1. ^*Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan
2. ^†Department of Genetics, INSERM U563 and Université Paul Sabatier, Purpan Hospital, Toulouse, France
3. ^‡Department of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford, UK
4. ^§Department of Obstetrics and Gynecology, University of Arkansas for Medical Science, Arkansas, USA
5. ^¶Genetic Skin Disease Group, St John's Institute of Dermatology, GKT Medical school, St Thomas' Hospital, London, UK
6. ^#Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA

Correspondence: Dr Akemi Ishida-Yamamoto, Department of Dermatology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan. Email: akemi@asahikawa-med.ac.jp

Received 12 June 2004; Revised 28 September 2004; Accepted 30 September 2004; Published online 19 January 2005.

Abstract

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a putative serine protease inhibitor encoded by serine protease inhibitor Kazal-type 5 (SPINK5). It is strongly expressed in differentiated keratinocytes in normal skin but expression is markedly reduced or absent in Netherton syndrome (NS), a severe ichthyosis caused by SPINK5 mutations. At present, however, both the precise intracellular localization and biological roles of LEKTI are not known. To understand the functional role of LEKTI, we examined the localization of LEKTI together with kallikrein (KLK)7 and KLK5, possible targets of LEKTI, in the human epidermis, by confocal laser scanning microscopy and immunoelectron microscopy. In normal skin, LEKTI, KLK7, and KLK5 were all found in the lamellar granule (LG) system, but were separately localized. LEKTI was expressed earlier than KLK7 and KLK5. In NS skin, LEKTI was absent and an abnormal split in the superficial stratum granulosum was seen in three of four cases. Collectively, these results suggest that in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion. Our data provide new insights into the biological functions of LG and the pathogenesis of NS.