Arginine- but not alanine-rich carboxy-termini trigger nuclear translocation of mutant keratin 10 in ichthyosis with confetti

J Cell Mol Med. 2019 Dec;23(12):8442-8452. doi: 10.1111/jcmm.14727. Epub 2019 Oct 22.


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.

Keywords: KRT10; alanine-rich C-terminus; arginine-rich C-terminus; carboxy terminus; ichthyosis with confetti; keratin 10; nuclear localization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Alanine / genetics
  • Alanine / metabolism
  • Arginine / genetics*
  • Arginine / metabolism
  • Cell Line
  • Cell Nucleus / genetics*
  • Cell Nucleus / metabolism
  • Exons / genetics
  • Frameshift Mutation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Ichthyosiform Erythroderma, Congenital / genetics*
  • Ichthyosiform Erythroderma, Congenital / metabolism
  • Ichthyosiform Erythroderma, Congenital / pathology
  • Keratin-10 / chemistry
  • Keratin-10 / genetics*
  • Keratin-10 / metabolism
  • Keratinocytes / metabolism
  • Microscopy, Confocal
  • Mutation*


  • Green Fluorescent Proteins
  • Keratin-10
  • Arginine
  • Alanine