title: Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides.
abstract: 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.
authors.affiliation: Department of Dermatology, School of Medicine, Kanazawa University, Kanazawa, Japan. kkomatu216@hotmail.com
authors.forename: Nahoko
authors.initials: N
authors.lastname: Komatsu
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.forename: Norio
authors.initials: N
authors.lastname: Otsuki
authors.forename: Rie
authors.initials: R
authors.lastname: Ohka
authors.forename: Osamu
authors.initials: O
authors.lastname: Amano
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Saijoh
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D002268:Carboxypeptidases / Q000378:metabolism; D002352:Carrier Proteins; D002478:Cells, Cultured; D002675:Child, Preschool; D003873:Dermatitis, Exfoliative / Q000235:genetics*; D005838:Genotype; D006201:Hair Diseases / Q000235:genetics*; D006801:Humans; D006868:Hydrolysis; D006967:Hypersensitivity / Q000235:genetics*; D007057:Ichthyosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D015603:Keratinocytes / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors / Q000502:physiology*; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013577:Syndrome; D014357:Trypsin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors; D002268:Carboxypeptidases; D014357:Trypsin