{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The X‐linked aristaless‐related homeobox gene (ARX) encodes a paired‐type homeodomain transcription factor that plays essential roles in the development and specification of both neural and endocrine tissues. In the developing forebrain, ARX regulates the proliferation, migration, and differentiation of neuronal progenitors—especially GABAergic interneurons and cortical neurons—by modulating transcriptional programs (for example, by repressing cell cycle inhibitors such as Cdkn1c and controlling targets like LMO1 and SHOX2). Alterations in ARX function compromise these processes and are causally linked to a spectrum of neurological disorders ranging from structural brain malformations (e.g., X‐linked lissencephaly with abnormal genitalia) to infantile spasms, epilepsy, and intellectual disability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": " Moreover, missense mutations and polyalanine expansions in ARX can lead to protein mislocalization, nuclear aggregation, and impaired DNA binding—mechanisms that underlie disease severity and phenotypic heterogeneity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its critical functions in brain development, ARX is a key regulator of endocrine cell fate. Within the pancreas and gut, ARX activity directs the specification and maintenance of hormone‐producing cell types: it promotes α‐cell identity in the pancreas while restricting alternative fates, and it participates in the allocation of enteroendocrine subtypes that are essential for glucose homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "22"}]}, {"type": "t", "text": " ARX also contributes to testicular differentiation by fostering fetal Leydig cell progenitor specification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, proper ARX function depends on efficient nuclear import—which is mediated at least in part by importin β1—and is influenced by epigenetic mechanisms and translational modulation, as seen in studies reporting re‐initiation of translation in the context of null mutations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Collectively, these findings establish ARX as a multifaceted developmental regulator whose precise transcriptional control in both neural and endocrine systems is critical for normal organogenesis. Disruption of ARX activity, whether by mutations that alter its DNA binding, subcellular localization, or transcriptional repression capacity, underpins a diverse array of human pathologies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kunio Kitamura, Masako Yanazawa, Noriyuki Sugiyama, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/11.8.981"}], "href": "https://doi.org/10.1093/hmg/11.8.981"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11971879"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11971879"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Eric Marsh, Carl Fulp, Ernest Gomez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awp107"}], "href": "https://doi.org/10.1093/brain/awp107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19439424"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19439424"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Carl T Fulp, Ginam Cho, Eric D Marsh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of Arx transcriptional targets in the developing basal forebrain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddn271"}], "href": "https://doi.org/10.1093/hmg/ddn271"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18799476"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18799476"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Gaia Colasante, Jacqueline C Simonet, Raffaele Calogero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cereb Cortex (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cercor/bht222"}], "href": "https://doi.org/10.1093/cercor/bht222"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23968833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23968833"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shirley Beguin, Valérie Crépel, Laurent Aniksztejn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An epilepsy-related ARX polyalanine expansion modifies glutamatergic neurons excitability and morphology without affecting GABAergic neurons development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cereb Cortex (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cercor/bhs138"}], "href": "https://doi.org/10.1093/cercor/bhs138"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22628459"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22628459"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cheryl Shoubridge, Tod Fullston, Jozef Gécz "}, {"type": "b", "children": [{"type": "t", "text": "ARX spectrum disorders: making inroads into the molecular pathology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.21288"}], "href": "https://doi.org/10.1002/humu.21288"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20506206"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20506206"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Cheryl Shoubridge, May Huey Tan, Grace Seiboth, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr601"}], "href": "https://doi.org/10.1093/hmg/ddr601"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22194193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22194193"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ingrid E Scheffer, R H Wallace, F L Phillips, et al. "}, {"type": "b", "children": [{"type": "t", "text": "X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/wnl.59.3.348"}], "href": "https://doi.org/10.1212/wnl.59.3.348"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12177367"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12177367"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Stefano Sartori, Roberta Polli, Elisa Bettella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pathogenic role of the X-linked cyclin-dependent kinase-like 5 and aristaless-related homeobox genes in epileptic encephalopathy of unknown etiology with onset in the first year of life."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Child Neurol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0883073810387827"}], "href": "https://doi.org/10.1177/0883073810387827"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21482751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21482751"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ilya M Nasrallah, Jeremy C Minarcik, Jeffrey A Golden "}, {"type": "b", "children": [{"type": "t", "text": "A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200408091"}], "href": "https://doi.org/10.1083/jcb.200408091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15533998"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15533998"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Cheryl Shoubridge, Desiree Cloosterman, Emma Parkinson-Lawerence, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2007.03.005"}], "href": "https://doi.org/10.1016/j.ygeno.2007.03.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17490853"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17490853"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Loredana Poeta, Francesca Fusco, Denise Drongitis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2012.11.008"}], "href": "https://doi.org/10.1016/j.ajhg.2012.11.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23246292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23246292"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "T Fullston, M Finnis, A Hackett, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1399-0004.2011.01685.x"}], "href": "https://doi.org/10.1111/j.1399-0004.2011.01685.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21496008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21496008"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Sangeeta Dhawan, Senta Georgia, Shuen-Ing Tschen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pancreatic β cell identity is maintained by DNA methylation-mediated repression of Arx."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2011.03.012"}], "href": "https://doi.org/10.1016/j.devcel.2011.03.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21497756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21497756"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Patrick Collombat, Jacob Hecksher-Sørensen, Jens Krull, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI29115"}], "href": "https://doi.org/10.1172/JCI29115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17404619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17404619"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Harini Chakravarthy, Xueying Gu, Martin Enge, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2017.01.009"}], "href": "https://doi.org/10.1016/j.cmet.2017.01.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28215845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28215845"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Yoshitaka Hayashi, Michiyo Yamamoto, Hiroyuki Mizoguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mice deficient for glucagon gene-derived peptides display normoglycemia and hyperplasia of islet {alpha}-cells but not of intestinal L-cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2009-0296"}], "href": "https://doi.org/10.1210/me.2009-0296"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19819987"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19819987"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Crystal L Wilcox, Natalie A Terry, Erik R Walp, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pancreatic α-cell specific deletion of mouse Arx leads to α-cell identity loss."}]}, {"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.0066214"}], "href": "https://doi.org/10.1371/journal.pone.0066214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23785486"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23785486"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Teresa L Mastracci, Crystal L Wilcox, Luis Arnes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression."}]}, {"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.2011.08.001"}], "href": "https://doi.org/10.1016/j.ydbio.2011.08.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21856296"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21856296"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Blair K Gage, Ali Asadi, Robert K Baker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Role of ARX in Human Pancreatic Endocrine Specification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0144100"}], "href": "https://doi.org/10.1371/journal.pone.0144100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26633894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26633894"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Anthony Beucher, Elisabet Gjernes, Caitlin Collin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice."}]}, {"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.0036449"}], "href": "https://doi.org/10.1371/journal.pone.0036449"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22570716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22570716"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Kanako Miyabayashi, Yuko Katoh-Fukui, Hidesato Ogawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aristaless related homeobox gene, Arx, is implicated in mouse fetal Leydig cell differentiation possibly through expressing in the progenitor cells."}]}, {"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.0068050"}], "href": "https://doi.org/10.1371/journal.pone.0068050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23840809"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23840809"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Wenbo Lin, Wenduo Ye, Lanlan Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The roles of multiple importins for nuclear import of murine aristaless-related homeobox protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.004242"}], "href": "https://doi.org/10.1074/jbc.M109.004242"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19494118"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19494118"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Tod Fullston, Louise Brueton, Tracey Willis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2009.139"}], "href": "https://doi.org/10.1038/ejhg.2009.139"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19738637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19738637"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Carmela Laperuta, Letizia Spizzichino, Pio D'Adamo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-8-25"}], "href": "https://doi.org/10.1186/1471-2350-8-25"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17480217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17480217"}]}]}]}