Netherthon syndrome (NS) is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding Lymphoepithelial Kazal-Type-related Inhibitor (LEKTI). LEKTI deficiency results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7 and KLK14. While the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to NS pathogenesis remain unknown. 
In this study, we generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in the stratum granulosum. The hair of TghKLK14 mice did not grow and hair follicles were hyperplastic when hKLK14 was overexpressed. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley’s layer. Dsg2 staining was increased while Dsg3 and Dsg4 expression was markedly reduced. In vitro studies showed that hKLK14 directly cleaves rhDSG3 and rhDSG4, suggesting that their degradation contributes to hair abnormalities. TghKLK14 mice displayed epidermal hyperproliferation and abnormal differentiation. Their skin showed an inflammatory signature, with enhanced expression of Il-36 family members and downstream targets involved in innate immunity. Immune cell infiltrates including eosinophils, mast cells, Cd4+ cells and Cd3+ cells were present. This in vivo study identifies KLK14 as an important contributor to hair defects, epidermal differentiation abnormalities and skin inflammation seen in NS.

Transgenic kallikrein 14 mice display major hair defects associated with desmoglein 3 and 4 degradation and an inflammatory signature