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.

PLACK syndrome shows remarkable phenotypic homogeneity

“…Other forms of PSS are associated with systemic manifestations, such as SAM syndrome (MIM615508) or Netherton syndrome (MIM256500) . More recently, a complex phenotype termed PLACK ( p eeling skin, l euconychia, a cral punctate keratosis, c heilitis and k nuckle pads) syndrome has been shown to result from loss‐of‐function mutations in CAST , the gene encoding calpastatin, a specific inhibitor of calpains, which function as a calcium‐dependent cysteine proteases …”

“…PLACK syndrome seems to be associated with genetic homogeneity, as all causative mutations reported to date in this rare disorder are loss‐of‐function mutations in CAST (Fig. c) , encoding calpastatin, a calpain inhibitor . Calpains are calcium‐dependent intracellular cysteine proteases normally expressed in human skin.…”

“…Calpains are calcium‐dependent intracellular cysteine proteases normally expressed in human skin. They have been shown to play an important role in the regulation of keratinocyte proliferation, epidermal differentiation and cornification, cell cycle regulation and apoptosis . Downregulation of CAPN12 , encoding calpain 12, which is predominantly expressed in the skin, has recently been shown to aggravate the clinical manifestations of ABCA12 mutations associated with autosomal recessive congenital ichthyosis, emphasizing the pivotal role played by calpains in normal epidermal differentiation …”

“…The present study, when considered collectively with previous cases reported in the literature, points to the existence of a core of remarkably reliable disease‐defining clinical features (Table ), sometimes associated with unusual features such as conjunctival injection as seen in this and a previous report.…”

Whole exome sequencing identifies a novel dominant missense mutation underlying leukonychia in a Pakistani family

“…Leukonychia in syndromic condition has also been reported in a number of studies [11,18,19]. A familial Bart-Pumphrey Syndrome-associated leukonychia was described, co-segregating with autosomal recessive missense mutation in Gap junction beta-2 (GJB2) gene [18].…”