{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPGAP3 is a key enzyme involved in the post‐translational maturation of glycosylphosphatidylinositol (GPI)‐anchored proteins. It catalyzes a crucial lipid remodeling step that ensures proper insertion and functioning of GPI‐anchored proteins at the cell surface. Disruption of PGAP3 function leads to impaired GPI‐anchor maturation, which in turn is associated with developmental abnormalities, elevated serum alkaline phosphatase levels, and neurological deficits characteristic of hyperphosphatasia with mental retardation syndrome (HPMRS), also known as Mabry syndrome. Several studies have identified pathogenic variants in PGAP3 that cause a congenital disorder of glycosylation with a predominantly neurodevelopmental phenotype, including intellectual disability, developmental delay, seizures, and brain malformations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental role, PGAP3 participates in the fine-tuning of cellular protein trafficking. Overexpression studies have demonstrated that tagged forms of PGAP3 result in the production of lyso-GPI-anchored proteins, thereby providing insight into the lipid remodeling process that governs the integration of GPI-anchored proteins into membrane microdomains. Moreover, functional investigations have revealed that naturally occurring haplotypes in PGAP3 (also known as PERLD1) can alter GPI-anchor biosynthesis and influence the alternative splicing of its transcript. These variations are associated with changes in immune cell responsiveness and have been linked to altered T-cell activation and proliferation, which may contribute to the predisposition to immune-mediated conditions such as allergic asthma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its established roles in GPI-anchor biosynthesis and immune cell regulation, emerging evidence indicates that PGAP3 may have significant implications in cancer biology. A circular RNA generated from the PGAP3 locus (circ-PGAP3) has been shown to act as a tumor suppressor in cervical cancer via modulation of the miR-769-5p/p53 axis, with lower circ-PGAP3 expression correlating with poorer prognosis. Furthermore, recent work has explored the clinical significance of PGAP3 expression in breast cancer, suggesting that alterations in PGAP3 may influence tumor behavior. These findings open potential avenues for therapeutic intervention by restoring proper PGAP3 function or expression in malignant contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Malcolm F Howard, Yoshiko Murakami, Alistair T Pagnamenta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2013.12.012"}], "href": "https://doi.org/10.1016/j.ajhg.2013.12.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24439110"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24439110"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alexej Knaus, Tomonari Awaya, Ingo Helbig, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.23006"}], "href": "https://doi.org/10.1002/humu.23006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27120253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27120253"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "M S Abdel-Hamid, M Y Issa, G A Otaify, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PGAP3-related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.13033"}], "href": "https://doi.org/10.1111/cge.13033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28390064"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28390064"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Heidre Bezuidenhout, Samantha Bayley, Liani Smit, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hyperphosphatasia with mental retardation syndrome type 4 in three unrelated South African patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.61797"}], "href": "https://doi.org/10.1002/ajmg.a.61797"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32845056"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32845056"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ruqaiah Altassan, Michael M Allers, Diederik De Graef, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defining the phenotype of PGAP3-congenital disorder of glycosylation; a review of 65 cases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2023.107688"}], "href": "https://doi.org/10.1016/j.ymgme.2023.107688"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37647829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37647829"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Guillaume Alain Castillon, Laetitia Michon, Reika Watanabe "}, {"type": "b", "children": [{"type": "t", "text": "Apical sorting of lysoGPI-anchored proteins occurs independent of association with detergent-resistant membranes but dependent on their N-glycosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E13-03-0160"}], "href": "https://doi.org/10.1091/mbc.E13-03-0160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23615438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23615438"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yang Yie Sio, Ramani Anantharaman, Sean Qiu En Lee, et al. 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