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Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity

Abstract

Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5−/− mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme–like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.

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Figure 1: Gene targeting of Spink5.
Figure 2: Anomalies in Spink5−/− mice epidermis and vibrissae.
Figure 3: Ichthyosiform phenotype of transplanted skin from Spink5−/− mice.
Figure 4: Skin barrier defect in Spink5−/− mice.
Figure 5: Ultrastructural anomalies in Spink5−/− mice.
Figure 6: Immunohistochemical analysis of epidermal markers and desmosomal proteins.
Figure 7: Relative expression levels of epidermal differentiation markers and desmosomal proteins.
Figure 8: Epidermal protease analysis.

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Acknowledgements

We thank P. Krimpenfort and R. Bin Ali for carrying out the blastocyst injections; B. Payre, I. Fourquaux and D. Crumrine for technical assistance for ultrastructural analyses; F. Capilla and D. Rosi for carrying out immunohistochemical analyses; L. Lamant for expertise in histopathological analysis; F. Galliano for participation in the targeting strategy; and V. Turlier for advice on TEWL measurements. This work was supported by grants from the Fondation pour la Recherche Médicale and the INSERM. P.D. was a recipient of a grant from the French Ministry of Research and Technology.

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Correspondence to Alain Hovnanian.

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Supplementary Fig. 1

Quantitative assessment of transcript levels in Spink5−/− mice skin. (PDF 83 kb)

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Descargues, P., Deraison, C., Bonnart, C. et al. Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 37, 56–65 (2005). https://doi.org/10.1038/ng1493

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