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KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype
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SYSNO ASEP 0483740 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype Author(s) Kašpárek, Petr (UMG-J)
Ileninová, Zuzana (UMG-J)
Žbodáková, Olga (UMG-J)
Kanchev, Ivan (UMG-J) RID
Benada, Oldřich (MBU-M) ORCID, RID
Chalupský, Karel (UMG-J)
Brattsand, M. (SE)
Beck, Inken (UMG-J) RID
Sedláček, Radislav (UMG-J) RIDNumber of authors 9 Article number e1006566 Source Title PLoS Genetics. - : Public Library of Science - ISSN 1553-7404
Roč. 13, č. 1 (2017)Number of pages 21 s. Language eng - English Country US - United States Keywords corneum chymotryptic enzyme ; serine-protease inhibitor ; skin barrier function ; mouse model ; hair-follicle ; subtilisin-a ; lekti ; kallikrein ; expression ; mice Subject RIV EB - Genetics ; Molecular Biology OECD category Microbiology Subject RIV - cooperation Institute of Microbiology - Microbiology, Virology R&D Projects ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2011032 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LO1509 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UMG-J - RVO:68378050 ; MBU-M - RVO:61388971 UT WOS 000394147700035 DOI https://doi.org/10.1371/journal.pgen.1006566 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2018
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