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A novel homozygous nonsense mutation in CAST associated with PLACK syndrome

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Abstract

Peeling skin syndrome is a heterogeneous group of rare disorders. Peeling skin, leukonychia, acral punctate keratoses, cheilitis and knuckle 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.

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Acknowledgments

The authors wish to express their gratitude to the family members for participating in this study and Prof. Dr. Esin ASAN for her valuable comments on semithin sections and electronmicrographs and TUBITAK-IGBAM for exome sequencing and bioinformatic advice.

Funding

This work was supported by the Uludag University Scientific Research Unit with Project number KUAP(T)-2014/36.

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Correspondence to Şehime Gülsün Temel.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants and their guardians for whom identifying information is included in this article.

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This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Part of this research was presented as a poster presentation at the American Academy of Dermatology Annual Meeting 2018, San Diego and the abstract was published in the Journal of American Academy Dermatology (JAAD) (2018): Volume 79, Issue 3, Supplement 1, Page AB16, DOI: https://doi.org/10.1016/j.jaad.2018.05.108.

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Temel, Ş.G., Karakaş, B., Şeker, Ü. et al. A novel homozygous nonsense mutation in CAST associated with PLACK syndrome. Cell Tissue Res 378, 267–277 (2019). https://doi.org/10.1007/s00441-019-03077-9

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