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Investigations into the filaggrin null phenotype: showcasing the methodology for CRISPR/Cas9 editing of human keratinocytes.
Journal of Investigative Dermatology 2023 March 8
Ever since the association between filaggrin (FLG) loss-of-function mutations and ichthyosis vulgaris and atopic dermatitis disease onset was identified, filaggrins function has been under investigation. Intra-individual genomic predisposition, immunological confounders, and environmental interactions complicate the comparison between FLG genotypes and related causal effects. Using CRISPR/Cas9, we generated human FLG knockout (ΔFLG) N/TERT-2G keratinocytes. Filaggrin deficiency was demonstrated by immunohistochemistry of human epidermal equivalent (HEE) cultures. Next to (partial) loss of structural proteins (IVL, HRNR, KRT2, and TGM1), the stratum corneum was more dense and lacked the typical basket weave appearance. In addition, electrical impedance spectroscopy and transepidermal water loss analyses highlighted a compromised epidermal barrier in ΔFLG-HEEs. Correction of FLG reinstated the presence of keratohyalin granules in the stratum granulosum, filaggrin protein expression, and expression of aforementioned proteins. The beneficial effects on stratum corneum formation were reflected by normalization of EIS and TEWL. This study demonstrates the causal phenotypical and functional consequences of filaggrin deficiency, indicating filaggrin is not only central in epidermal barrier function but also vital for epidermal differentiation by orchestrating the expression of other important epidermal proteins. These observations pave the way to fundamental investigations into the exact role of filaggrin in skin biology and disease.
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