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

[benign recurrent intrahepatic cholestasis]

The bile salt export pump (BSEP , ABCB 11 ) 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 ).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 in vitro activity studies respectively .Benign recurrent intrahepatic cholestasis was considered in a brother and sister who both suffered from intermittent cholestasis since childhood . Gene sequencing of ABCB 11 identified the novel missense mutation p .G 374 S , 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 in vivo findings , HEK 293 cells showed regular membrane targeting of human BSEP (G 374 S ), whereas in vitro transport measurements revealed a strongly reduced transport activity .The novel mutation p .G 374 S 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 .G 374 S mutation causes a transitional phenotype between BRIC -2 and PFIC -2 .

Diseases
Validation

Diseases presenting "intermittent cholestasis" symptom

benign recurrent intrahepatic cholestasis

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