{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:20:00Z","timestamp":1762521600079},"reference-count":26,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2013,6,12]],"date-time":"2013-06-12T00:00:00Z","timestamp":1370995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"the German Research Foundation"},{"name":"the Collaborative Research Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aims<\/jats:title><jats:p>The bile salt export pump (<jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content>,<jats:italic> <jats:styled-content style=\"fixed-case\">ABCB<\/jats:styled-content>11<\/jats:italic>) is essential for bile salt secretion at the canalicular membrane of liver cells. Clinical phenotypes associated with <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content> mutations are commonly categorized as benign recurrent intrahepatic cholestasis (<jats:styled-content style=\"fixed-case\">BRIC<\/jats:styled-content>\u20102) or progressive familial intrahepatic cholestasis (<jats:styled-content style=\"fixed-case\">PFIC<\/jats:styled-content>\u20102).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The molecular basis of <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content>\u2010associated liver disease in a sibling pair was characterized by immunostaining, gene sequencing, bile salt analysis and recombinant expression in mammalian cells and yeast for localization and <jats:italic>in vitro<\/jats:italic> activity studies respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Benign recurrent intrahepatic cholestasis was considered in a brother and sister who both suffered from intermittent cholestasis since childhood. Gene sequencing of <jats:italic><jats:styled-content style=\"fixed-case\">ABCB<\/jats:styled-content>11<\/jats:italic> identified the novel missense mutation p.G374S, which is localized in the putative sixth transmembrane helix of <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content>. Liver fibrosis was present in the brother at the age of 18 with progression to cirrhosis within 3\u00a0years. Immunofluorescence of liver tissue showed clear canalicular <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content> expression; however, biliary concentration of bile salts was drastically reduced. In line with these <jats:italic>in vivo<\/jats:italic> findings, <jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells showed regular membrane targeting of human <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content><jats:sup>G374S<\/jats:sup>, whereas <jats:italic>in vitro<\/jats:italic> transport measurements revealed a strongly reduced transport activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The novel mutation p.G374S impairs transport function without disabling membrane localization of <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content>. While all other known <jats:styled-content style=\"fixed-case\">BSEP<\/jats:styled-content> mutations within transmembrane helices are associated with <jats:styled-content style=\"fixed-case\">PFIC<\/jats:styled-content>\u20102, the new p.G374S mutation causes a transitional phenotype between <jats:styled-content style=\"fixed-case\">BRIC<\/jats:styled-content>\u20102 and <jats:styled-content style=\"fixed-case\">PFIC<\/jats:styled-content>\u20102.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.12217","type":"journal-article","created":{"date-parts":[[2013,5,16]],"date-time":"2013-05-16T16:00:33Z","timestamp":1368720033000},"page":"1527-1535","source":"Crossref","is-referenced-by-count":23,"title":["A novel mutation within a transmembrane helix of the bile salt export pump (<scp>BSEP<\/scp>,<i><scp>ABCB<\/scp>11<\/i>) with delayed development of cirrhosis"],"prefix":"10.1111","volume":"33","author":[{"given":"Jan","family":"Stindt","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectiology University Hospital D\u00fcsseldorf Germany"},{"name":"Institute of Biochemistry Heinrich\u2010Heine\u2010University D\u00fcsseldorf D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp","family":"Ellinger","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Heinrich\u2010Heine\u2010University D\u00fcsseldorf D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Weissenberger","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectiology University Hospital D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carola","family":"Dr\u00f6ge","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectiology University Hospital D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diran","family":"Herebian","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology University Hospital D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ertan","family":"Mayatepek","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics and Neonatology University Hospital D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard","family":"Homey","sequence":"additional","affiliation":[{"name":"Dermatological Clinic University Hospital D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Braun","sequence":"additional","affiliation":[{"name":"Dermatological Clinic University Hospital D\u00fcsseldorf Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Schulte am 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