title: KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype.
abstract: Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.|Faculty of Sciences, Charles University in Prague, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Kasparek
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Ileninova
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.
authors.forename: Olga
authors.identifier: 0000-0003-0188-1324
authors.initials: O
authors.lastname: Zbodakova
authors.affiliation: Czech Centre for Phenogenomics, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kanchev
authors.affiliation: Laboratory of Molecular Structure Characterization, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., Prague, Czech Republic.
authors.forename: Oldrich
authors.initials: O
authors.lastname: Benada
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.|Czech Centre for Phenogenomics, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Chalupsky
authors.affiliation: Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Brattsand
authors.affiliation: Czech Centre for Phenogenomics, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.
authors.forename: Inken M
authors.initials: IM
authors.lastname: Beck
authors.affiliation: Laboratory of Transgenic Models of Diseases, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.|Czech Centre for Phenogenomics, Division BIOCEV, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Vestec, Czech Republic.
authors.forename: Radislav
authors.identifier: 0000-0002-3352-392X
authors.initials: R
authors.lastname: Sedlacek
mesh_terms: D000818:Animals; D017353:Gene Deletion; D007610:Kallikreins / Q000235:genetics*; D051379:Mice; D056770:Netherton Syndrome / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015843:Serpins / Q000235:genetics
chemical_list: D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015843:Serpins; C495972:Spink5 protein, mouse; D007610:Kallikreins; C495973:Klk5 protein, mouse; C495974:Klk7 protein, mouse