Netherton syndrome is a congenital
ichthyosis associated with
erythroderma, hair shaft defects, and atopic features. The mutations of the secretory
serine protease inhibitor Kazal-type 5 gene have been identified in
Netherton syndrome patients; however, the actual physiologic substrates of the
serine protease inhibitor Kazal-type 5 proprotein are unknown, and how the genetic defects cause characteristic skin phenotype remains uncertain. Here, we describe the
serine protease inhibitor Kazal-type 5 gene mutations, including two novel non-sense mutations, and genotype-phenotype correlation in three
Netherton syndrome patients in two unrelated Japanese families. Furthermore, based on the reappraisal of the structure of the
serine protease inhibitor Kazal-type 5 proprotein, demonstration of the presence of
carboxypeptidase in normal keratinocytes, and the observation of
mRNA localization of the
serine protease inhibitor Kazal-type 5 transcripts in the uppermost epidermis as well as pilosebaceous units, we propose a hypothetical model of proteolytic processing of the
serine protease inhibitor Kazal-type 5 proprotein in the epidermis and inhibitory regulation of corneocyte desquamation by a set of
serine protease inhibitor Kazal-type 5-derived
peptides. This hypothesis is supported by the marked increase of
trypsin-like hydrolytic activity demonstrated in stratum corneum samples from our
Netherton syndrome patients. The findings in this study suggest that the defective inhibitory regulation of desquamation due to the
serine protease inhibitor Kazal-type 5 gene mutations may cause over-desquamation of corneocytes in
Netherton syndrome, leading to severe skin permeability barrier dysfunction.