{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSialic acid acetylesterase (SIAE) functions as a critical negative regulator of B lymphocyte receptor signaling, thereby helping to maintain immunological tolerance. Evidence from murine models and human genetic studies demonstrates that loss‐of‐function and functionally defective SIAE variants can act in a dominant negative manner, and have been associated with increased susceptibility to various autoimmune disorders such as rheumatoid arthritis, type I diabetes, and anti‐PIT-1 antibody syndrome. In these studies, defective SIAE alleles were enriched in autoimmune subjects, suggesting that even heterozygous mutations have significant functional impact. However, results are heterogeneous—while some studies demonstrate a strong genetic link between defective variants and autoimmunity, others in diseases such as Graves’ disease, certain populations of rheumatoid arthritis patients, and juvenile idiopathic arthritis have not confirmed such associations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in immune tolerance, SIAE’s enzymatic activity—specifically its ability to deacetylate sialic acids—affects the composition and function of cell surface glycoconjugates, thereby influencing cell signaling thresholds. In the context of childhood acute lymphoblastic leukemia, decreased SIAE activity correlates with enhanced levels of 9-O-acetylated sialoglycoproteins, a hallmark of the disease that likely contributes to aberrant signaling. Similarly, placental studies have identified an upregulation of SIAE expression in preeclampsia, suggesting that perturbations in SIAE activity may also affect placental function and vascular remodeling via immune-associated signaling pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations have explored the role of SIAE in other autoimmune contexts. In primary biliary cirrhosis, resequencing studies identified rare non-synonymous mutations in SIAE as potential independent risk factors for disease development. Conversely, studies focusing on autoimmune Addison's disease have sought to determine an association with rare SIAE variants, while others report that these variants may not be causative in some autoimmune phenotypes. Collectively, these findings underscore that SIAE, through its modulation of sialic acid O-acetylation, plays a central role in regulating immune cell signaling. Nonetheless, its impact appears to be context-dependent, warranting further research to delineate the precise mechanisms by which altered SIAE activity contributes to diverse pathological conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ira Surolia, Stephan P Pirnie, Vasant Chellappa, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "M89V Sialic acid Acetyl Esterase (SIAE) and all other non-synonymous common variants of this gene are catalytically normal."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0053453"}], "href": "https://doi.org/10.1371/journal.pone.0053453"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23308225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23308225"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Masaaki Yamamoto, Genzo Iguchi, Hironori Bando, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A missense single-nucleotide polymorphism in the sialic acid acetylesterase (SIAE) gene is associated with anti-PIT-1 antibody syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1507/endocrj.ej13-0539"}], "href": "https://doi.org/10.1507/endocrj.ej13-0539"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24748456"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24748456"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "K Szymański, A Skórka, A Szypowska, et al. 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