Reference : Alterations in SLC4A2, SLC26A7 and SLC26A9 DriveAcid–Base Imbalance in Gastric Neuroe...
Scientific journals : Article
Human health sciences : Endocrinology, metabolism & nutrition
Alterations in SLC4A2, SLC26A7 and SLC26A9 DriveAcid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
Calvete, Oriol []
Reyes, José [Spanish National Cancer Center > > Human Genetics Group > >]
VALDES SOCIN, Hernan Gonzalo mailto [Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'endocrinologie clinique >]
Martin, Paloma []
Marazuela, Monica []
Barroso, Alicia []
Castells, Antoni []
Torres-Ruiz, Raul []
Rodriguez-Perales, Sandra []
Curras-Freixes, Maria []
Benitez, Javier [Spanish National Cancer research > > Human Genetics Group > >]
Multidisciplinary Digital Publishing Institute (MDPI)
Yes (verified by ORBi)
[en] SCL4A2 ; SLC26A7 ; SLC26A9 ; ATP4A ; APS ; zutoimmune polyendocrine syndrome ; thyrogastric syndrome ; Hashimoto ; Graves disease ; autoimmune gastritis ; Biermer disease ; physiopathology ; genetics ; mutations ; ATPase H/K ; familial thyrogastric syndrome ; acide-base imbalance ; gastric NET ; neuroendocrine tumorigenesis ; novel classification ; Achlorhydria ; PTH1R ; PTH2R
[en] bstract:Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune systemmalfunction and entails several autoimmune diseases co-occurring in different tissues of the samepatient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenicmechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid–base imbal-ance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors withsecondary autoimmune pathologies. Here, we propose the genetic exploration of APS involvinggastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario.The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered differ-ent pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A.Exploratoryin vitrostudies suggested that the uncovered genes were involved in a pathogenicmechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panelwith 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total,64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of thestudied patients and none of the healthy controls. Our studies reveal a constellation of solute carriersthat co-express in the tissues affected with different autoimmune diseases, proposing a unique geneticorigin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanismfor polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a newwindow leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinicalmanagement of patients.
Researchers ; Professionals
This article belongs to the Collection Gastrointestinal Disease: From Molecular and Cellular Mechanisms to Novel Therapeutics. Copyright:© 2021 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (

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