{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPADI6 is a unique member of the peptidylarginine deiminase family that was first characterized as a distinct human gene with a restricted expression pattern—mainly in the ovary, testis, and peripheral blood leukocytes—and is proposed to be orthologous to the mouse ePAD isoform. Unlike many of its enzymatically active relatives, early analyses of hPADVI (human PADI6) revealed limited or undetectable catalytic activity, suggesting that PADI6 might instead function in a non‐enzymatic capacity. Its expression in reproductive tissues implicates it in cytoskeletal reorganization and early developmental processes rather than conventional protein deimination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have subsequently underscored an essential maternal‐effect role for PADI6. Mutations in this gene have been associated with severe reproductive phenotypes including early embryonic arrest, recurrent implantation failure, and hydatidiform moles. In affected individuals, loss‐of‐function alleles lead to impaired zygotic genome activation and abnormal imprinting, pointing to a critical role for PADI6 as a component of the subcortical maternal complex (SCMC) that establishes the oocyte’s developmental competence. Moreover, identification of PADI6 variants in patients with multilocus imprinting disturbances and related pregnancy losses further broadens its impact on reproductive health, while genetic association studies hint at a potential link between the PADI6 locus and epigenetic regulation influencing diseases beyond infertility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent structural studies have further refined our understanding of PADI6’s function. The high‐resolution crystal structure of human PAD6 indicates that it adopts a conformation reminiscent of the inactive states of its family members, with its active site arranged in a nonproductive fashion that could preclude conventional substrate binding. This structural insight supports the hypothesis that instead of catalyzing citrullination, PADI6 may serve a scaffolding or regulatory role within the cytoplasmic lattice of oocytes and early embryos, thereby contributing to the precise regulation of early developmental events."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stéphane Chavanas, Marie-Claire Méchin, Hidenari Takahara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2003.12.038"}], "href": "https://doi.org/10.1016/j.gene.2003.12.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15087120"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15087120"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jiayi Zhang, Jianliang Dai, Enpeng Zhao, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2016.06.024"}], "href": "https://doi.org/10.1016/j.ajhg.2016.06.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27545678"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27545678"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "JianHua Qian, Ngoc Minh Phuong Nguyen, Maryam Rezaei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41431-018-0141-3"}], "href": "https://doi.org/10.1038/s41431-018-0141-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29693651"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29693651"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Maria Vittoria Cubellis, Laura Pignata, Ankit Verma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Epigenetics (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13148-020-00925-2"}], "href": "https://doi.org/10.1186/s13148-020-00925-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32928291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32928291"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Thomas Eggermann, Gundula Kadgien, Matthias Begemann, et al. 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