{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:44:21Z","timestamp":1787237061795,"version":"build-2736575974"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["21ek0109550h0001"],"award-info":[{"award-number":["21ek0109550h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Association des Pancr\u00e9atites Chroniques H\u00e9r\u00e9ditaires"},{"name":"Association Ga\u00e9tan Sale\u00fcn, France"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82120108006"],"award-info":[{"award-number":["82120108006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Else Kr\u00f6ner-Fresenius-Foundation","award":["2017_A108 \u2013 EKFZ-Witt"],"award-info":[{"award-number":["2017_A108 \u2013 EKFZ-Witt"]}]},{"DOI":"10.13039\/501100014843","name":"Else Kr\u00f6ner-Fresenius-Zentrum f\u00fcr Ern\u00e4hrungsmedizin","doi-asserted-by":"publisher","award":["2022-EKFZ-Witt"],"award-info":[{"award-number":["2022-EKFZ-Witt"]}],"id":[{"id":"10.13039\/501100014843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG WI 2036\/3-1"],"award-info":[{"award-number":["DFG WI 2036\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009053","name":"The Wellcome Trust DBT India Alliance","doi-asserted-by":"publisher","award":["IA\/M\/16\/1\/502"],"award-info":[{"award-number":["IA\/M\/16\/1\/502"]}],"id":[{"id":"10.13039\/501100009053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Gastroenterol"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The transient receptor potential cation channel subfamily V member 6 (\n                      <jats:italic>TRPV6<\/jats:italic>\n                      ) gene, encoding a calcium-selective ion channel, was recently identified as a susceptibility gene for pancreatitis. This study aimed to clarify the natural history of\n                      <jats:italic>TRPV6<\/jats:italic>\n                      -related pancreatitis and the impact of pancreas-specific deletion of\n                      <jats:italic>Trpv6<\/jats:italic>\n                      on pancreatitis in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Clinical information of the patients carrying functionally impaired\n                      <jats:italic>TRPV6<\/jats:italic>\n                      variants, defined by Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging and minigene assays, was collected from six international centers. Cumulative rates were assessed using Kaplan\u2013Meier analysis. As controls, Japanese patients with alcohol-unrelated\u00a0pancreatitis carrying pathogenic variants in\n                      <jats:italic>PRSS1<\/jats:italic>\n                      or\n                      <jats:italic>SPINK1<\/jats:italic>\n                      , as well as those without pathogenic variants in pancreatitis susceptibility genes, were enrolled. A pancreas-specific\n                      <jats:italic>Trpv6<\/jats:italic>\n                      conditional knockout mouse was established by crossing the\n                      <jats:italic>Trpv6<\/jats:italic>\n                      floxed mouse and the\n                      <jats:italic>Pdx-1-Cre<\/jats:italic>\n                      mouse. Pancreatitis was induced by repeated intraperitoneal injections of caerulein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ninety-four patients with functionally impaired\n                      <jats:italic>TRPV6<\/jats:italic>\n                      variants, including six splice-site variants, were enrolled. The median age at symptom onset was 16\u00a0years. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 55.5%, 20.1%, 10.8%, and 41.6% at 30\u00a0years, and 81.5%, 49.6%, 45.4%, and 69.9% at 50\u00a0years, respectively. Pancreas-specific\n                      <jats:italic>Trpv6<\/jats:italic>\n                      knockout mice developed more severe acute and chronic pancreatitis than the control mice. Caerulein treatment increased the TRPV6 expression in pancreatic acinar cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Functionally impaired\n                      <jats:italic>TRPV6<\/jats:italic>\n                      variants significantly influenced the clinical outcomes of chronic pancreatitis. TRPV6 in pancreatic acinar cells might play a protective role against pancreatitis in mice.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00535-025-02323-y","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T13:32:47Z","timestamp":1763386367000},"page":"207-221","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["TRPV6-related pancreatitis: natural history and the impact of the pancreas-specific deletion on pancreatitis in mice"],"prefix":"10.1007","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7184-7282","authenticated-orcid":false,"given":"Atsushi","family":"Masamune","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Masson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Bin","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka Magdalena","family":"Rygiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudipta Dhar","family":"Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Kikuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehiro","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitomi","family":"Nakasuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Takikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren","family":"Jie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasumasa","family":"Sekino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waku","family":"Hatta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Niihori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Sakaguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinciane","family":"Rebours","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Buscail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben Thomas","family":"Kurien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhya S.","family":"Visweswariah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Rosendahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Ferec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grzegorz","family":"Oracz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Witt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuan","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Min","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Hamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"2323_CR1","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.pan.2016.02.001","volume":"16","author":"DC Whitcomb","year":"2016","unstructured":"Whitcomb DC, Frulloni L, Garg P, et al. Chronic pancreatitis: an international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016;16:218\u201324.","journal-title":"Pancreatology"},{"key":"2323_CR2","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1053\/j.gastro.2018.11.081","volume":"156","author":"J Mayerle","year":"2019","unstructured":"Mayerle J, Sendler M, Hegyi E, et al. Genetics, cell biology, and pathophysiology of pancreatitis. Gastroenterology. 2019;156:1951-68.e1.","journal-title":"Gastroenterology"},{"key":"2323_CR3","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/S0140-6736(20)31318-0","volume":"396","author":"G Beyer","year":"2020","unstructured":"Beyer G, Habtezion A, Werner J, et al. Chronic pancreatitis. Lancet. 2020;396:499\u2013512.","journal-title":"Lancet"},{"key":"2323_CR4","doi-asserted-by":"publisher","first-page":"e070920","DOI":"10.1136\/bmj-2023-070920","volume":"384","author":"OJ Hines","year":"2024","unstructured":"Hines OJ, Pandol SJ. Management of chronic pancreatitis. BMJ. 2024;384:e070920.","journal-title":"BMJ"},{"key":"2323_CR5","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/ng1096-141","volume":"14","author":"DC Whitcomb","year":"1996","unstructured":"Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141\u20135.","journal-title":"Nat Genet"},{"key":"2323_CR6","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1056\/NEJM199809033391001","volume":"339","author":"N Sharer","year":"1998","unstructured":"Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med. 1998;339:645\u201352.","journal-title":"N Engl J Med"},{"key":"2323_CR7","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1056\/NEJM199809033391002","volume":"339","author":"JA Cohn","year":"1998","unstructured":"Cohn JA, Friedman KJ, Noone PG, et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med. 1998;339:653\u20138.","journal-title":"N Engl J Med"},{"key":"2323_CR8","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/76088","volume":"25","author":"H Witt","year":"2000","unstructured":"Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000;25:213\u20136.","journal-title":"Nat Genet"},{"key":"2323_CR9","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/ng.2007.44","volume":"40","author":"J Rosendahl","year":"2008","unstructured":"Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nat Genet. 2008;40:78\u201382.","journal-title":"Nat Genet"},{"key":"2323_CR10","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/ng.2730","volume":"45","author":"H Witt","year":"2013","unstructured":"Witt H, Beer S, Rosendahl J, et al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis. Nat Genet. 2013;45:1216\u201320.","journal-title":"Nat Genet"},{"key":"2323_CR11","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1053\/j.gastro.2020.01.005","volume":"158","author":"A Masamune","year":"2020","unstructured":"Masamune A, Kotani H, S\u00f6rgel FL, et al. Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis. Gastroenterology. 2020;158:1626-41.e8.","journal-title":"Gastroenterology"},{"key":"2323_CR12","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1002\/humu.24032","volume":"41","author":"WB Zou","year":"2020","unstructured":"Zou WB, Wang YC, Ren XL, et al. TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population. Hum Mutat. 2020;41:1351\u20137.","journal-title":"Hum Mutat"},{"key":"2323_CR13","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1002\/humu.24315","volume":"43","author":"S Hamada","year":"2022","unstructured":"Hamada S, Masson E, Chen JM, et al. Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis. Hum Mutat. 2022;43:228\u201339.","journal-title":"Hum Mutat"},{"key":"2323_CR14","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1016\/j.pan.2021.09.005","volume":"21","author":"G Oracz","year":"2021","unstructured":"Oracz G, Zar\u00f3d M, Ewers M, et al. Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients. Pancreatology. 2021;21:1434\u201342.","journal-title":"Pancreatology"},{"key":"2323_CR15","doi-asserted-by":"publisher","first-page":"1058057","DOI":"10.3389\/fgene.2022.1058057","volume":"13","author":"IA Shah","year":"2023","unstructured":"Shah IA, Prasad H, Banerjee S, et al. A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis. Front Genet. 2023;13:1058057.","journal-title":"Front Genet"},{"key":"2323_CR16","doi-asserted-by":"publisher","first-page":"146192","DOI":"10.1016\/j.gene.2022.146192","volume":"817","author":"V Khattar","year":"2022","unstructured":"Khattar V, Wang L, Peng JB. Calcium selective channel TRPV6: structure, function, and implications in health and disease. Gene. 2022;817:146192.","journal-title":"Gene"},{"key":"2323_CR17","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.ceca.2017.04.006","volume":"67","author":"C Fecher-Trost","year":"2017","unstructured":"Fecher-Trost C, Wissenbach U, Weissgerber P. TRPV6: from identification to function. Cell Calcium. 2017;67:116\u201322.","journal-title":"Cell Calcium"},{"key":"2323_CR18","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1359\/jbmr.061110","volume":"22","author":"SD Bianco","year":"2007","unstructured":"Bianco SD, Peng JB, Takanaga H, et al. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Miner Res. 2007;22:274\u201385.","journal-title":"J Bone Miner Res"},{"key":"2323_CR19","doi-asserted-by":"publisher","first-page":"ra27","DOI":"10.1126\/scisignal.2001791","volume":"4","author":"P Weissgerber","year":"2011","unstructured":"Weissgerber P, Kriebs U, Tsvilovskyy V, et al. Male fertility depends on Ca2+ absorption by TRPV6 in epididymal epithelia. Sci Signal. 2011;4:ra27.","journal-title":"Sci Signal"},{"key":"2323_CR20","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1007\/s10620-014-3476-9","volume":"60","author":"E Nakano","year":"2015","unstructured":"Nakano E, Masamune A, Niihori T, et al. Targeted next-generation sequencing effectively analyzed the cystic fibrosis transmembrane conductance regulator gene in pancreatitis. Dig Dis Sci. 2015;60:1297\u2013307.","journal-title":"Dig Dis Sci"},{"key":"2323_CR21","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1254\/jphs.10169FP","volume":"114","author":"Y Sudo","year":"2010","unstructured":"Sudo Y, Matsuo K, Tetsuo T, et al. Derived (mutated)-types of TRPV6 channels elicit greater Ca2+ influx into the cells than ancestral-types of TRPV6: evidence from Xenopus oocytes and mammalian cell expression system. J Pharmacol Sci. 2010;114:281\u201391.","journal-title":"J Pharmacol Sci"},{"key":"2323_CR22","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1007\/s00535-020-01704-9","volume":"55","author":"A Masamune","year":"2020","unstructured":"Masamune A, Kikuta K, Kume K, et al. Nationwide epidemiological survey of chronic pancreatitis in Japan: introduction and validation of the new Japanese diagnostic criteria 2019. J Gastroenterol. 2020;55:1062\u201371.","journal-title":"J Gastroenterol"},{"key":"2323_CR23","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1046\/j.1440-1746.2002.02762.x","volume":"17","author":"RK Tandon","year":"2002","unstructured":"Tandon RK, Sato N, Garg PK. Chronic pancreatitis: Asia-Pacific consensus report. J Gastroenterol Hepatol. 2002;17:508\u201318.","journal-title":"J Gastroenterol Hepatol"},{"key":"2323_CR24","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/j.ebiom.2019.09.032","volume":"48","author":"N Muller","year":"2019","unstructured":"Muller N, Sarantitis I, Rouanet M, et al. Natural history of SPINK1 germline mutation related-pancreatitis. EBioMedicine. 2019;48:581\u201391.","journal-title":"EBioMedicine"},{"key":"2323_CR25","doi-asserted-by":"publisher","first-page":"e1378","DOI":"10.1016\/j.cgh.2021.08.033","volume":"20","author":"N Ru","year":"2022","unstructured":"Ru N, Xu XN, Cao Y, et al. The impacts of genetic and environmental factors on the progression of chronic pancreatitis. Clin Gastroenterol Hepatol. 2022;20:e1378\u201387.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"41","key":"2323_CR26","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.2337\/dc18-S002","volume":"2018","author":"American Diabetes Association","year":"2018","unstructured":"American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care. 2018;2018(41):S13-27.","journal-title":"Diabetes Care"},{"key":"2323_CR27","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1053\/j.gastro.2004.12.008","volume":"128","author":"JN Jensen","year":"2005","unstructured":"Jensen JN, Cameron E, Garay MV, et al. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology. 2005;128:728\u201341.","journal-title":"Gastroenterology"},{"key":"2323_CR28","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.bbrc.2013.02.095","volume":"433","author":"K Kikuta","year":"2013","unstructured":"Kikuta K, Masamune A, Hamada S, et al. Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic beta-cells. Biochem Biophys Res Commun. 2013;433:292\u20137.","journal-title":"Biochem Biophys Res Commun"},{"key":"2323_CR29","doi-asserted-by":"publisher","first-page":"G1089","DOI":"10.1152\/ajpgi.00571.2005","volume":"291","author":"C Moreno","year":"2006","unstructured":"Moreno C, Nicaise C, Gustot T, et al. Chemokine receptor CCR5 deficiency exacerbates caerulein-induced acute pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2006;291:G1089\u201399.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2323_CR30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1124\/jpet.121.000744","volume":"379","author":"R Matsumoto","year":"2021","unstructured":"Matsumoto R, Hamada S, Tanaka Y, et al. Nuclear factor erythroid 2-related factor 2 depletion sensitizes pancreatic cancer cells to gemcitabine via aldehyde dehydrogenase 3a1 repression. J Pharmacol Exp Ther. 2021;379:33\u201340.","journal-title":"J Pharmacol Exp Ther"},{"key":"2323_CR31","doi-asserted-by":"publisher","first-page":"e2402550","DOI":"10.1002\/advs.202402550","volume":"11","author":"MJ Wang","year":"2024","unstructured":"Wang MJ, Wang YC, Masson E, et al. SEC16A variants predispose to chronic pancreatitis by impairing ER-to-Golgi transport and inducing ER stress. Adv Sci (Weinh). 2024;11:e2402550.","journal-title":"Adv Sci (Weinh)"},{"key":"2323_CR32","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1038\/nprot.2016.097","volume":"11","author":"L Broutier","year":"2016","unstructured":"Broutier L, Andersson-Rolf A, Hindley CJ, et al. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat Protoc. 2016;11:1724\u201343.","journal-title":"Nat Protoc"},{"key":"2323_CR33","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/nm.1951","volume":"15","author":"A Ootani","year":"2009","unstructured":"Ootani A, Li X, Sangiorgi E, et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. 2009;15:701\u20136.","journal-title":"Nat Med"},{"key":"2323_CR34","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1038\/nm.3201","volume":"19","author":"JF Dekkers","year":"2013","unstructured":"Dekkers JF, Wiegerinck CL, de Jonge HR, et al. A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med. 2013;19:939\u201345.","journal-title":"Nat Med"},{"key":"2323_CR35","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"2323_CR36","doi-asserted-by":"publisher","first-page":"e0276397","DOI":"10.1371\/journal.pone.0276397","volume":"17","author":"G Berke","year":"2022","unstructured":"Berke G, Gede N, Szadai L, et al. Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: a meta-analysis. PLoS ONE. 2022;17:e0276397.","journal-title":"PLoS ONE"},{"key":"2323_CR37","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1007\/s00535-012-0590-3","volume":"47","author":"K Kume","year":"2012","unstructured":"Kume K, Masamune A, Ariga H, et al. Do genetic variants in the SPINK1 gene affect the level of serum PSTI? J Gastroenterol. 2012;47:1267\u201374.","journal-title":"J Gastroenterol"},{"key":"2323_CR38","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1053\/j.gastro.2020.03.027","volume":"158","author":"M Sahin-T\u00f3th","year":"2020","unstructured":"Sahin-T\u00f3th M. Channelopathy of the pancreas causes chronic pancreatitis. Gastroenterology. 2020;158:1538\u201340.","journal-title":"Gastroenterology"},{"key":"2323_CR39","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","volume":"24","author":"\u00c5 Segerstolpe","year":"2016","unstructured":"Segerstolpe \u00c5, Palasantza A, Eliasson P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 2016;24:593\u2013607.","journal-title":"Cell Metab"},{"key":"2323_CR40","doi-asserted-by":"publisher","first-page":"e0198365","DOI":"10.1371\/journal.pone.0198365","volume":"13","author":"L Hao","year":"2018","unstructured":"Hao L, Wang LS, Liu Y, et al. The different course of alcoholic and idiopathic chronic pancreatitis: a long-term study of 2,037 patients. PLoS ONE. 2018;13:e0198365.","journal-title":"PLoS ONE"},{"key":"2323_CR41","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.dld.2019.07.004","volume":"52","author":"XY Tang","year":"2020","unstructured":"Tang XY, Zou WB, Yu FF, et al. Meta-analysis of the impact of the SPINK1 c.194 + 2T > C variant in chronic pancreatitis. Dig Liver Dis. 2020;52:143\u20138.","journal-title":"Dig Liver Dis"},{"key":"2323_CR42","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.dld.2017.04.023","volume":"49","author":"M Di Leo","year":"2017","unstructured":"Di Leo M, Bianco M, Zuppardo RA, et al. Meta-analysis of the impact of SPINK1 p. N34S gene variation in Caucasic patients with chronic pancreatitis. An update. Dig Liver Dis. 2017;49:847\u201353.","journal-title":"Dig Liver Dis"},{"key":"2323_CR43","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1136\/gut.2008.149179","volume":"58","author":"V Rebours","year":"2009","unstructured":"Rebours V, Boutron-Ruault MC, Schnee M, et al. The natural history of hereditary pancreatitis: a national series. Gut. 2009;58:97\u2013103.","journal-title":"Gut"},{"key":"2323_CR44","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1007\/s00535-017-1388-0","volume":"53","author":"A Masamune","year":"2018","unstructured":"Masamune A, Kikuta K, Hamada S, et al. Nationwide survey of hereditary pancreatitis in Japan. J Gastroenterol. 2018;53:152\u201360.","journal-title":"J Gastroenterol"},{"key":"2323_CR45","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/s41424-018-0069-5","volume":"9","author":"WB Zou","year":"2018","unstructured":"Zou WB, Tang XY, Zhou DZ, et al. SPINK1, PRSS1, CTRC, and CFTR genotypes influence disease onset and clinical outcomes in chronic pancreatitis. Clin Transl Gastroenterol. 2018;9:204.","journal-title":"Clin Transl Gastroenterol"},{"key":"2323_CR46","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1016\/j.ajhg.2018.04.006","volume":"102","author":"Y Suzuki","year":"2018","unstructured":"Suzuki Y, Chitayat D, Sawada H, et al. TRPV6 variants interfere with maternal-fetal calcium transport through the placenta and cause transient neonatal hyperparathyroidism. Am J Hum Genet. 2018;102:1104\u201314.","journal-title":"Am J Hum Genet"},{"key":"2323_CR47","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1136\/gutjnl-2015-311168","volume":"65","author":"WB Zou","year":"2016","unstructured":"Zou WB, Boulling A, Masson E, et al. Clarifying the clinical relevance of SPINK1 intronic variants in chronic pancreatitis. Gut. 2016;65:884\u20136.","journal-title":"Gut"},{"key":"2323_CR48","doi-asserted-by":"publisher","first-page":"102481","DOI":"10.1016\/j.ceca.2021.102481","volume":"100","author":"P Wartenberg","year":"2021","unstructured":"Wartenberg P, Lux F, Busch K, et al. A TRPV6 expression atlas for the mouse. Cell Calcium. 2021;100:102481.","journal-title":"Cell Calcium"},{"key":"2323_CR49","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1097\/01.LAB.0000043910.41414.E7","volume":"82","author":"L Zhuang","year":"2002","unstructured":"Zhuang L, Peng JB, Tou L, et al. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Investig. 2002;82:1755\u201364.","journal-title":"Lab Investig"},{"key":"2323_CR50","doi-asserted-by":"publisher","first-page":"110937","DOI":"10.1016\/j.celrep.2022.110937","volume":"39","author":"AS Meena","year":"2022","unstructured":"Meena AS, Shukla PK, Bell B, et al. TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response. Cell Rep. 2022;39:110937.","journal-title":"Cell Rep"},{"key":"2323_CR51","doi-asserted-by":"publisher","first-page":"104181","DOI":"10.1016\/j.ebiom.2022.104181","volume":"82","author":"Z Hou","year":"2022","unstructured":"Hou Z, Ding Q, Li Y, et al. Intestinal epithelial \u03b2 Klotho is a critical protective factor in alcohol-induced intestinal barrier dysfunction and liver injury. EBioMedicine. 2022;82:104181.","journal-title":"EBioMedicine"},{"key":"2323_CR52","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/S1542-3565(04)00013-8","volume":"2","author":"N Howes","year":"2004","unstructured":"Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol. 2004;2:252\u201361.","journal-title":"Clin Gastroenterol Hepatol"}],"container-title":["Journal of Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00535-025-02323-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00535-025-02323-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00535-025-02323-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T09:03:46Z","timestamp":1771664626000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00535-025-02323-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":52,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["2323"],"URL":"https:\/\/doi.org\/10.1007\/s00535-025-02323-y","relation":{},"ISSN":["0944-1174","1435-5922"],"issn-type":[{"value":"0944-1174","type":"print"},{"value":"1435-5922","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]},"assertion":[{"value":"18 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}