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Article
Nature Genetics  37, 56 - 65 (2004)
Published online: 26 December 2004; | doi:10.1038/ng1493

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

Pascal Descargues1, Céline Deraison1, Chrystelle Bonnart1, Maaike Kreft2, Mari Kishibe3, Akemi Ishida-Yamamoto3, Peter Elias4, Yann Barrandon5, Giovanna Zambruno6, Arnoud Sonnenberg2 & Alain Hovnanian1, 7

1  INSERM U563, Paul Sabatier University, Place du Dr Baylac, 31059 Toulouse, cedex 3, France.

2  The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

3  Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510, Japan.

4  Department of Dermatology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.

5  Laboratory of Stem Cell Dynamics, School of Life Sciences, Swiss Federal Institute of Technology, AAB building, 1015 Lausanne, Switzerland.

6  Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata, IRCCS Via Monti di Creta 104 00167 Roma, Italy.

7  Department of Medical Genetics, Purpan Hospital, 31059 Toulouse, cedex 3, France.

Correspondence should be addressed to Alain Hovnanian alain.hovnanian@toulouse.inserm.fr
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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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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