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

Zhimiao Lin, Jiahui Zhao, Daniela Nitoiu, Claire A. Scott, Vincent Plagnol, Frances J. D. Smith, Neil J. Wilson, Christian Cole, Mary E. Schwartz, W. H. Irwin McLean, Huijun Wang, Cheng Feng, Lina Duo, Eray Yihui Zhou, Yali Ren, Lanlan Dai, Yulan Chen, Jianguo Zhang, Xun Xu, Edel A. O'TooleDavid P. Kelsell, Yong Yang

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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. Invitro 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.

Original languageEnglish
Pages (from-to)440-447
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number3
Early online date12 Feb 2015
Publication statusPublished - 5 Mar 2015

Fingerprint Dive into the research topics of 'Loss-of-function mutations in <i>CAST </i>cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads'. Together they form a unique fingerprint.

Cite this