1. ¹Dienst Dermatologie, Academisch Ziekenhuis-Vrije Universiteit Brussel, Brussels, Belgium
2. ²Dermatology Research, UCSF, San Francisco, California, USA
3. ³Arexis AB, Gothenburg, Sweden
4. ⁴Dermatology, University of Innsbruck, Innsbruck, Austria
5. ⁵Medical Genetics, AZ-VUB, Brussels, Belgium
6. ⁶Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Texas, USA
7. ⁷Dermatology, University of Umea, Umea, Sweden

Correspondence: Dr Jean-Pierre Hachem, Dienst Dermatologie and Toxicologie, Academisch Ziekenhuis-Vrije Universiteit Brussel, Laarbeeklaan 101, Brussel 1090, Belgium. E-mail: jeanpierre.hachem@az.vub.ac.be

Received 30 November 2005; Revised 24 January 2006; Accepted 7 February 2006; Published online 6 April 2006.

Abstract

Mutations in the SPINK5 gene encoding the serine protease (SP) inhibitor, lymphoepithelial-Kazal-type 5 inhibitor (LEKTI), cause Netherton syndrome (NS), a life-threatening disease, owing to proteolysis of the stratum corneum (SC). We assessed here the basis for phenotypic variations in nine patients with "mild", "moderate", and "severe" NS. The magnitude of SP activation correlated with both the barrier defect and clinical severity, and inversely with residual LEKTI expression. LEKTI co-localizes within the SC with kallikreins 5 and 7 and inhibits both SP. The permeability barrier abnormality in NS was further linked to SC thinning and proteolysis of two lipid hydrolases (-glucocerebrosidase and acidic sphingomyelinase), with resultant disorganization of extracellular lamellar membranes. SC attenuation correlated with phenotype-dependent, SP activation, and loss of corneodesmosomes, owing to desmoglein (DSG)1 and desmocollin (DSC)1 degradation. Although excess SP activity extended into the nucleated layers in NS, degrading desmosomal mid-line structures with loss of DSG1/DSC1, the integrity of the nucleated epidermis appears to be maintained by compensatory upregulation of DSG3/DSC3. Maintenance of sufficient permeability barrier function for survival correlated with a compensatory acceleration of lamellar body secretion, providing a partial permeability barrier in NS. These studies provide a mechanistic basis for phenotypic variations in NS, and describe compensatory mechanisms that permit survival of NS patients in the face of unrelenting SP attack.