cathepsin-g and Skin-Diseases

Generalized pustular psoriasis (GPP) is an autoinflammatory skin disease whose pathogenesis has not yet been fully elucidated. Alpha-1-antichymotrypsin(ACT) is a protein encoded by the SERPINA3 gene and an inhibitor of cathepsin G. One study of a European sample suggested that the loss of ACT function caused by SERPINA3 mutation is implicated in GPP. However, the role of SERPINA3 in the pathogenesis of GPP in other ethnic populations is unclear. To explore this, seventy children with GPP were performed next-generation sequencing to identify rare variants in the SERPINA3 gene. Bioinformatic analysis and functional tests were used to determine the effects of the variants, and a comprehensive analysis was performed to determine the pathogenicity of the variants and whether they are associated with GPP. One rare deletion and three rare missense variants were identified in the SERPINA3 gene in GPP. The deletion variant c.1246_1247del was found to result in a mutant protein with an extension of 10 amino acids and a C-terminal of 20 amino acids that was completely different from the wild-type. This mutant was found to impede secretion of ACT, thus failing to function as an inhibitor of cathepsin G. Two missense variants were found to reduce the ability of ACT to inhibit cathepsin G enzymatic activity. The association analysis suggested that the deletion variant is associated with GPP. This study identified four rare novel mutations of SERPINA3 and demonstrated that three of these mutations result in loss of function, contributing to the pathogenesis of pediatric-onset GPP in the Asian population.

Topics: Cathepsin G; Child; Humans; Interleukins; Mutation; Psoriasis; Serpins; Skin Diseases

Mid-dermal elastolysis (MDE) is a particular elastic tissue disorder in which selective loss of elastic fibres occurs in the mid-dermis. It is clinically characterized by the appearance of fine wrinkling of the epidermis and perifollicular protrusion which gives the skin an aged appearance. It is sometimes associated with an inflammatory event such as urticaria while other cases are regarded as idiopathic. The pathogenesis of MDE is still obscure. Some authors have underlined the role of macrophage activation and others have imputed UV radiation. We report here a typical case of MDE arising after several attacks of solar urticaria. Electron microscopic and biochemical studies were carried out. Ultrastructural examination showed active elastophagocytosis by macrophages and mast cells, often degranulated, near phagocytosing cells. Biochemical studies demonstrated that fibroblasts derived from lesional skin of the MDE patient produced high levels of elastase and cathepsin G compared with fibroblasts from a healthy sex- and age-matched control. Phagocytosis of morphologically normal elastic tissue is a noticeable characteristic feature of MDE. In our case mast-cell activation and the abnormal synthesis and/or release of fibroblast elastolytic enzymes seemed to play a role in the pathogenesis of the MDE.

Topics: Adult; Cathepsin G; Cathepsins; Cells, Cultured; Elasticity; Female; Fibroblasts; Humans; Microscopy, Electron; Pancreatic Elastase; Radiation Injuries; Reference Values; Serine Endopeptidases; Skin; Skin Aging; Skin Diseases; Sunlight; Urticaria