Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads

Am J Hum Genet. 2015 Mar 5;96(3):440-7. doi: 10.1016/j.ajhg.2014.12.026.

Zhimiao Lin ¹, Jiahui Zhao ¹, Daniela Nitoiu ², Claire A Scott ², Vincent Plagnol ³, Frances J D Smith ⁴, Neil J Wilson ⁴, Christian Cole ⁵, Mary E Schwartz ⁶, W H Irwin McLean ⁴, Huijun Wang ⁷, Cheng Feng ¹, Lina Duo ⁷, Eray Yihui Zhou ¹, Yali Ren ⁸, Lanlan Dai ⁹, Yulan Chen ⁹, Jianguo Zhang ⁹, Xun Xu ⁹, Edel A O'Toole ², David P Kelsell ¹⁰, Yong Yang ¹¹

Affiliations

1 Department of Dermatology, Peking University First Hospital, Beijing 100034, China; Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing 100034, China.
2 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.
3 Department of Genetics, University College London, London WC1E 6BT, UK.
4 Centre for Dermatology and Genetic Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK.
5 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.
6 PC Project, Salt Lake City, UT 84109, USA.
7 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.
8 Laboratory of Electron Microscopy, Peking University First Hospital, Beijing 100034, China.
9 BGI-Shenzhen, Shenzhen 518083, China.
10 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.
11 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.

PMID: 25683118 DOI: 10.1016/j.ajhg.2014.12.026

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.

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