1. ¹Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
2. ²Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
3. ³Department of Dermatology, Graduate School of Medical Science, School of Medicine, Kanazawa University, Kanazawa, Japan
4. ⁴Department of Hygiene, Graduate School of Medical Science, School of Medicine, Kanazawa University, Kanazawa, Japan
5. ⁵Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
6. ⁶Department of Dermatology, Ehime University School of Medicine, Ehime, Japan
7. ⁷Department of Dermatology, School of Medicine, Juntendo University, Tokyo, Japan
8. ⁸Department of Dermatology, Yamanashi Prefectural Central Hospital, Kofu, Japan
9. ⁹Department of Dermatology, Maizuru Kyousai Hospital, Maizuru, Japan

Correspondence: Dr Eleftherios P. Diamandis, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 6th Floor, Room m6-201, 60 Murray Street, Toronto, Ontario, Canada M5T 3L9. E-mail: ediamandis@mtsinai.on.ca

Received 21 February 2007; Revised 28 August 2007; Accepted 31 August 2007; Published online 8 November 2007.

Abstract

Netherton syndrome (NS) is a congenital ichthyosiform dermatosis caused by serine protease inhibitor Kazal-type 5 (SPINK5) mutations. Tissue kallikreins (KLKs) and lymphoepithelial Kazal-type-related inhibitor (LEKTI) (SPINK5 product) may contribute to the balance of serine proteases/inhibitors in skin and influence skin barrier function and desquamation. SPINK5 mutations, causing NS, lead to truncated LEKTI; each NS patient possesses LEKTI of a different length, depending on the location of mutations. This study aims to elucidate genotype/phenotype correlations in Japanese NS patients and to characterize the functions of each LEKTI domain. Since we were unable to demonstrate truncated proteins in tissue from patients with NS, we used recombinant protein to test the hypothesis that the length of LEKTI correlated with protease inhibitory activity. Genotype/phenotype correlations were observed with cutaneous severity, growth retardation, skin infection, stratum corneum (SC) protease activities, and KLK levels in the SC. Predominant inhibition by LEKTI domains against overall SC protease activities was trypsin-like (Phe-Ser-Arg-) activity by LEKTI domains 6–12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 12–15, chymotrypsin-like activity by all domains, and furin-like activity by none. KLK levels were significantly elevated in the SC and serum of NS patients. These data link LEKTI domain deficiency and clinical manifestations in NS patients and pinpoints to possibilities for targeted therapeutic interventions.