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Human Molecular Genetics Advance Access originally published online on July 29, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 19 2417-2430
DOI: 10.1093/hmg/ddg247
© 2003 Oxford University Press

LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome

Emmanuelle Bitoun1,{dagger}, Alessia Micheloni2,{dagger}, Laurence Lamant3, Chrystelle Bonnart3, Alessandro Tartaglia-Polcini2, Christian Cobbold1, Talal Al Saati3, Feliciana Mariotti2, Juliette Mazereeuw-Hautier3, Franck Boralevi4, Daniel Hohl5, John Harper6, Christine Bodemer7, Marina D'Alessio2 and Alain Hovnanian1,3,*

1Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK, 2Immacolata Dermatological Hospital, IDI-IRCCS, Rome 00167, Italy, 3INSERM U563, Purpan Hospital, Toulouse 31059, France, 4Pellegrin Hospital for Children, Bordeaux 33076, France, 5Department of Dermatology, CHUV Beaumont Hospital, Lausanne CH1011, Switzerland, 6Great Ormond Street Hospital for Children, London WC1N 3JH, UK and 7Department of Dermatology, Necker Hospital, Paris 71015, France

Received April 25, 2003; Accepted July 16, 2003

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 three 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.

* To whom correspondence should be addressed at: INSERM U563, Purpan Hospital, Place du Dr Baylac, 31059 Toulouse cedex 3, France. Tel: +33 561158432; Fax: +33 561499036; Email: alain.hovnanian{at}toulouse.inserm.fr

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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