A novel mutation within a transmembrane helix of the bile salt export pump (BSEP, ABCB11) with delayed development of cirrhosis. (12th June 2013)

• Record Type: Journal Article
• Authors: Stindt, Jan; Ellinger, Philipp; Weissenberger, Katrin; Dröge, Carola; Herebian, Diran; Mayatepek, Ertan; Homey, Bernhard; Braun, Stephan; Schulte am Esch, Jan; Horacek, Michael; Canbay, Ali; Schmitt, Lutz; Häussinger, Dieter; Kubitz, Ralf
• Is Part Of: Liver international. Volume 33:Number 10(2013:Nov.)
• Page Start: 1527
• Page End: 1535
• Publication Date: 2013-06-12
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12217
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12217-abs-0001"> <title>Abstract</title> <sec id="liv12217-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>The bile salt export pump (BSEP, <italic> ABCB11</italic>) is essential for bile salt secretion at the canalicular membrane of liver cells. Clinical phenotypes associated with BSEP mutations are commonly categorized as benign recurrent intrahepatic cholestasis (BRIC‐2) or progressive familial intrahepatic cholestasis (PFIC‐2).</p> </sec> <sec id="liv12217-sec-0002" sec-type="section"> <title>Methods</title> <p>The molecular basis of BSEP‐associated 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 <italic>in vitro</italic> activity studies respectively.</p> </sec> <sec id="liv12217-sec-0003" sec-type="section"> <title>Results</title> <p>Benign recurrent intrahepatic cholestasis was considered in a brother and sister who both suffered from intermittent cholestasis since childhood. Gene sequencing of <italic>ABCB11</italic> identified the novel missense mutation p.G374S, which is localized in the putative sixth transmembrane helix of BSEP. Liver fibrosis was present in the brother at the age of 18 with progression to cirrhosis within 3 years. Immunofluorescence of liver tissue showed clear canalicular BSEP expression; however, biliary concentration of bile salts was drastically reduced. In line with these <italic>in vivo</italic> findings, HEK293 cells showed regular membrane targeting of human BSEP<sup>G374S</sup>, whereas <italic>in vitro</italic> transport measurements revealed a strongly reduced transport activity.</p> </sec> <sec id="liv12217-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The novel mutation p.G374S impairs transport function without disabling membrane localization of BSEP. While all other known BSEP mutations within transmembrane helices are associated with PFIC‐2, the new p.G374S mutation causes a transitional phenotype between BRIC‐2 and PFIC‐2.</p> </sec> </abstract>