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.

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

“…One of the proteases that has been suggested to be implicated in profilaggrin processing is the stratum corneum chymotryptic enzyme (SSCE) 31,32 , which is possibly regulated by the serine protease inhibitor LETKI, encoded by SPINK5 [32][33][34] . Interestingly, an insertion in the 3′ untranslated region of the kallikrein 7 gene (KLK7) encoding SCCE 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 35 has been reported to be associated with eczema.…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…157,158 In recent years, it has become evident that this most critical SC functionethe permeability barriereis impaired in most ichthyosis forms. 11,60,[159][160][161][162][163][164] Several murine knockout models for ichthyosis [Spink5 (e/e), Tgm1 (e/e), Abca12 (e/e) mice, [165][166][167] Alox12b (e/e), 168 Cldn1(e/e) 169 ] have demonstrated neonatal lethality as a result of dehydration, underscoring the critical role of these genes in permeability barrier competence. Mutations that either alter the lipid composition of the SC membranesedisorders of lipid metabolismeor affect the function of the corneocyte structural proteinsedisorders of keratinocyte proteinseresult in increased water movement through the intercellular pathway.…”

“…89 Detachment of the SC from the SG with asymmetric cleavage of corneodesmosomes is a specific feature of NS. 165,212 The image of the SC as viewed by conventional EM is still artifactual. In frozen sections, where lipid extraction is avoided, eg, by hydrophilic staining procedures, the compact structure of the SC can be appreciated.…”

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

“…Synthesized as a large (145 kD) polypro tein containing 15 Kazal domains, LEKTI is cleaved by furin to liberate a series of smaller fragments comprising one or more inhibitory units that target distinct protease subsets (Bitoun et al, 2003;Fortugno et al, 2011). LEKTI of rapid dehydration (Yang et al, 2004;Descargues et al, 2005;Hewett et al, 2005).…”