TGM5 encodes transglutaminase 5 (TG5), a protein cross-linking enzyme that plays a critical role in epidermal barrier formation and maintenance. TG5 catalyzes the cross-linking of structural proteins during terminal keratinocyte differentiation, contributing to the formation of the cornified cell envelope 1. The enzyme is strongly expressed in epidermal granular cells and is essential for maintaining cell-cell adhesion between the outermost epidermal layers 1. Functionally, TG5 performs vital protein cross-linking activities that stabilize the epidermal barrier at the junction between the stratum granulosum and stratum corneum 2. Loss-of-function mutations in TGM5 cause acral peeling skin syndrome (APSS), a rare autosomal recessive disorder characterized by superficial blistering and peeling of hands and feet 34. The most common pathogenic mutation, p.Gly113Cys, completely abolishes TG5 enzymatic activity and occurs frequently in European populations as a founder mutation 13. When TGM5 is deficient, keratinocytes upregulate compensatory mechanisms including increased expression of other structural proteins like corneodesmosin, keratin 1, keratin 10, involucrin, and loricrin to maintain epidermal barrier integrity 45. APSS is often misdiagnosed as localized epidermolysis bullosa simplex, highlighting the importance of TGM5 mutation screening in differential diagnosis 3.