{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSEPTIN12 is a testis‐specific member of the septin GTPase family that plays a pivotal role in the terminal differentiation of male germ cells. It is essential for proper sperm morphogenesis by forming filamentous structures that contribute notably to the formation of the sperm tail annulus and overall structural integrity. Loss‐of‐function mutations impair septin filament assembly, leading to defective annulus formation, abnormal head–tail junctions, and other sperm morphological abnormalities. These defects have been associated with various forms of male infertility, including asthenozoospermia and teratozoospermia."}, {"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": "\nMechanistically, SEPTIN12 interacts with other septin family members (such as SEPT7, SEPT6, SEPT2, and SEPT4) to assemble into octameric filaments, a process critically dependent on its GTP-binding domain. These filaments not only provide structural support but also interact with key cytoskeletal elements, including α- and β-tubulins, and with membrane-associated proteins like NDC1 and SUN5 to ensure proper sperm head–tail coupling. Disruption of these interactions through missense mutations or truncated variants interferes with filament formation, perturbing the organization of the sperm neck region and overall tail structure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies of SEPTIN12 have revealed several variants—including mutations such as T89M, D197N, c.474G>A, and p.Gln225Lys—that compromise its function and correlate with distinct spermatogenic failures, including non-obstructive azoospermia and meiotic arrest. In addition, transcriptional studies show that its expression is tightly regulated by androgen and estrogen receptor elements in the promoter region, underlining the importance of hormonal control in spermatogenesis. These findings underscore that proper SEPTIN12 function and regulation are critical for the assembly of the sperm annulus and for maintaining nuclear integrity, thereby safeguarding male fertility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yung-Che Kuo, Ying-Hung Lin, Hau-Inh Chen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The expression level of septin12 is critical for spermiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2009.080955"}], "href": "https://doi.org/10.2353/ajpath.2009.080955"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19359518"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19359518"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yung-Che Kuo, Yi-Ru Shen, Hau-Inh Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SEPT12 orchestrates the formation of mammalian sperm annulus by organizing core octameric complexes with other SEPT proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.158998"}], "href": "https://doi.org/10.1242/jcs.158998"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25588830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25588830"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ying-Hung Lin, Ya-Yun Wang, Hau-Inh Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SEPTIN12 genetic variants confer susceptibility to teratozoospermia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0034011"}], "href": "https://doi.org/10.1371/journal.pone.0034011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22479503"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22479503"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Pao-Lin Kuo, Han-Sun Chiang, Ya-Yun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SEPT12-microtubule complexes are required for sperm head and tail formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms141122102"}], "href": "https://doi.org/10.3390/ijms141122102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24213608"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24213608"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tsung-Hsuan Lai, Ying-Yu Wu, Ya-Yun Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gaae022"}], "href": "https://doi.org/10.1093/molehr/gaae022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38870534"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38870534"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hiroe Miyakawa, Toshinobu Miyamoto, Eitetsu Koh, et al. 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