TGM1

TGM1 (transglutaminase 1) encodes a membrane-associated, calcium-dependent transglutaminase that catalyzes protein crosslinking during terminal keratinocyte differentiation and is essential for formation of the epidermal cornified cell envelope, a structure required for skin barrier integrity^[1][2]. Mechanistically, TGM1 promotes covalent crosslinking of structural proteins including involucrin, loricrin, small proline-rich proteins, desmosomal proteins, and trichohyalin, while also contributing to the attachment of ω-hydroxyceramides to the cornified envelope, thereby integrating protein and lipid components of the epidermal barrier^[2][3][4]. Through these activities, TGM1 regulates epidermal cornification, permeability barrier formation, and prevention of transepidermal water loss^[1][4][5]. Deficiency of TGM1 disrupts cornified envelope assembly, alters intercellular lipid organization, and impairs barrier function, resulting in severe epidermal abnormalities in both human disease and experimental models^[3][5][6]. Clinically, TGM1 mutations represent a major genetic cause of autosomal recessive congenital ichthyosis, particularly lamellar ichthyosis, where loss of enzymatic activity leads to hyperkeratosis, scaling, dehydration risk, and defective epidermal differentiation^[4][6][7]. In disease-model systems, TGM1-deficient keratinocytes and knockout mice reproduce key pathological features of lamellar ichthyosis and therefore provide valuable platforms for studying epidermal barrier biology and therapeutic development^[5][7]. Compared with other members of the transglutaminase family, TGM1 is distinguished by its predominant role in cornified envelope assembly and epidermal barrier maturation, making it a central target for mechanistic studies of skin cornification disorders^[1][2]. For experimental applications, gene-replacement approaches and TGM1 restoration strategies have been investigated as potential methods to recover barrier function in TGM1-deficient lamellar ichthyosis models^[7][8].