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- W4366171510 abstract "Keratin 9 mutations result in debilitating palmoplantar hyperkeratosis when dominantly mutated in humans, e.g. patients with the dominant-negative keratin 9 mutation p.N161S (c.482A>G) exhibit severe hyperkeratosis at baseline. In contrast, we report a previously unrecognized mono-allelic mutation of keratin 9 p.E283X (c.847G>T), generating a STOP codon without symptoms or with blisters only developing after physical stress. Therefore, monoallelic expression of wild type keratin 9 should be a feasible gene-editing goal for the severe form. We therefore tested, whether a STOP codon can be introduced into p.N161S by using a ribonucleoprotein (RNP) based double-nickase approach in patient-derived keratinocytes. After harvesting clones with an intact wild type allele and a frameshift-induced STOP codon on the mutated strand we demonstrate improved keratin 9 integrity comparable to p.E283X or wild type cells as assessed by immunofluorescence staining. Upon heat stress 90% of p.N161S keratinocytes exhibited abnormal keratin aggregates, whereas in p.E283X keratinocytes and in gene edited p.N161S keratinocytes the frequency of keratin aggregates was low. Because gene editing poses the risk of unintended insertions/deletions or translocations, we employed comprehensive CAST-Seq and NGS analyses, which did not reveal any off-target translocations or mismatches. Our results obtained in primary patient-derived cells transfected by carrier-free electroporation of double-nickase allele-specific RNPs demonstrate restoration of keratin 9 intermediate filament integrity with an excellent safety profile and major therapeutic potential." @default.
- W4366171510 created "2023-04-19" @default.
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- W4366171510 date "2023-05-01" @default.
- W4366171510 modified "2023-09-28" @default.
- W4366171510 title "803 Editing a missense to a nonsense keratin 9 gene mutation restores intermediate filament integrity" @default.
- W4366171510 doi "https://doi.org/10.1016/j.jid.2023.03.813" @default.
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