In a 28-year-old man (IWC100) with ichthyosis with confetti (IWC; 609165), Lim et al. (2016) identified heterozygosity for a de novo 1-bp deletion (c.1373delG) at the last base of exon 6 of the KRT10 gene, causing a frameshift that replaced the endogenous glycine-rich tail domain of keratin-10 with an alanine-rich motif that extended the C terminus by 19 additional amino acids. Immunolocalization in affected skin showed an overall reduction in suprabasal K10 staining, with evidence of filament network collapse and focal aggregates within the nucleus; these findings were not seen in revertant or normal control skin. Costaining with a nucleolar marker revealed K10 aggregates within the nucleolus. Immunolocalization of the KRT10 binding partner KRT1 (139350) also demonstrated nuclear mislocalization. Laser-capture microdissection of 3 white spots revealed that each revertant spot harbored copy-neutral loss of heterozygosity in the proximal q arm of chromosome 17 extending to the telomere, consistent with reversion via mitotic recombination. For all 3 revertant spots, the region of crossover was estimated to fall between SNPs rs6505079 and rs8078229.
Renz et al. (2019) stated that the correct designation for this mutation is c.1373+1delG. Analysis of NKc21 keratinocytes transfected with the variant from patient IWC100 revealed 5 different splicing products, including 3 that encoded K10 with an arginine tail (K10arg), 1 that encoded a truncated K10 protein, and a minor transcript encoding K10 with an alanine tail (K10ala). Immunofluorescence analysis demonstrated aberrant nuclear localization of K10arg but not of K10ala; however, the presence of K10arg was shown to enable cotranslocation of non-K10arg, including wildtype or truncated K10, into the nucleus. The authors concluded that arginine-rich, rather than alanine-rich, K10 tails are responsible for the pathogenic nuclear localization of K10 in patients with IWC.
