{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRFX6 is a pivotal transcription factor that orchestrates pancreatic endocrine cell differentiation and sustains mature islet cell function. Acting downstream of the pro‐endocrine factor Neurog3, RFX6 is indispensable for the generation of multiple hormone‐producing cell types, including β‑cells responsible for insulin synthesis and secretion, and it modulates key components such as Ca²⁺ channels and gene networks in both β‑cells and α‑cells. These regulatory functions are essential for maintaining energy homeostasis and proper glycemic control."}, {"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": "\nMutations in the RFX6 gene cause a spectrum of monogenic diabetes disorders—from severe neonatal diabetes often accompanied by gastrointestinal anomalies (as seen in Mitchell–Riley syndrome) to maturity‑onset diabetes of the young (MODY) with reduced penetrance. Studies employing patient‐derived induced pluripotent stem cells, in vivo animal models, and human genetic analyses have demonstrated that both homozygous and heterozygous loss‐of‑function mutations impair pancreatic endoderm formation and functional islet cell differentiation, ultimately leading to compromised insulin and incretin responses and glucose regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in pancreatic development, RFX6 has emerged as an oncogenic factor in prostate cancer and possibly other malignancies. Genome‑wide association and functional studies in prostate cancer have identified RFX6 as a susceptibility locus whose altered expression—mediated by risk alleles and enhanced by transcription factors such as HOXB13—is associated with increased tumor cell proliferation, metastasis, epithelial–mesenchymal transition, and resistance to antiandrogen therapies. Similar observations in hepatocellular carcinoma hint at broader roles in tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its endocrine functions, RFX6 plays a crucial role in gastrointestinal development. Early during endodermal patterning, it is broadly expressed throughout the anterior gut, before later becoming restricted to cells with endocrine functions in the pancreas and intestine. Experimental models, including studies in Xenopus and human intestinal organoids, have revealed that RFX6 regulates important downstream targets such as PDX1 to establish duodenal identity and proper intestinal morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAs a member of the regulatory factor X (RFX) family, RFX6 exemplifies the multifunctional properties of transcription factors that are critical for organogenesis and disease. Its diverse roles—from driving the differentiation and maintenance of hormone‐secreting pancreatic cells to modulating cellular identity in the gastrointestinal tract and influencing oncogenic pathways—underscore its significance as a central regulator in both developmental biology and pathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stuart B Smith, Hui-Qi Qu, Nadine Taleb, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "A novel RFX6 heterozygous mutation (p.R652X) in maturity-onset diabetes mellitus: A case report."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Diabetes Investig (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jdi.13545"}], "href": "https://doi.org/10.1111/jdi.13545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33721395"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33721395"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hazem Ibrahim, Diego Balboa, Jonna Saarimäki-Vire, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-024-06163-y"}], "href": "https://doi.org/10.1007/s00125-024-06163-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38743124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38743124"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ryo Takata, Shusuke Akamatsu, Michiaki Kubo, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.2862"}], "href": "https://doi.org/10.1038/ng.2862"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24390282"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24390282"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Qing-Zhi Long, Yue-Feng Du, Xiao-Ying Ding, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Replication and fine mapping for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in the Chinese population."}]}, {"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.0037866"}], "href": "https://doi.org/10.1371/journal.pone.0037866"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22662242"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22662242"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Na-Na Wang, Yong Xu, Kuo Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Susceptibility loci associations with prostate cancer risk in northern Chinese men."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asian Pac J Cancer Prev (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7314/apjcp.2013.14.5.3075"}], "href": "https://doi.org/10.7314/apjcp.2013.14.5.3075"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23803082"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23803082"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Xing-Hui Li, Yong Xu, Kuo Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of THADA, FOXP4, GPRC6A/RFX6 genes and 8q24 risk alleles with prostate cancer in Northern Chinese men."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J BUON (2015)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26537068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26537068"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Zhiyu Qiu, Chenwei Wang, Pinzhu Huang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFβ Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Sci (Weinh) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/advs.202401492"}], "href": "https://doi.org/10.1002/advs.202401492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38932472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38932472"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Esther J Pearl, Zeina Jarikji, Marko E Horb "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of Rfx6 and mutant variants associated with neonatal diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2010.12.043"}], "href": "https://doi.org/10.1016/j.ydbio.2010.12.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21215266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21215266"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "J Guillermo Sanchez, Scott Rankin, Emily Paul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RFX6 regulates human intestinal patterning and function upstream of PDX1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.202529"}], "href": "https://doi.org/10.1242/dev.202529"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38587174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38587174"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Syed Aftab, Lucie Semenec, Jeffrey Shih-Chieh Chu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification and characterization of novel human tissue-specific RFX transcription factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Evol Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2148-8-226"}], "href": "https://doi.org/10.1186/1471-2148-8-226"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18673564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18673564"}]}]}]}