; Chen, Yulan12; Zhang, Jianguo12; Xu, Xun12; O′ Toole, Edel A.3; Kelsell, David P.3; Yang, Yong1,2,10
刊名: AMERICAN JOURNAL OF HUMAN GENETICS
发表日期: 2015-03-05
DOI: 10.1016/j.ajhg.2014.12.026
卷: 96, 期:3, 页:440-447
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Genetics & Heredity
研究领域[WOS]: Genetics & Heredity
关键词[WOS]: CALPAIN-MEDIATED PROTEOLYSIS ; SERINE-PROTEASE INHIBITOR ; ENCODING CYSTATIN-A ; PALMOPLANTAR KERATOSIS ; MISSENSE MUTATION ; ADHESION DYNAMICS ; FOCAL ADHESION ; APOPTOSIS ; MICE ; DERMATITIS
英文摘要:

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs*8, p.Lys142*, and p.Val584Trpfs*37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.

语种: 英语
所属项目编号: 81425020 ; 81271744 ; 81201220 ; YETP0069 ; CXB201108250094A ; 098439/Z/12/Z
项目资助者: China National Funds for Distinguished Young Scientists ; National Natural Science Foundation of China ; Beijing Higher Education Young Elite Teacher Project ; Shenzhen Key Laboratory of Cognitive Genomics ; Pachyonychia Congenita Project ; Wellcome Trust Strategic Award ; Barts ; London Charity
WOS记录号: WOS:000350747800016
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/67542
Appears in Collections:北京大学第一临床医学院_皮肤性病科_期刊论文

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作者单位: 1.Beijing Key Lab Mol Diag Dermatoses, Beijing 100034, Peoples R China
2.UCL, Dept Genet, London WC1E 6BT, England
3.Univ Dundee, Coll Life Sci, Div Computat Biol, Dundee DD1 5EH, Scotland
4.PC Project, Salt Lake City, UT 84109 USA
5.BGI Shenzhen, Shenzhen 518083, Peoples R China
6.Peking Univ, Hosp 1, Dept Dermatol, Beijing 100034, Peoples R China
7.Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China
8.Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Cutaneous Res, London E1 2AT, England
9.Univ Dundee, Ctr Dermatol & Genet Med, Coll Life Sci & Med, Dundee DD1 5EH, Scotland
10.Univ Dundee, Ctr Dermatol & Genet Med, Coll Dent, Dundee DD1 5EH, Scotland
11.Univ Dundee, Ctr Dermatol & Genet Med, Coll Nursing, Dundee DD1 5EH, Scotland
12.Peking Univ, Hosp 1, Lab Electron Microscopy, Beijing 100034, Peoples R China

Recommended Citation:
Lin, Zhimiao,Zhao, Jiahui,Nitoiu, Daniela,et al. Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads[J]. AMERICAN JOURNAL OF HUMAN GENETICS,2015,96(3):440-447.
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