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.
Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominantly inherited genodermatosis. Only seven families with NFJS are currently reported in literature. Mutations in keratin 14 (KRT14) additionally cause dermatopathia pigmentosa reticularis (DPR), a phenotypically similar disease, as well as epidermolysis bullosa simplex (EBS). Our study aimed on identification of the causative mutation in an unknown family with NFJS and gain of knowledge on genotype-phenotype correlation in KRT14. We examined a five generation family with NFJS phenotype in eight individuals. Initially, the index patient visited our clinic because of difficulties in registration of her fingerprints. Since birth she has suffered from anhidrosis and palmoplantar keratoderma. Additionally, she had had patchy hyperpigmentations which disappeared over time. Clinical investigations on further family members revealed a heterogeneous severity of phenotype in the affected family members. We isolated gDNA from patients' lymphocytes and performed Sanger sequencing of exon 1 of KRT14. By that we identified a two base pair insertion leading to a frameshift and a premature stop codon after 10 amino acids. The same mutation, which is unknown in large databases like gnomAD (123,136 exome and 15,496 whole-genome sequences), has been found in further affected family members. The correlation between the genotype and phenotype in patients with KRT14 mutation is not completely understood. We present clinical and sequence data from this family and discuss them in context of the original NFJS family as well as other descriptions in literature.
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