IR@PKUHSC  > 北京大学第一临床医学院  > 皮肤性病科
学科主题临床医学
Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads
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
2015-03-05
DOI10.1016/j.ajhg.2014.12.026
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
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 ; 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
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
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 ; 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
Cited Times:4[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67542
Collection北京大学第一临床医学院_皮肤性病科
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
GB/T 7714
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.
APA Lin, Zhimiao.,Zhao, Jiahui.,Nitoiu, Daniela.,Scott, Claire A..,Plagnol, Vincent.,...&Yang, Yong.(2015).Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads.AMERICAN JOURNAL OF HUMAN GENETICS,96(3),440-447.
MLA Lin, Zhimiao,et al."Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads".AMERICAN JOURNAL OF HUMAN GENETICS 96.3(2015):440-447.
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