Human Molecular Genetics Advance Access published online on July 29, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg247
© 2003 by Oxford University Press
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1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
* To whom correspondence should be addressed. E-mail: alain.hovnanian{at}toulouse.inserm.fr.
SPINK5, encoding the putative multi-domain serine protease inhibitor LEKTI, was recently identified as the defective gene in the severe autosomal recessive ichthyosiform skin condition, Netherton Syndrome (NS). Using monoclonal and polyclonal antibodies, we show that LEKTI is a marker of epithelial differentiation, strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. LEKTI expression was also demonstrated in normal differentiated human primary keratinocytes (HK) through detection of a 145 kDa full-length protein and a shorter isoform of 125 kDa. Both proteins are N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least 3 C-terminal fragments of 42, 65 and 68 kDa, also identified in conditioned media. Processing of the 145 and 125 kDa precursors was prevented in HK by treatment with a furin inhibitor. In addition, in vitro cleavage of the recombinant 145 kDa precursor by furin generated C-terminal fragments of 65 and 68 kDa, further supporting the involvement of furin in LEKTI processing. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from NS patients. Defective expression of LEKTI in skin sections was a constant feature in NS patients, whilst an extended reactivity pattern was observed in samples from other keratinizing disorders, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of NS. The identification of novel processed forms of LEKTI provides the basis for future functional and structural studies of fragments with physiological relevance.
Article
LEKTI proteolytic processing in human primary keratinocytes, tissue distribution, and defective expression in Netherton syndrome
2 Immacolata Dermatological Hospital, IDI-IRCCS, Rome 00167, Italy
3 INSERM U563, Purpan Hospital, Toulouse 31059, France
4 Pellegrin Hospital for Children, Bordeaux 33076, France
5 Department of Dermatology, CHUV Beaumont Hospital, Lausanne CH1011, Switzerland
6 Great Ormond Street Hospital for Children, London WC1N 3JH, UK
7 Department of Dermatology, Necker Hospital, Paris 71015, France
8 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; INSERM U563, Purpan hospital, Place du Dr Baylac, 31059 Toulouse cedex 3, France
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