Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases.

[benign recurrent intrahepatic cholestasis]

Human BSEP (ABCB 11 ) mutations are the molecular basis for at least three clinical forms of liver disease , progressive familial intrahepatic cholestasis type 2 (PFIC 2 ), benign recurrent intrahepatic cholestasis type 2 (BRIC 2 ), and intrahepatic cholestasis of pregnancy (ICP ). To better understand the pathobiology of these disease phenotypes , we hypothesized that different mutations may cause significant differences in protein defects . Therefore we compared the effect of two PFIC 2 mutations (D 482 G , E 297 G ) with two BRIC 2 mutations (A 570 T and R 1050 C ) and one ICP mutation (N 591 S ) with regard to the subcellular localization , maturation , and function of the rat Bsep protein . Bile salt transport was retained in all but the E 297 G mutant . Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK 293 cells compared with wild-type (WT ) Bsep in the following order : WT > N 591 S > R 1050 C approximately A 570 T approximately E 297 G > D 482 G . Total cell protein and surface protein expression were reduced to the same extent , suggesting that trafficking of these mutants to the plasma membrane is not impaired . All Bsep mutants accumulate in perinuclear aggresome-like structures in the presence of the proteasome inhibitor MG-132 , suggesting that mutations are associated with protein instability and ubiquitin-dependent degradation . Reduced temperature , sodium butyrate , and sodium 4 -phenylbutyrate enhanced the expression of the mature and cell surface D 482 G protein in HEK 293 cells . These results suggest that the clinical phenotypes of PFIC 2 , BRIC 2 , and ICP may directly correlate with the amount of mature protein that is expressed at the cell surface and that strategies to stabilize cell surface mutant protein may be therapeutic .

Diseases
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Diseases presenting "protein instability" symptom

benign recurrent intrahepatic cholestasis

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