{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTransglutaminase 5 (TG5), encoded by the TGM5 gene, is a calcium‐dependent enzyme that plays a critical role in terminal epidermal differentiation. TG5 mediates the cross‐linking of structural proteins in the epidermal granular cells to form the cornified cell envelope, a process essential for cell–cell adhesion and maintenance of the skin barrier. Mutations, such as the recurrent G113C variant, compromise TG5 activity and have been implicated in acral peeling skin syndrome (APSS), a disorder characterized by superficial epidermal separation (‐."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical analyses indicate that the full-length TG5 exhibits low cross-linking activity until it is proteolytically processed into a more active 53‐kDa form. Post-translational modifications, including N-terminal acetylation, along with the presence of regulatory motifs such as GTP binding domains, further modulate its function. Moreover, overexpression studies have shown that intracellular TG5 activity can induce cell death, suggesting that precise regulation of its enzymatic activity is crucial for skin homeostasis. These observations underscore TG5’s involvement in the final steps of keratinocyte differentiation and its potential broader role in epidermal biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther insights into TG5’s role have emerged from studies on skin disorders, where compensatory upregulation of other epidermal differentiation markers (including keratins, involucrin, loricrin, and corneodesmosin) is observed in the context of TGM5 deficiency. Such findings highlight the enzyme’s importance in sustaining epidermal integrity and the possibility of inter-pathway modulation, as seen in cases where mutations in ALOXE3 can suppress the clinical manifestation of TGM5-related APSS. In addition, genetic association studies have begun to explore TGM5 variants in non-skin conditions, such as their potential link with non-small cell lung cancer susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrew J Cassidy, Maurice A M van Steensel, Peter M Steijlen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2012.166"}], "href": "https://doi.org/10.1038/jid.2012.166"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22622422"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22622422"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "W Szczecinska, D Nesteruk, K Wertheim-Tysarowska, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Inactive and highly active, proteolytically processed transglutaminase-5 in epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jid.2008.146"}], "href": "https://doi.org/10.1038/jid.2008.146"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18509357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18509357"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Agne Liedén, Mårten C G Winge, Annika Sääf, et al. 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