A novel homozygous nonsense mutation in CAST associated with PLACK syndrome

• Published in: Cell and tissue research Vol. 378; no. 2; pp. 267 - 277
• Main Authors: Temel, Şehime Gülsün, Karakaş, B., Şeker, Ü., Turkgenç, B., Zorlu, Ö., Sarıcaoğlu, H., Oğur, Ç., Kütük, Ö., Kelsell, D. P., Yakıcıer, M. C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2019; Springer; Springer Nature B.V
• Subjects: Adult; Atrophy; Biomedical and Life Sciences; Biomedicine; Calcium-Binding Proteins - genetics; Calpain; Calpastatin; Child, Preschool; Codon, Nonsense - genetics; Dermatitis, Exfoliative - genetics; DNA sequencing; Ethylenediaminetetraacetic acid; Female; Fibroblasts; Heredity; Homozygote; Human Genetics; Humans; Male; Medical colleges; Methylene blue; Molecular Medicine; Mutation; Nonsense mutation; Nucleotide sequencing; Proteolysis; Proteomics; Regular Article; Skin; Skin - metabolism; Skin - pathology; Skin Diseases, Genetic - genetics; Calpastatin; Peeling skin syndrome; PLACK syndrome; Whole exome sequencing; gene; CAST gene
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-019-03077-9

Peeling skin syndrome is a heterogeneous group of rare disorders. P eeling skin, l eukonychia, a cral punctate keratoses, c heilitis and k nuckle pads (PLACK syndrome, OMIM616295) is a newly described form of PSS with an autosomal recessive mode of inheritance. We report a 5.5-year-old boy with features of PLACK syndrome. Additionally, he had mild cerebral atrophy and mild muscle involvements. Whole exome sequencing was performed in genomic DNA of this individual and subsequent analysis revealed a homozygous c.544G > T (p.Glu182*) nonsense mutation in the CAST gene encoding calpastatin. Sanger sequencing confirmed this variant and demonstrated that his affected aunt was also homozygous. Real-time qRT-PCR and immunoblot analysis showed reduced calpastatin expression in skin fibroblasts derived from both affected individuals compared to heterozygous family members. In vitro calpastatin activity assays also showed decreased activity in affected individuals. This study further supports a key role for calpastatin in the tight regulation of proteolytic pathways within the skin.