title: 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.
authors.affiliation: INSERM U563, Paul Sabatier University, Place du Dr Baylac, 31059 Toulouse, cedex 3, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Descargues
authors.forename: Céline
authors.initials: C
authors.lastname: Deraison
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Bonnart
authors.forename: Maaike
authors.initials: M
authors.lastname: Kreft
authors.forename: Mari
authors.initials: M
authors.lastname: Kishibe
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.forename: Peter
authors.initials: P
authors.lastname: Elias
authors.forename: Yann
authors.initials: Y
authors.lastname: Barrandon
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D051183:Desmoglein 1; D004817:Epidermis / Q000473:pathology / Q000648:ultrastructure; D007610:Kallikreins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D012697:Serine Endopeptidases / Q000378:metabolism*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors / Q000235:genetics* / Q000378:metabolism; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D012873:Skin Diseases, Genetic / Q000378:metabolism* / Q000473:pathology
chemical_list: D015820:Cadherins; D051183:Desmoglein 1; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors; D015843:Serpins; C495972:Spink5 protein, mouse; D007610:Kallikreins; C495973:Klk5 protein, mouse; C495974:Klk7 protein, mouse; D012697:Serine Endopeptidases