title: Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads.
abstract: 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.
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors: Zhimiao
authors: Z
authors: Lin
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors: Jiahui
authors: J
authors: Zhao
authors: Centre for Cutaneous Research, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Daniela
authors: D
authors: Nitoiu
authors: Centre for Cutaneous Research, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Claire A
authors: CA
authors: Scott
authors: Department of Genetics, University College London, London WC1E 6BT, UK.
authors: Vincent
authors: V
authors: Plagnol
authors: Centre for Dermatology and Genetic Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors: Frances J D
authors: FJ
authors: Smith
authors: Centre for Dermatology and Genetic Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors: Neil J
authors: NJ
authors: Wilson
authors: Centre for Dermatology and Genetic Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK; Division of Computational Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors: Christian
authors: C
authors: Cole
authors: PC Project, Salt Lake City, UT 84109, USA.
authors: Mary E
authors: ME
authors: Schwartz
authors: Centre for Dermatology and Genetic Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
authors: W H Irwin
authors: WH
authors: McLean
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.
authors: Huijun
authors: H
authors: Wang
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors: Cheng
authors: C
authors: Feng
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China.
authors: Lina
authors: L
authors: Duo
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
authors: Eray Yihui
authors: EY
authors: Zhou
authors: Laboratory of Electron Microscopy, Peking University First Hospital, Beijing 100034, China.
authors: Yali
authors: Y
authors: Ren
authors: BGI-Shenzhen, Shenzhen 518083, China.
authors: Lanlan
authors: L
authors: Dai
authors: BGI-Shenzhen, Shenzhen 518083, China.
authors: Yulan
authors: Y
authors: Chen
authors: BGI-Shenzhen, Shenzhen 518083, China.
authors: Jianguo
authors: J
authors: Zhang
authors: BGI-Shenzhen, Shenzhen 518083, China.
authors: Xun
authors: X
authors: Xu
authors: Centre for Cutaneous Research, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Edel A
authors: EA
authors: O'Toole
authors: Centre for Cutaneous Research, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. Electronic address: d.p.kelsell@qmul.ac.uk.
authors: David P
authors: DP
authors: Kelsell
authors: Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China. Electronic address: dryongyang@bjmu.edu.cn.
authors: Yong
authors: Y
authors: Yang
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002613:Cheilitis / Q000235:genetics*; D004817:Epidermis / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes; D007642:Keratosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009260:Nail Diseases / Q000235:genetics*; D010375:Pedigree; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D034741:RNA, Small Interfering; C033668:calpastatin