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. Epub 2015 Feb 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / genetics
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Cell Adhesion / genetics
  • Cheilitis / genetics*
  • Epidermis / metabolism
  • Female
  • Homozygote
  • Humans
  • In Situ Nick-End Labeling
  • Keratinocytes
  • Keratosis / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Nail Diseases / genetics*
  • Pedigree
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Skin / pathology
  • Skin Diseases / genetics*


  • Calcium-Binding Proteins
  • RNA, Small Interfering
  • calpastatin