{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:01:18Z","timestamp":1791403278090,"version":"4.3.3"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:00:00Z","timestamp":1584489600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:00:00Z","timestamp":1584489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015850","name":"Digestive Medical Coordinated Development Center of Beijing Hospitals Authority","doi-asserted-by":"crossref","award":["XXT06"],"award-info":[{"award-number":["XXT06"]}],"id":[{"id":"10.13039\/501100015850","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations in the adenosine triphosphate-binding cassette subfamily C member 2 (\n                      <jats:italic>ABCC2<\/jats:italic>\n                      ) gene, which encodes multidrug resistance-associated protein 2 (MRP2). However, little is known about the causative mutation of DJS in China. Recently, we have reported\n                      <jats:italic>ABCC2<\/jats:italic>\n                      p.G693R mutation in two unrelated cases. In the present study, we investigated the pathogenicity of the\n                      <jats:italic>ABCC2<\/jats:italic>\n                      p.G693R mutation in DJS in China.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Clinical and genetic analysis was conducted for the two patients with the\n                      <jats:italic>ABCC2<\/jats:italic>\n                      p.G693R mutation. Whole exome sequencing for mutations in other known hyperbilirubinemia-related genes was conducted for the cases with\n                      <jats:italic>ABCC2<\/jats:italic>\n                      p.G693R. Expression and cellular localization of the mutant MRP2 p.G693R were analyzed by Western blotting and immunofluorescence assay, respectively. Organic anion transport activity was evaluated by the analysis of glutathione-conjugated-monochlorobimane.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The two DJS patients with\n                      <jats:italic>ABCC2<\/jats:italic>\n                      p.G693R mutation, which was conserved among different species, showed typical hyperbilirubinemia phenotype. No pathogenic mutation was identified in the other known hyperbilirubinemia related genes. Functional studies in three cell lines showed that the expression, localization and the organic anion transport activity were significantly compromised by MRP2 p.G693R mutation compared with wild-type MRP2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The recurrent\n                      <jats:italic>ABCC2<\/jats:italic>\n                      p.G693R mutation is associated with loss of function of the MRP2 protein and may result in hyperbilirubinemia in DJS in China.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-020-1346-4","type":"journal-article","created":{"date-parts":[[2020,3,17]],"date-time":"2020-03-17T23:03:16Z","timestamp":1584486196000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A recurrent ABCC2 p.G693R mutation resulting in loss of function of MRP2 and hyperbilirubinemia in Dubin-Johnson syndrome in China"],"prefix":"10.1186","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3220-6041","authenticated-orcid":false,"given":"Lina","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jidong","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojuan","family":"Ou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"1346_CR1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1097\/00005792-195409000-00001","volume":"33","author":"IN Dubin","year":"1954","unstructured":"Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore). 1954;33:155\u201397.","journal-title":"Medicine (Baltimore)"},{"key":"1346_CR2","first-page":"549","volume":"39","author":"M Shani","year":"1970","unstructured":"Shani M, Seligsohn U, Gilon E, Sheba C, Adam A. Dubin-Johnson syndrome in Israel. I. Clinical, laboratory, and genetic aspects of 101 cases. Q J Med. 1970;39:549\u201367.","journal-title":"Q J Med"},{"key":"1346_CR3","doi-asserted-by":"publisher","first-page":"161-167.e1","DOI":"10.1016\/j.jpeds.2017.12.058","volume":"196","author":"Takao Togawa","year":"2018","unstructured":"Togawa T, Mizuochi T, Sugiura T, Kusano H, Tanikawa K, Sasaki T, Ichinose F, et al. Clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome: a multicenter study in Japan. J Pediatr. 2018. https:\/\/doi.org\/10.1016\/j.jpeds.2017.12.058.","journal-title":"The Journal of Pediatrics"},{"key":"1346_CR4","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1124\/dmd.113.055772","volume":"42","author":"D Keppler","year":"2014","unstructured":"Keppler D. The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos. 2014;42:561\u20135.","journal-title":"Drug Metab Dispos"},{"key":"1346_CR5","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1111\/liv.13351","volume":"37","author":"S Gazzin","year":"2017","unstructured":"Gazzin S, Masutti F, Vitek L, Tiribelli C. The molecular basis of jaundice: an old symptom revisited. Liver Int. 2017;37:1094\u2013102.","journal-title":"Liver Int"},{"key":"1346_CR6","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1053\/jhep.2002.36368","volume":"36","author":"K Hashimoto","year":"2002","unstructured":"Hashimoto K, Uchiumi T, Konno T, Ebihara T, Nakamura T, Wada M, Sakisaka S, et al. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. 2002;36:1236\u201345.","journal-title":"Hepatology"},{"key":"1346_CR7","first-page":"4201","volume":"16","author":"L Wu","year":"2018","unstructured":"Wu L, Zhang W, Jia S, Zhao X, Zhou D, Xu A, Duan W, et al. Mutation analysis of the ABCC2 gene in Chinese patients with Dubin-Johnson syndrome. Exp Ther Med. 2018;16:4201\u20136.","journal-title":"Exp Ther Med"},{"key":"1346_CR8","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1111\/liv.14013","volume":"39","author":"W Zhang","year":"2019","unstructured":"Zhang W, Xu A, Li Y, Zhao S, Zhou D, Wu L, Zhang B, et al. A novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China. Liver Int. 2019;39:1120\u20137.","journal-title":"Liver Int"},{"key":"1346_CR9","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1136\/jmedgenet-2018-105348","volume":"55","author":"T Lv","year":"2018","unstructured":"Lv T, Zhang W, Xu A, Li Y, Zhou D, Zhang B, Li X, et al. Non- mutations in haemochromatosis in China: combination of heterozygous mutations involving signal peptide variants. J Med Genet. 2018;55:650\u201360.","journal-title":"J Med Genet"},{"key":"1346_CR10","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/sj.bjp.0704284","volume":"134","author":"SA Terlouw","year":"2001","unstructured":"Terlouw SA, Masereeuw R, van den Broek PH, Notenboom S, Russel FG. Role of multidrug resistance protein 2 (MRP2) in glutathione-bimane efflux from Caco-2 and rat renal proximal tubule cells. Br J Pharmacol. 2001;134:931\u20138.","journal-title":"Br J Pharmacol"},{"key":"1346_CR11","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1111\/jgh.14036","volume":"33","author":"SW Park","year":"2018","unstructured":"Park SW, Jun CH, Choi SK, Kim HJ, Kim GE. Hepatobiliary and pancreatic: a black liver of Dubin-Johnson syndrome. J Gastroenterol Hepatol. 2018;33:562.","journal-title":"J Gastroenterol Hepatol"},{"key":"1346_CR12","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1124\/dmd.116.074740","volume":"45","author":"RR Gilibili","year":"2017","unstructured":"Gilibili RR, Chatterjee S, Bagul P, Mosure KW, Murali BV, Mariappan TT, Mandlekar S, et al. Coproporphyrin-I: a fluorescent, endogenous optimal probe substrate for ABCC2 (MRP2) suitable for vesicle-based MRP2 inhibition assay. Drug Metab Dispos. 2017;45:604\u201311.","journal-title":"Drug Metab Dispos"},{"key":"1346_CR13","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1053\/j.gastro.2014.03.047","volume":"146","author":"S Erlinger","year":"2014","unstructured":"Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146:1625\u201338.","journal-title":"Gastroenterology"},{"key":"1346_CR14","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1002\/humu.22041","volume":"33","author":"R Arlanov","year":"2012","unstructured":"Arlanov R, Porter A, Strand D, Brough R, Karpova D, Kerb R, Wojnowski L, et al. Functional characterization of protein variants of the human multidrug transporter ABCC2 by a novel targeted expression system in fibrosarcoma cells. Hum Mutat. 2012;33:750\u201362.","journal-title":"Hum Mutat"},{"key":"1346_CR15","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1097\/01213011-200505000-00002","volume":"15","author":"JS Hulot","year":"2005","unstructured":"Hulot JS, Villard E, Maguy A, Morel V, Mir L, Tostivint I, William-Faltaos D, et al. A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet Genomics. 2005;15:277\u201385.","journal-title":"Pharmacogenet Genomics"},{"key":"1346_CR16","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1124\/dmd.104.003335","volume":"33","author":"HE Meyer zu Schwabedissen","year":"2005","unstructured":"Meyer zu Schwabedissen HE, Jedlitschky G, Gratz M, Haenisch S, Linnemann K, Fusch C, Cascorbi I, et al. Variable expression of MRP2 (ABCC2) in human placenta: influence of gestational age and cellular differentiation. Drug Metab Dispos. 2005;33:896\u2013904.","journal-title":"Drug Metab Dispos"},{"key":"1346_CR17","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1023\/B:PHAM.0000026422.06207.33","volume":"21","author":"M Hirouchi","year":"2004","unstructured":"Hirouchi M, Suzuki H, Itoda M, Ozawa S, Sawada J, Ieiri I, Ohtsubo K, Sugiyama Y. Characterization of the cellular localization, expression level, and function of SNP variants of MRP2\/ABCC2. Pharm Res. 2004;21:742\u20138.","journal-title":"Pharm Res"},{"key":"1346_CR18","doi-asserted-by":"publisher","first-page":"36923","DOI":"10.1074\/jbc.M105047200","volume":"276","author":"R Mor-Cohen","year":"2001","unstructured":"Mor-Cohen R, Zivelin A, Rosenberg N, Shani M, Muallem S, Seligsohn U. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem. 2001;276:36923\u201330.","journal-title":"J Biol Chem"},{"key":"1346_CR19","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/hep.21165","volume":"43","author":"A Floreani","year":"2006","unstructured":"Floreani A, Carderi I, Variola A, Rizzotto ER, Nicol J, Bergasa NV. A novel multidrug-resistance protein 2 gene mutation identifies a subgroup of patients with primary biliary cirrhosis and pruritus. Hepatology. 2006;43:1152\u20134.","journal-title":"Hepatology"},{"key":"1346_CR20","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1097\/FPC.0b013e328348c786","volume":"21","author":"V Megaraj","year":"2011","unstructured":"Megaraj V, Zhao T, Paumi CM, Gerk PM, Kim RB, Vore M. Functional analysis of nonsynonymous single nucleotide polymorphisms of multidrug resistance-associated protein 2 (ABCC2). Pharmacogenet Genomics. 2011;21:506\u201315.","journal-title":"Pharmacogenet Genomics"},{"key":"1346_CR21","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1097\/FPC.0b013e32834d672b","volume":"21","author":"L Elens","year":"2011","unstructured":"Elens L, Tyteca D, Panin N, Courtoy P, Lison D, Demoulin JB, Haufroid V. Functional defect caused by the 4544G>a SNP in ABCC2: potential impact for drug cellular disposition. Pharmacogenet Genomics. 2011;21:884\u201393.","journal-title":"Pharmacogenet Genomics"},{"key":"1346_CR22","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1210\/jc.2002-021580","volume":"88","author":"JB Cheng","year":"2003","unstructured":"Cheng JB, Jacquemin E, Gerhardt M, Nazer H, Cresteil D, Heubi JE, Setchell KDR, et al. Molecular genetics of 3\u03b2-Hydroxy-\u03945-C27-steroid Oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease. J Clin Endocrinol Metab. 2003;88:1833\u201341.","journal-title":"J Clin Endocrinol Metab"},{"key":"1346_CR23","doi-asserted-by":"publisher","first-page":"98","DOI":"10.4103\/0366-6999.172603","volume":"129","author":"HY Huang","year":"2016","unstructured":"Huang HY, Zhou H, Wang H, Chen YX, Fang F. Novel mutations in the 3\u03b2-hydroxy-\u03945-C27-steroid dehydrogenase gene (HSD3B7) in a patient with neonatal cholestasis. Chin Med J. 2016;129:98\u2013100.","journal-title":"Chin Med J"},{"key":"1346_CR24","doi-asserted-by":"publisher","first-page":"7266","DOI":"10.4081\/pr.2017.7266","volume":"9","author":"G Bossi","year":"2017","unstructured":"Bossi G, Giordano G, Rispoli GA, Maggiore G, Naturale M, Marchetti D, Iascone M. Atypical clinical presentation and successful treatment with oral cholic acid of a child with defective bile acid synthesis due to a novel mutation in the gene. Pediatric Reports. 2017;9:7266.","journal-title":"Pediatric Reports"},{"key":"1346_CR25","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1007\/s11095-017-2160-0","volume":"34","author":"X Wen","year":"2017","unstructured":"Wen X, Joy MS, Aleksunes LM. In vitro transport activity and trafficking of MRP2\/ABCC2 polymorphic variants. Pharm Res. 2017;34:1637\u201347.","journal-title":"Pharm Res"},{"key":"1346_CR26","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1111\/j.1872-034X.2012.01103.x","volume":"43","author":"T Uchiumi","year":"2013","unstructured":"Uchiumi T, Tanamachi H, Kuchiwaki K, Kajita M, Matsumoto S, Yagi M, Kanki T, et al. Mutation and functional analysis of ABCC2\/multidrug resistance protein 2 in a Japanese patient with Dubin-Johnson syndrome. Hepatol Res. 2013;43:569\u201375.","journal-title":"Hepatol Res"},{"key":"1346_CR27","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1159\/000450911","volume":"35","author":"D Keppler","year":"2017","unstructured":"Keppler D. Progress in the molecular characterization of Hepatobiliary transporters. Dig Dis. 2017;35:197\u2013202.","journal-title":"Dig Dis"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-020-1346-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13023-020-1346-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-020-1346-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T20:34:38Z","timestamp":1616013278000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-020-1346-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,18]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["1346"],"URL":"https:\/\/doi.org\/10.1186\/s13023-020-1346-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.17212\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.17212\/v2","asserted-by":"object"}]},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,18]]},"assertion":[{"value":"8 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"74"}}