{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:13:43Z","timestamp":1785150823253,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T00:00:00Z","timestamp":1670457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, <jats:ext-link>https:\/\/www.omim.org\/entry\/602347<\/jats:ext-link>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>Between September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (<jats:italic>ABCB4<\/jats:italic>), <jats:ext-link>https:\/\/www.omim.org\/entry\/171060<\/jats:ext-link>] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, \u03b3-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of <jats:italic>ABCB4<\/jats:italic> (c.1560 + 2T &amp;gt; A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant <jats:italic>ABCB4<\/jats:italic> pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>MDR3 immunohistochemistry and molecular genetic analyses of <jats:italic>ABCB4<\/jats:italic> are essential for the accurate diagnosis of PFIC3.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2022.962408","type":"journal-article","created":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T15:28:00Z","timestamp":1670513280000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case series of progressive familial intrahepatic cholestasis type 3: Characterization of variants in ABCB4 in China"],"prefix":"10.3389","volume":"9","author":[{"given":"Jinlin","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Mi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1055\/s-0031-1272831","article-title":"Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings.","volume":"31","author":"Morotti","year":"2011","journal-title":"Semin Liver Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1016\/j.dld.2019.04.013","article-title":"Familial intrahepatic cholestasis: new and wide perspectives.","volume":"51","author":"Vitale","year":"2019","journal-title":"Dig Liver Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jceh.2013.10.005","article-title":"Progressive familial intrahepatic cholestasis.","volume":"4","author":"Srivastava","year":"2014","journal-title":"J Clin Exp Hepatol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1124\/dmd.105.008854","article-title":"Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).","volume":"34","author":"Lang","year":"2006","journal-title":"Drug Metab Dispos."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1002\/hep.23539","article-title":"ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history.","volume":"51","author":"Davit-Spraul","year":"2010","journal-title":"Hepatology."},{"key":"B6","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1159\/000324137","article-title":"An update on genetic analysis of cholestatic liver diseases: digging deeper.","volume":"29","author":"Mullenbach","year":"2011","journal-title":"Dig Dis."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/s12876-018-0835-6","article-title":"Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis.","volume":"18","author":"Sharma","year":"2018","journal-title":"BMC Gastroenterol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"7470","DOI":"10.3748\/wjg.v26.i47.7470","article-title":"Molecular overview of progressive familial intrahepatic cholestasis.","volume":"26","author":"Amirneni","year":"2020","journal-title":"World J Gastroenterol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/s0168-8278(03)00049-7","article-title":"Progressive familial intrahepatic cholestasis type 3 revealed by oral contraceptive pills.","volume":"38","author":"Ganne-Carri\u00e9","year":"2003","journal-title":"J Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/s00535-015-1110-z","article-title":"ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression.","volume":"51","author":"Degiorgio","year":"2016","journal-title":"J Gastroenterol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1055\/s-0038-1667299","article-title":"ABCB4 gene aberrations in human liver disease: an evolving spectrum.","volume":"38","author":"Reichert","year":"2018","journal-title":"Semin Liver Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1016\/j.jhep.2020.12.010","article-title":"Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB\/c.Abcb4(-\/-) mouse model of PFIC3.","volume":"74","author":"Wei","year":"2021","journal-title":"J Hepatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"558","DOI":"10.5223\/pghn.2020.23.6.558","article-title":"Phenotypic and molecular characteristics of children with progressive familial intrahepatic cholestasis in South China.","volume":"23","author":"Zhang","year":"2020","journal-title":"Pediatr Gastroenterol Hepatol Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1002\/hep.28300","article-title":"A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3.","volume":"63","author":"Delaunay","year":"2016","journal-title":"Hepatology."},{"key":"B15","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.jhep.2009.04.009","article-title":"EASL Clinical Practice Guidelines: management of cholestatic liver diseases.","volume":"51","year":"2009","journal-title":"J Hepatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.jhep.2007.07.006","article-title":"Grading and staging systems for inflammation and fibrosis in chronic liver diseases.","volume":"47","author":"Goodman","year":"2007","journal-title":"J Hepatol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1055\/s-0030-1253223","article-title":"The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.","volume":"30","author":"Davit-Spraul","year":"2010","journal-title":"Semin Liver Dis."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1002\/hep.26424","article-title":"Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients.","volume":"58","author":"Poupon","year":"2013","journal-title":"Hepatology."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2014-206919","article-title":"Pregnancy and ABCB4 gene mutation: risk of recurrent cholelithiasis.","volume":"2015","author":"Elderman","year":"2015","journal-title":"BMJ Case Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/s41594-019-0354-3","article-title":"Structure of the human lipid exporter ABCB4 in a lipid environment.","volume":"27","author":"Olsen","year":"2020","journal-title":"Nat Struct Mol Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1016\/j.bbadis.2017.07.029","article-title":"Genetic determinants of cholangiopathies: Molecular and systems genetics.","volume":"1864","author":"Reichert","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.clinre.2015.12.008","article-title":"The pathophysiology of intrahepatic cholestasis of pregnancy.","volume":"40","author":"Dixon","year":"2016","journal-title":"Clin Res Hepatol Gastroenterol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.biocel.2017.05.028","article-title":"Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases.","volume":"89","author":"Khabou","year":"2017","journal-title":"Int J Biochem Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"95","DOI":"10.2147\/HMER.S137209","article-title":"Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment.","volume":"10","author":"Gunaydin","year":"2018","journal-title":"Hepat Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1194\/jlr.RA120000889","article-title":"Stimulation of ABCB4\/MDR3 ATPase activity requires an intact phosphatidylcholine lipid.","volume":"61","author":"Prescher","year":"2020","journal-title":"J Lipid Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1053\/gast.2001.23984","article-title":"The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.","volume":"120","author":"Jacquemin","year":"2001","journal-title":"Gastroenterology."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1002\/hep.20682","article-title":"Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.","volume":"41","author":"Keitel","year":"2005","journal-title":"Hepatology."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1921","DOI":"10.1053\/j.gastro.2011.07.042","article-title":"Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity.","volume":"141","author":"Groen","year":"2011","journal-title":"Gastroenterology."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1016\/j.jhep.2011.04.014","article-title":"Interaction of bile salts with rat canalicular membrane vesicles: evidence for bile salt resistant microdomains.","volume":"55","author":"Guyot","year":"2011","journal-title":"J Hepatol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/srep26872","article-title":"Functional characterization of ABCB4 mutations found in progressive familial intrahepatic cholestasis type 3.","volume":"6","author":"Park","year":"2016","journal-title":"Sci Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.bone.2013.03.012","article-title":"Modeling hepatic osteodystrophy in Abcb4 deficient mice.","volume":"55","author":"Hochrath","year":"2013","journal-title":"Bone."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/6292818","article-title":"Evaluation of a novel missense mutation in ABCB4 gene causing progressive familial intrahepatic cholestasis type 3.","volume":"2020","author":"Saleem","year":"2020","journal-title":"Dis Markers."},{"key":"B34","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1002\/hep.27170","article-title":"Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations.","volume":"60","author":"Gautherot","year":"2014","journal-title":"Hepatology."},{"key":"B35","doi-asserted-by":"publisher","first-page":"5303","DOI":"10.1016\/s0021-9258(19)67788-4","article-title":"Structure of the human MDR3 gene and physical mapping of the human MDR locus.","volume":"266","author":"Lincke","year":"1991","journal-title":"J Biol Chem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1038\/sj.ejhg.5201908","article-title":"Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3).","volume":"15","author":"Degiorgio","year":"2007","journal-title":"Eur J Hum Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00439-013-1358-4","article-title":"The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.","volume":"133","author":"Stenson","year":"2014","journal-title":"Hum Genet."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.962408\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T15:28:02Z","timestamp":1670513282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.962408\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,8]]},"references-count":37,"alternative-id":["10.3389\/fmed.2022.962408"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.962408","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,8]]},"article-number":"962408"}}