ArticleAmerican journal of human genetics2015
Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads.
Article in American journal of human genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 48 citations in OpenAlex.
- Whole exome sequencing identifies a novel dominant missense mutation underlying leukonychia in a Pakistani family.Journal of human genetics · 2018Trial
- Leukonychia and peeling skin in an 11-year-old girl.JAAD case reports · 2026Article
- Proteolytic dysregulation in the skin: insight from rare monogenic skin diseases.Cell and tissue research · 2026Review
- Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.Clinical, cosmetic and investigational dermatology · 2026Article
- Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene.Genes · 2025Article
- Genomic analysis of mobility measures on 5-month-old gilts associated with structural soundness.Journal of animal science · 2025Article
- Genetic Findings in Short Turkish Children Born to Consanguineous Parents.Hormone research in paediatrics · 2025Observational
- Calpain Regulation and Dysregulation-Its Effects on the Intercalated Disk.International journal of molecular sciences · 2023Review
- Thermostable Proteins from HaCaT Keratinocytes Identify a Wide Breadth of Intrinsically Disordered Proteins and Candidates for Liquid-Liquid Phase Separation.International journal of molecular sciences · 2022Article
- Leukonychia: What Can White Nails Tell Us?American journal of clinical dermatology · 2022Review
- Acral peeling in Nagashima type palmo-plantar keratosis patients reveals the role of serine protease inhibitor B 7 in keratinocyte adhesion.Experimental dermatology · 2022Article
- Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity.Frontiers in molecular neuroscience · 2022Review
- Targeted inhibition of endothelial calpain delays wound healing by reducing inflammation and angiogenesis.Cell death & disease · 2020Article
- Pseudoaneurysm rupture presenting as bleeding from the cannulation site in a paediatric patient with dilated cardiomyopathy and congenital skin lesions requiring EXCOREuropean heart journal. Case reports · 2020Article
- Diagnosis and Management of Inherited Palmoplantar Keratodermas.Acta dermato-venereologica · 2020Review
- Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions.American journal of human genetics · 2016Article
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Authors and funding
22 authors at 6 institutions in 3 countries.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.