{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:01:40Z","timestamp":1790823700559,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI16\/00440"],"award-info":[{"award-number":["PI16\/00440"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"H2020 BRIDGES project","award":["634935"],"award-info":[{"award-number":["634935"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013base 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\u2013base 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.<\/jats:p>","DOI":"10.3390\/cells10123500","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T01:28:11Z","timestamp":1639358891000},"page":"3500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid\u2013Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2623-2876","authenticated-orcid":false,"given":"Oriol","family":"Calvete","sequence":"first","affiliation":[{"name":"Human Genetics Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"},{"name":"Network of Research on Rare Diseases (CIBERER), 28029 Madrid, Spain"},{"name":"Grupo Espa\u00f1ol de Tumores Neuroendocrinos y Endocrinos (GETNE), 28054 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Reyes","sequence":"additional","affiliation":[{"name":"Grupo Espa\u00f1ol de Tumores Neuroendocrinos y Endocrinos (GETNE), 28054 Madrid, Spain"},{"name":"Department of Gastroenterology, Hospital Comarcal de Inca, 07300 Inca, Spain"},{"name":"Health Investigation Institute (IDISBA), 07120 Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7435-8908","authenticated-orcid":false,"given":"Hern\u00e1n","family":"Vald\u00e9s-Socin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Centre Hospitalier Universitaire de Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Martin","sequence":"additional","affiliation":[{"name":"Human Genetics Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"},{"name":"Network of Research on Rare Diseases (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1158-9618","authenticated-orcid":false,"given":"M\u00f3nica","family":"Marazuela","sequence":"additional","affiliation":[{"name":"Hospital la Princesa, Instituto de Investigaci\u00f3n Princesa, University Aut\u00f3noma of Madrid, 28006 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Barroso","sequence":"additional","affiliation":[{"name":"Human Genetics Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-9465","authenticated-orcid":false,"given":"Javier","family":"Escalada","sequence":"additional","affiliation":[{"name":"Endocrinology and Nutrition Department, Cl\u00ednica Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, 28009 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-2033","authenticated-orcid":false,"given":"Antoni","family":"Castells","sequence":"additional","affiliation":[{"name":"Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9606-0398","authenticated-orcid":false,"given":"Ra\u00fal","family":"Torres-Ruiz","sequence":"additional","affiliation":[{"name":"Molecular Cytogenetics and Genome Editing Unit, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Rodr\u00edguez-Perales","sequence":"additional","affiliation":[{"name":"Molecular Cytogenetics and Genome Editing Unit, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Curr\u00e1s-Freixes","sequence":"additional","affiliation":[{"name":"Endocrinology and Nutrition Department, Cl\u00ednica Universidad de Navarra, 28027 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Ben\u00edtez","sequence":"additional","affiliation":[{"name":"Human Genetics Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"},{"name":"Network of Research on Rare Diseases (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"vi1","DOI":"10.1093\/rheumatology\/kez387","article-title":"The innate immune perspective of autoimmune and autoinflammatory conditions","volume":"58","author":"Frizinsky","year":"2019","journal-title":"Rheumatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nrrheum.2017.198","article-title":"Autoimmunity and primary immunodeficiency: Two sides of the same coin?","volume":"14","author":"Schmidt","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1210\/edrv.23.3.0466","article-title":"Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: Autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction","volume":"23","author":"Betterle","year":"2002","journal-title":"Endocr. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1056\/NEJMra1713301","article-title":"Autoimmune polyendocrine syndromes","volume":"378","author":"Husebye","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.autrev.2013.07.006","article-title":"Autoimmune polyendocrine syndromes","volume":"13","author":"Cutolo","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/ni.3777","article-title":"The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation","volume":"18","author":"Manthiram","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nri.2016.9","article-title":"AIRE expands: New roles in immune tolerance and beyond","volume":"16","author":"Anderson","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","first-page":"688","article-title":"Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison\u2019s disease","volume":"85","author":"Vaidya","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.jaci.2016.12.978","article-title":"Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies","volume":"140","author":"Fischer","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.autrev.2018.08.011","article-title":"The changing face of chronic autoimmune atrophic gastritis: An updated comprehensive perspective","volume":"18","author":"Massironi","year":"2019","journal-title":"Autoimmun. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1093\/hmg\/ddv054","article-title":"Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastricneuroendocrine tumour","volume":"24","author":"Calvete","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1007\/s10120-017-0723-8","article-title":"A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis","volume":"21","author":"Calvete","year":"2017","journal-title":"Gastric Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1242\/dmm.025890","article-title":"A knockin mouse model for human ATP4aR703C mutation identified in familial gastric neuroendocrine tumors recapitulates the premalignant condition of the human disease and suggests new therapeutic strategies","volume":"9","author":"Calvete","year":"2016","journal-title":"Dis. Model. Mech."},{"key":"ref_14","first-page":"52","article-title":"A genetic origin for acid\u2013base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours","volume":"23","author":"Marra","year":"2019","journal-title":"Gastric Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"553110","DOI":"10.3389\/fmed.2021.553110","article-title":"Case Report: CMV Infection and Same Mechanism-Originated Intestinal Inflammation Compatible With Bowel\/Crohn\u2019s Disease Is Suggested in ATP4A Mutated-Driven Gastric Neuroendocrine Tumors","volume":"8","author":"Calvete","year":"2021","journal-title":"Front. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fendo.2017.00092","article-title":"Hashimoto\u2019s thyroiditis and autoimmune gastritis","volume":"8","author":"Cellini","year":"2017","journal-title":"Front. Front. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"29470","DOI":"10.1074\/jbc.M109.044396","article-title":"Deletion of the chloride transporter Slc26a7 causes distal renal tubular acidosis and impairs gastric acid secretion","volume":"284","author":"Xu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17955","DOI":"10.1073\/pnas.0800616105","article-title":"Deletion of the chloride transporter Slc26a9 causes loss of tubulovesicles in parietal cells and impairs acid secretion in the stomach","volume":"105","author":"Xu","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jhep.2008.12.006","article-title":"When lightning strikes twice: The plot thickens for a dual role of the anion exchanger 2 (AE2\/SLC4A2) in the pathogenesis and treatment of primary biliary cirrhosis","volume":"50","author":"Fickert","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3928\/0090-4481-19800401-07","article-title":"Autoimmune polyglandular syndromes","volume":"9","author":"Neufeld","year":"1980","journal-title":"Pediatr. Ann."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2147\/CEG.S109123","article-title":"Autoimmune atrophic gastritis: Current perspectives","volume":"10","author":"Minalyan","year":"2017","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrgastro.2013.101","article-title":"Autoimmune atrophic gastritis-pathogenesis, pathology and management","volume":"10","author":"Neumann","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.autrev.2011.01.009","article-title":"Pernicious anemia-Genetic insights","volume":"10","author":"Banka","year":"2011","journal-title":"Autoimmun. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/cphy.c180027","article-title":"Slc26 family of anion transporters in the gastrointestinal tract: Expression, function, regulation, and role in disease","volume":"9","author":"Seidler","year":"2019","journal-title":"Compr. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.autrev.2014.10.016","article-title":"Autoimmune thyroid disorders","volume":"14","author":"Antonelli","year":"2015","journal-title":"Autoimmun. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1210\/jc.2017-02202","article-title":"Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis","volume":"103","author":"Zou","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e99631","DOI":"10.1172\/jci.insight.99631","article-title":"Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism","volume":"3","author":"Cangul","year":"2018","journal-title":"JCI Insight"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ravi, N., Yang, M., Mylona, N., Wennerberg, J., and Paulsson, K. (2020). Global RNA expression and DNA methylation patterns in primary anaplastic thyroid cancer. Cancers, 12.","DOI":"10.3390\/cancers12030680"},{"key":"ref_29","first-page":"579","article-title":"The thyrogastric syndrome: Its effects on micronutriments and gastric tumorigenesis | Le syndrome auto-immun thyro-gastrique: Ses effets sur les micronutriments et la tumorigen\u00e8se gastrique","volume":"68","author":"Lutteri","year":"2013","journal-title":"Rev. Med. De Liege"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1443-1661.1998.tb00562.x","article-title":"Gastric carcinoid tumor associated with Graves\u2019 disease: A case report","volume":"10","author":"Saitoh","year":"1998","journal-title":"Dig. Endosc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1210\/jc.2007-2134","article-title":"Autoimmune gastritis in type 1 diabetes: A clinically oriented review","volume":"93","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1111\/j.1365-2230.2006.02171.x","article-title":"Vitiligo associated with other autoimmune diseases: Polyglandular autoimmune syndrome types 3B + C and 4","volume":"31","author":"Amerio","year":"2006","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/jaut.1995.0009","article-title":"Associated autoimmunity in addison\u2019s disease","volume":"8","author":"Zelissen","year":"1995","journal-title":"J. Autoimmun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/S0929-6646(09)60181-9","article-title":"Coexistence of pernicious anemia and myasthenia gravis-A rare combination of autoimmune diseases in Taiwan","volume":"105","author":"Chang","year":"2006","journal-title":"J. Formos. Med Assoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.det.2016.11.013","article-title":"Genetics of Vitiligo","volume":"35","author":"Spritz","year":"2017","journal-title":"Dermatol. Clin."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-018-1012-z","article-title":"Genomic screening for monogenic forms of diabetes","volume":"16","author":"Biesecker","year":"2018","journal-title":"BMC Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"893","DOI":"10.2337\/dc16-0145","article-title":"Mechanisms of diabetes improvement following bariatric\/metabolic surgery","volume":"39","author":"Batterham","year":"2016","journal-title":"Diabetes Care"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3500\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:45:23Z","timestamp":1760168723000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3500"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123500"],"URL":"https:\/\/doi.org\/10.3390\/cells10123500","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,10]]}}}