ORIGINAL RESEARCH article
Front. Med.
Sec. Gastroenterology
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1656718
This article is part of the Research TopicMolecular Mechanisms and Precision Medicine in Rare DiseasesView all 5 articles
Gain-of-Function mutations in KATP channel subunits compromise colonic tight junction integrity and epithelial homeostasis in murine models of Cantú Syndrome
Provisionally accepted
Fatima Maqoud1*
Domenica Mallardi1Antonella Orlando1
Domenico Tricarico2
Colin G Nichols3
Marina Antonacci2Giusy Bianco1Raffaele Armentano1Ilaria Grassi1
Anna Maria Valentini1
Francesco Russo1*- 1Ospedale Specializzato in Gastroenterologia Saverio de Bellis, Castellana Grotte, Italy
- 2Universita degli Studi di Bari Aldo Moro Dipartimento di Farmacia Scienze del Farmaco, Bari, Italy
- 3Washington University in St Louis, St. Louis, United States
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Cantú syndrome (CS) is a rare genetic disorder caused by gain-of-function (GOF) mutations in the KCNJ8 (Kir6.1) or ABCC9 (SUR2) subunits of ATP-sensitive potassium (KATP) channels. Multisystem abnormalities, including cardiovascular defects, hypertrichosis, and skeletal malformations, characterize CS. However, its impact on intestinal homeostasis remains poorly understood. This study examines the effects of CS-associated KATP channel overactivity on tight junction (TJ) proteins and epithelial barrier integrity in murine models. Using heterozygous (SUR2 wt/AV ) and homozygous (SUR2 AV/AV ) SUR2(A478V) mutants, as well as Kir6.1(V65M) mice, we analyzed mRNA and protein expression of TJ components (Occludin, Claudin-1, ZO-1), histology, and immunohistochemistry. Results revealed significant dysregulation of TJ protein expression: Occludin was upregulated in SUR2 AV/AV mice but downregulated in SUR2 wt/AV and Kir6.1 mutants, while Claudin-1 and ZO-1 were consistently reduced. Immunohistochemistry confirmed disrupted TJ localization and diminished apical junctional integrity in mutants. Histological analysis revealed epithelial disorganization, smooth muscle hypertrophy, fibrosis, and inflammatory infiltration, accompanied by increased caspase-3 activity and decreased BCL2 and BCL2L1 gene expression. These findings suggest that KATP channel hyperactivity in CS disrupts tight junction (TJ) dynamics, compromises epithelial barrier function, and induces structural remodeling in the colon. The study establishes a novel link between KATP channel dysregulation, metabolic-epithelial interactions, and intestinal pathophysiology in CS, highlighting potential therapeutic targets to mitigate barrier dysfunction.
Keywords: Cantú syndrome, murine model, Ion Channels, KATP Channels, Gain-of-function mutation, Tight Junctions, colonic epithelium, barrier dysfunction
Received: 30 Jun 2025; Accepted: 26 Aug 2025.
Copyright: © 2025 Maqoud, Mallardi, Orlando, Tricarico, Nichols, Antonacci, Bianco, Armentano, Grassi, Valentini and Russo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Fatima Maqoud, Ospedale Specializzato in Gastroenterologia Saverio de Bellis, Castellana Grotte, Italy
Francesco Russo, Ospedale Specializzato in Gastroenterologia Saverio de Bellis, Castellana Grotte, Italy
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