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Lookup NU author(s): Dr Magomet Aushev, Dr Bettina Burger
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© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.Ichthyosis with confetti (IWC) is a genodermatosis associated with dominant-negative variants in keratin 10 (KRT10) or keratin 1 (KRT1). These frameshift variants result in extended aberrant proteins, localized to the nucleus rather than the cytoplasm. This mislocalization is thought to occur as a result of the altered carboxy (C)-terminus, from poly-glycine to either a poly-arginine or -alanine tail. Previous studies on the type of C-terminus and subcellular localization of the respective mutant protein are divergent. In order to fully elucidate the pathomechanism of IWC, a greater understanding is critical. This study aimed to establish the consequences for localization and intermediate filament formation of altered keratin 10 (K10) C-termini. To achieve this, plasmids expressing distinct KRT10 variants were generated. Sequences encoded all possible reading frames of the K10 C-terminus as well as a nonsense variant. A keratinocyte line was transfected with these plasmids. Additionally, gene editing was utilized to introduce frameshift variants in exon 6 and exon 7 at the endogenous KRT10 locus. Cellular localization of aberrant K10 was observed via immunofluorescence using various antibodies. In each setting, immunofluorescence analysis demonstrated aberrant nuclear localization of K10 featuring an arginine-rich C-terminus. However, this was not observed with K10 featuring an alanine-rich C-terminus. Instead, the protein displayed cytoplasmic localization, consistent with wild-type and truncated forms of K10. This study demonstrates that, of the various 3′ frameshift variants of KRT10, exclusively arginine-rich C-termini lead to nuclear localization of K10.
Author(s): Renz P, Imahorn E, Spoerri I, Aushev M, March OP, Wariwoda H, Von Arb S, Volz A, Itin PH, Reichelt J, Burger B
Publication type: Article
Publication status: Published
Journal: Journal of Cellular and Molecular Medicine
Year: 2019
Volume: 23
Issue: 12
Pages: 8442-8452
Print publication date: 12/11/2019
Online publication date: 22/10/2019
Acceptance date: 06/09/2019
ISSN (print): 1582-1838
ISSN (electronic): 1582-4934
Publisher: Blackwell Publishing Inc.
URL: https://doi.org/10.1111/jcmm.14727
DOI: 10.1111/jcmm.14727
PubMed id: 31638346
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