| Title | Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads |
| Authors | Lin, Zhimiao Zhao, Jiahui Nitoiu, Daniela Scott, Claire A. Plagnol, Vincent Smith, Frances J. D. Wilson, Neil J. Cole, Christian Schwartz, Mary E. McLean, W. H. Irwin Wang, Huijun Feng, Cheng Duo, Lina Zhou, Eray Yihui Ren, Yali Dai, Lanlan Chen, Yulan Zhang, Jianguo Xu, Xun O'Toole, Edel A. Kelsell, David P. Yang, Yong |
| Affiliation | Peking Univ, Hosp 1, Dept Dermatol, Beijing 100034, Peoples R China. Beijing Key Lab Mol Diag Dermatoses, Beijing 100034, Peoples R China. Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Cutaneous Res, London E1 2AT, England. UCL, Dept Genet, London WC1E 6BT, England. Univ Dundee, Ctr Dermatol & Genet Med, Coll Life Sci & Med, Dundee DD1 5EH, Scotland. Univ Dundee, Ctr Dermatol & Genet Med, Coll Dent, Dundee DD1 5EH, Scotland. Univ Dundee, Ctr Dermatol & Genet Med, Coll Nursing, Dundee DD1 5EH, Scotland. Univ Dundee, Coll Life Sci, Div Computat Biol, Dundee DD1 5EH, Scotland. PC Project, Salt Lake City, UT 84109 USA. Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China. Peking Univ, Hosp 1, Lab Electron Microscopy, Beijing 100034, Peoples R China. BGI Shenzhen, Shenzhen 518083, Peoples R China. |
| Keywords | CALPAIN-MEDIATED PROTEOLYSIS SERINE-PROTEASE INHIBITOR ENCODING CYSTATIN-A PALMOPLANTAR KERATOSIS MISSENSE MUTATION ADHESION DYNAMICS FOCAL ADHESION APOPTOSIS MICE DERMATITIS |
| Issue Date | 2015 |
| Publisher | american journal of human genetics |
| Citation | AMERICAN JOURNAL OF HUMAN GENETICS.2015,96,(3),440-447. |
| 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. |
| URI | http://hdl.handle.net/20.500.11897/159820 |
| ISSN | 0002-9297 |
| DOI | 10.1016/j.ajhg.2014.12.026 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 第一医院 |
