{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T07:53:33Z","timestamp":1792310013140,"version":"4.4.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cant\u00fa syndrome (CS) is a rare genetic disorder caused by gain-of-function (GOF) mutations in the <jats:italic>KCNJ8<\/jats:italic> (Kir6.1) or <jats:italic>ABCC9<\/jats:italic> (SUR2) subunits of ATP-sensitive potassium (KATP) channels. CS is characterized by multisystem abnormalities such as cardiovascular defects, hypertrichosis, and skeletal malformations, but its impact on intestinal homeostasis remains poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the effects of CS-associated KATP channel overactivity on epithelial barrier integrity and tight junction (TJ) proteins using murine models. Heterozygous (SUR2<jats:sup>wt\/AV<\/jats:sup>) and homozygous (SUR2<jats:sup>AV\/AV<\/jats:sup>) SUR2(A478V) mutants, as well as Kir6.1(V65M) mice, were studied. mRNA and protein expression of Occludin, Claudin-1, and ZO-1 were analyzed, alongside histological and immunohistochemical assessments. Markers of apoptosis and survival, including caspase-3 activity and BCL2\/BCL2L1 expression, were also evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GOF mutations in KATP channels caused significant dysregulation of TJ proteins. Occludin expression was increased in SUR2<jats:sup>AV\/AV<\/jats:sup> mice but decreased in SUR2<jats:sup>wt\/AV<\/jats:sup> and Kir6.1 mutants, while Claudin-1 and ZO-1 were consistently reduced across all models. Immunohistochemistry revealed disrupted TJ localization and reduced apical junctional integrity. Histological analyzes showed epithelial disorganization, smooth muscle hypertrophy, fibrosis, and inflammatory infiltration. These alterations were accompanied by increased caspase-3 activity and reduced BCL2 and BCL2L1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings demonstrate that CS-associated KATP channel GOF mutations disrupt tight junction dynamics and induces structural remodeling of the colon. This establishes a novel link between KATP channel dysregulation, metabolic-epithelial interactions, and intestinal pathophysiology in CS. Furthermore, the results highlight potential therapeutic targets to mitigate barrier dysfunction, providing a basis for developing interventions to address gastrointestinal symptoms in CS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1656718","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T05:24:33Z","timestamp":1757568273000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Gain-of-function mutations in KATP channel subunits compromise colonic tight junction integrity and epithelial homeostasis in murine models of Cant\u00fa syndrome"],"prefix":"10.3389","volume":"12","author":[{"given":"Fatima","family":"Maqoud","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenica","family":"Mallardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Orlando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Tricarico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Antonacci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Armentano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Grassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Valentini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1016\/j.ajhg.2012.04.014","article-title":"Cant\u00fa syndrome is caused by mutations in ABCC9","volume":"90","author":"Van Bon","year":"2012","journal-title":"Am J Hum Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"17387","DOI":"10.1074\/jbc.M117.804971","article-title":"Conserved functional consequences of disease-associated mutations in the slide helix of Kir6","volume":"292","author":"Cooper","year":"2017","journal-title":"J Biol Chem"},{"key":"B3","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1085\/jgp.201511495","article-title":"Differential mechanisms of Cant\u00fa syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel","volume":"146","author":"Cooper","year":"2015","journal-title":"J Gen Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1590\/1806-9282.20220866","article-title":"Craniofacial findings in syndromes associated with cafe-Au-lait spots: a literature review","volume":"69","author":"Carvalho","year":"2023","journal-title":"Rev Assoc Med Bras"},{"key":"B5","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1007\/BF00281261","article-title":"A distinct osteochondrodysplasia with hypertrichosis- Individualization of a probable autosomal recessive entity","volume":"60","author":"Cant\u00fa","year":"1982","journal-title":"Hum Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1161\/CIRCRESAHA.112.300514","article-title":"KATP channels and cardiovascular disease: suddenly a syndrome","volume":"112","author":"Nichols","year":"2013","journal-title":"Circ Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1002\/ajmg.a.33885","article-title":"Cant\u00fa syndrome: report of nine new cases and expansion of the clinical phenotype","author":"Scurr","year":"2011","journal-title":"Am J Med Genet A"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e121153","DOI":"10.1172\/jci.insight.121153","article-title":"Cardiovascular consequences of KATP overactivity in cantu syndrome","volume":"3","author":"Huang","year":"2018","journal-title":"JCI Insight."},{"key":"B9","doi-asserted-by":"publisher","first-page":"zqaa004","DOI":"10.1093\/function\/zqaa004","article-title":"The mechanism of high-output cardiac hypertrophy arising from potassium channel gain-of-function in cant\u00fa syndrome","volume":"1","author":"Mcclenaghan","year":"2020","journal-title":"Function."},{"key":"B10","doi-asserted-by":"publisher","first-page":"17587","DOI":"10.1074\/jbc.M117.810325","article-title":"Molecular and functional characterization of the endothelial ATP-sensitive potassium channel","volume":"292","author":"Aziz","year":"2017","journal-title":"J Biol Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"5842","DOI":"10.1046\/j.1432-1327.2000.01672.x","article-title":"K(ATP) channels gated by intracellular nucleotides and phospholipids","volume":"267","author":"Baukrowitz","year":"2000","journal-title":"Eur J Biochem"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1073\/pnas.0505974103","article-title":"Hybrid assemblies of ATP-sensitive K channels determine their muscle-type-dependent biophysical and pharmacological properties","volume":"103","author":"Tricarico","year":"2006"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/cphy.c170048","article-title":"ATP-Sensitive potassium channels and their physiological and pathophysiological roles","volume":"8","author":"Tinker","year":"2018","journal-title":"Compr Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/nature04711","article-title":"KATP channels as molecular sensors of cellular metabolism","volume":"440","author":"Colin","year":"2006","journal-title":"Nat."},{"key":"B15","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1161\/HYPERTENSIONAHA.120.15355","article-title":"Endothelial ATP-sensitive potassium channel protects against the development of hypertension and atherosclerosis","volume":"76","author":"Li","year":"2020","journal-title":"Hypertension."},{"key":"B16","doi-asserted-by":"publisher","first-page":"693","DOI":"10.2337\/dbi22-0030","article-title":"KATP Channels and the metabolic regulation of insulin secretion in health and disease: the 2022 banting medal for scientific achievement award lecture","volume":"72","author":"Ashcroft","year":"2023","journal-title":"Diabetes."},{"key":"B17","doi-asserted-by":"publisher","first-page":"4079","DOI":"10.3390\/ijms25074079","article-title":"Exploring the pathophysiology of ATP-dependent potassium channels in insulin resistance","volume":"25","author":"Rodr\u00edguez-Rivera","year":"2024","journal-title":"Int J Mol Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1097\/MIB.0000000000000504","article-title":"Mechanisms underlying dysregulation of electrolyte absorption in inflammatory bowel disease-associated diarrhea","volume":"21","author":"Priyamvada","year":"2015","journal-title":"Inflamm Bowel Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1016\/j.jpedsurg.2016.02.060","article-title":"Altered expression of ATP-sensitive K+ channels in hirschsprung's disease","volume":"51","author":"Tomuschat","year":"2016","journal-title":"J Pediatr Surg."},{"key":"B20","doi-asserted-by":"publisher","first-page":"141443","DOI":"10.1172\/jci.insight.141443","article-title":"Kir6","volume":"5","author":"York","year":"2020","journal-title":"JCI Insight."},{"key":"B21","doi-asserted-by":"publisher","first-page":"881","DOI":"10.5009\/gnl15414","article-title":"Potassium channelopathies and gastrointestinal ulceration","volume":"10","author":"Han","year":"2016","journal-title":"Gut Liver."},{"key":"B22","doi-asserted-by":"publisher","first-page":"5732","DOI":"10.3748\/wjg.v25.i38.5732","article-title":"Role of ion channels in gastrointestinal cancer","volume":"25","author":"Anderson","year":"2019","journal-title":"World J Gastroenterol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1152\/physrev.00018.2022","article-title":"The enteric nervous system","volume":"103","author":"Sharkey","year":"2023","journal-title":"Physiol Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1292\/jvms.19-0197","article-title":"ATP-dependent potassium channels contribute to motor regulation of esophageal striated muscle in rats","volume":"81","author":"Horii","year":"2019","journal-title":"J Vet Med Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"C520","DOI":"10.1152\/ajpcell.00393.2020","article-title":"Potassium channels in intestinal epithelial cells and their pharmacological modulation: a systematic review","volume":"320","author":"Cosme","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1124\/mol.112.081596","article-title":"Hydrogen sulfide as an allosteric modulator of ATP-sensitive potassium channels in colonic inflammation","volume":"83","author":"Gade","year":"2013","journal-title":"Mol Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"494","DOI":"10.5056\/jnm15061","article-title":"Targeting ion channels: an important therapeutic implication in gastrointestinal dysmotility in patients with spinal cord injury","volume":"21","author":"Radulovic","year":"2015","journal-title":"J Neurogastroenterol Motil."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3107","DOI":"10.1113\/JP279612","article-title":"Kir6","volume":"598","author":"Davis","year":"2020","journal-title":"J. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/nrgastro.2012.32","article-title":"The enteric nervous system and neurogastroenterology","volume":"9","author":"Furness","year":"2012","journal-title":"Nat Rev Gastroenterol Hepatol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41575-020-0271-2","article-title":"Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility","volume":"17","author":"Spencer","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1111\/bph.14459","article-title":"Nitric oxide and its role as a non-adrenergic, non-cholinergic inhibitory neurotransmitter in the gastrointestinal tract","volume":"176","author":"Kenton Sanders","year":"2019","journal-title":"Br J Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1111\/j.1365-2982.2012.01956.x","article-title":"Ionic conductances regulating the excitability of colonic smooth muscles","volume":"24","author":"Koh","year":"2012","journal-title":"J Neurogastroenterol Motil"},{"key":"B33","doi-asserted-by":"publisher","first-page":"4163","DOI":"10.1242\/jcs.02540","article-title":"Sulphonylurea receptors differently modulate ICC pacemaker Ca2+ activity and smooth muscle contractility","volume":"118","author":"Nakayama","year":"2005","journal-title":"J Cell Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1007\/s12272-010-0319-x","article-title":"Phentolamine inhibits the pacemaker activity of mouse interstitial cells of dis by activating ATP-sensitive K+ channels","volume":"33","author":"Ahn","year":"2010","journal-title":"Arch Pharm Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1146\/annurev.physiol.68.040504.094718","article-title":"Interstitial cells of cajal as pacemakers in the gastrointestinal tract","volume":"68","author":"Sanders","year":"2006","journal-title":"Annu Rev Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1152\/ajpcell.00361.2004","article-title":"Pacemaker potentials generated by interstitial cells of cajal in the murine intestine","volume":"288","author":"Kito","year":"2005","journal-title":"Am J Physiol Cell Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1124\/jpet.105.091595","article-title":"Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels","volume":"316","author":"Distrutti","year":"2006","journal-title":"J Pharmacol Exp Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2645465","DOI":"10.1155\/2018\/2645465","article-title":"Tight junction in the intestinal epithelium: Its association with diseases and regulation by phytochemicals","volume":"2018","author":"Lee","year":"2018","journal-title":"J Immunol Res Vol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1038\/nrm.2016.80","article-title":"Tight junctions: from simple barriers to multifunctional molecular gates","volume":"17","author":"Zihni","year":"2016","journal-title":"Nat Rev Mol Cell Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s00424-016-1919-1","article-title":"Claudin proteins, outside-in signaling, and carcinogenesis","volume":"469","author":"Singh","year":"2017","journal-title":"Pflugers Arch"},{"key":"B41","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1152\/physrev.00019.2012","article-title":"Claudins and the modulation of tight junction permeability","volume":"93","author":"G\u00fcnzel","year":"2013","journal-title":"Physiol Rev."},{"key":"B42","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/j.cell.2006.06.043","article-title":"ZO-1 and ZO-2 independently determine where claudins are polymerized in tight-junction strand formation","volume":"126","author":"Umeda","year":"2006","journal-title":"Cell."},{"key":"B43","doi-asserted-by":"publisher","first-page":"604885","DOI":"10.3389\/fphar.2020.604885","article-title":"Pathophysiological consequences of KATP channel overactivity and pharmacological response to glibenclamide in skeletal muscle of a murine model of cant\u00f9 syndrome","volume":"11","author":"Scala","year":"2020","journal-title":"Front Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.3390\/cells10071791","article-title":"Consequences of sur2(a478v) mutation in skeletal muscle of murine model of cantu syndrome","volume":"10","author":"Scala","year":"2021","journal-title":"Cells."},{"key":"B45","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1152\/ajplung.00285.2017","article-title":"Ion channels of the lung and their role in disease pathogenesis. REVIEW ion channels and transporters in lung function and disease","volume":"313","author":"Bartoszewski","year":"2017","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1124\/jpet.105.085449","article-title":"The role of protein kinase C isoforms in modulating injury and repair of the intestinal barrier","volume":"316","author":"Farhadi","year":"2006","journal-title":"J Pharmacol Exp Ther."},{"key":"B47","doi-asserted-by":"publisher","first-page":"7210","DOI":"10.2741\/3223","article-title":"Oxidative stress-induced disruption of epithelial and endothelial tight junctions","volume":"13","author":"Rao","year":"2008","journal-title":"Front Biosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1042\/bj20011804","article-title":"Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress","volume":"368","author":"Rao","year":"2002","journal-title":"Biochem J."},{"key":"B49","doi-asserted-by":"publisher","first-page":"14463","DOI":"10.3390\/ijms232214463","article-title":"Redox and metabolic regulation of intestinal barrier function and associated disorders","volume":"23","author":"Lin","year":"2022","journal-title":"Int J Mol Sci."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1656718\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T05:24:34Z","timestamp":1757568274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1656718\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":49,"alternative-id":["10.3389\/fmed.2025.1656718"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1656718","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,11]]},"article-number":"1656718"}}