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Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario

Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not underst...

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Autores principales: Calvete, Oriol, Reyes, José, Valdés-Socin, Hernán, Martin, Paloma, Marazuela, Mónica, Barroso, Alicia, Escalada, Javier, Castells, Antoni, Torres-Ruiz, Raúl, Rodríguez-Perales, Sandra, Currás-Freixes, María, Benítez, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700745/
https://www.ncbi.nlm.nih.gov/pubmed/34944008
http://dx.doi.org/10.3390/cells10123500
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author Calvete, Oriol
Reyes, José
Valdés-Socin, Hernán
Martin, Paloma
Marazuela, Mónica
Barroso, Alicia
Escalada, Javier
Castells, Antoni
Torres-Ruiz, Raúl
Rodríguez-Perales, Sandra
Currás-Freixes, María
Benítez, Javier
author_facet Calvete, Oriol
Reyes, José
Valdés-Socin, Hernán
Martin, Paloma
Marazuela, Mónica
Barroso, Alicia
Escalada, Javier
Castells, Antoni
Torres-Ruiz, Raúl
Rodríguez-Perales, Sandra
Currás-Freixes, María
Benítez, Javier
author_sort Calvete, Oriol
collection PubMed
description Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism 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 imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 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 the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for 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 new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.
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spelling pubmed-87007452021-12-24 Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario Calvete, Oriol Reyes, José Valdés-Socin, Hernán Martin, Paloma Marazuela, Mónica Barroso, Alicia Escalada, Javier Castells, Antoni Torres-Ruiz, Raúl Rodríguez-Perales, Sandra Currás-Freixes, María Benítez, Javier Cells Article Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism 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 imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 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 the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for 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 new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients. MDPI 2021-12-10 /pmc/articles/PMC8700745/ /pubmed/34944008 http://dx.doi.org/10.3390/cells10123500 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Calvete, Oriol
Reyes, José
Valdés-Socin, Hernán
Martin, Paloma
Marazuela, Mónica
Barroso, Alicia
Escalada, Javier
Castells, Antoni
Torres-Ruiz, Raúl
Rodríguez-Perales, Sandra
Currás-Freixes, María
Benítez, Javier
Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
title Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
title_full Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
title_fullStr Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
title_full_unstemmed Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
title_short Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid–Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario
title_sort alterations in slc4a2, slc26a7 and slc26a9 drive acid–base imbalance in gastric neuroendocrine tumors and uncover a novel mechanism for a co-occurring polyautoimmune scenario
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700745/
https://www.ncbi.nlm.nih.gov/pubmed/34944008
http://dx.doi.org/10.3390/cells10123500
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