ABCB11 p.Arg1050Cys
| Reviews: |
p.Arg1050Cys
D
|
| Predicted by SNAP2: | A: D (75%), C: D (71%), D: D (85%), E: D (71%), F: D (85%), G: D (80%), H: N (82%), I: D (80%), K: N (53%), L: D (80%), M: D (75%), N: N (57%), P: D (85%), Q: D (53%), S: D (63%), T: D (71%), V: D (85%), W: D (85%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, S: D, T: D, V: D, W: D, Y: N, |
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[hide] Hepatocellular carcinoma in ten children under fiv... Hepatology. 2006 Aug;44(2):478-86. Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikci B, Ozcay F, Laszlo A, Tiszlavicz L, Moore L, Raftos J, Arnell H, Fischler B, Nemeth A, Papadogiannakis N, Cielecka-Kuszyk J, Jankowska I, Pawlowska J, Melin-Aldana H, Emerick KM, Whitington PF, Mieli-Vergani G, Thompson RJ
Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
Hepatology. 2006 Aug;44(2):478-86., [PMID:16871584]
Abstract [show]
Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational-analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)--or "neonatal hepatitis" suggesting PFIC--that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or "neonatal hepatitis" suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13-52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11.
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No. Sentence Comment
180 IVS18ϩ1GϾA, found in patient B, was (in combination with 3148CϾT [R1050C]) associated with "benign" recurrent intrahepatic cholestasis (BRIC)-namely, intrahepatic cholestasis with intermittent clinical manifestations (published as IVS19ϩ1GϾA through typographical error [L. Klomp, personal communication]).36 IVS16-8TϾG, found in patient A, has been associated with PFIC in several other patients.
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ABCB11 p.Arg1050Cys 16871584:180:84
status: NEW184 Of interest is the difference in phenotype between patient B, with PFIC in association with the genotype IVS18ϩ1GϾA / 74CϾA (S25X), and a patient with BRIC whose less severe disease was associated with the IVS18ϩ1GϾA / 3148CϾT (R1050C) genotype.24 Factors modulating penetrance of ABCB11 mutation have yet to be defined.
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ABCB11 p.Arg1050Cys 16871584:184:264
status: NEW[hide] The bile salt export pump. Pflugers Arch. 2007 Feb;453(5):611-20. Epub 2006 Oct 19. Stieger B, Meier Y, Meier PJ
The bile salt export pump.
Pflugers Arch. 2007 Feb;453(5):611-20. Epub 2006 Oct 19., [PMID:17051391]
Abstract [show]
Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts. Bsep is extensively regulated at the transcriptional and posttranscriptional level, which directly modulates canalicular bile formation. Pathophysiological alterations of Bsep by either inherited mutations or acquired processes such as inhibition by drugs or disease-related down regulation may lead to a wide spectrum of mild to severe forms of liver disease. Furthermore, many genetic variants of Bsep are known, some of which potentially render individuals susceptible to acquired forms of liver disease.
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160 Their bile flow rate is slightly but not significantly lower in comparison to controls, but the total bile salt output into bile is massively reduced and their liver bile salt concen- S114R G238V V284L* C336S D482G R487H S593R E636G G982R G1004D R1153CD R1268Q E186G E297G R432T I498T I498T T923P A926P R1050C R1128H S194P G260D N519S A1228V V444A K461E M677V R698H PFIC2 BRIC2 acquired cholestasis SNP Fig. 2 Putative secondary structure of Bsep (NT-005403) generated with the TOPO program (http://www.sacs.ucsf.edu/TOPO-run/wtopo.pl).
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ABCB11 p.Arg1050Cys 17051391:160:303
status: NEW[hide] Prediction of drug-induced intrahepatic cholestasi... Expert Opin Drug Saf. 2007 Jan;6(1):71-86. Sakurai A, Kurata A, Onishi Y, Hirano H, Ishikawa T
Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump.
Expert Opin Drug Saf. 2007 Jan;6(1):71-86., [PMID:17181454]
Abstract [show]
Drug-induced intrahepatic cholestasis is one of the major causes of hepatotoxicity, which often occur during the drug discovery and development process. Human ATP-binding cassette transporter ABCB11 (sister of P-glycoprotein/bile salt export pump) mediates the elimination of cytotoxic bile salts from liver cells to bile, and, therefore, plays a critical role in the generation of bile flow. The authors have recently developed in vitro high-speed screening and quantitative structure-activity relationship analysis methods to investigate the interaction of ABCB11 with a variety of compounds. Based on the extent of inhibition of the bile salt export pump, the authors analysed the quantitative structure-activity relationship to identify chemical groups closely associated with the inhibition of ABCB11. This approach provides a new tool to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.
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No. Sentence Comment
120 H2N COOH S56L G238V G260D C336S L339V V444A K461E D482G T923P K930X G982R R1090X R1153C Outside Inside R1268Q A1228VE1186K R1128H R1057X R1050C A926P A865V R698H E636G M677V S593R E592Q N591S R575XA570T Q558H I498T R432T R415Q R299K E297G V284A I206V S194P E186G cholestasis Expert Opin. Drug Saf. (2007) 6(1) Table 1.
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ABCB11 p.Arg1050Cys 17181454:120:137
status: NEW126 [46] - 22 2767 A→C Thr923Pro BRIC2 [45] - 22 2776 G→C Ala926Pro BRIC2 [45] - 22 2788 A→T Lys930X PFIC2 [43] - 23 2944 G→A Gly982Arg PFIC2 [47] - 23 3148 C→T Arg1050Cys BRIC2 [45] - 23 3169 C→T Arg1057X PFIC2 [35,47] - 24 3213 G→del Frame shift at position 1071 PFIC2 [47] - 24 3268 C→T Arg1090X PFIC2 [47] *Although Jansen et al. [47] reports the S114R variant, amino acid 114 in the wild type is Trp instead of Ser. BRIC2: Benign recurrent intrahepatic cholestasis type 2; del: Deletion; ICP: Intrahepatic cholestasis of pregnancy; NCBI: National Center for Biotechnology Information; PFIC2: Progressive familial intrahepatic cholestasis type 2.
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ABCB11 p.Arg1050Cys 17181454:126:192
status: NEW[hide] Levels of plasma membrane expression in progressiv... Am J Physiol Cell Physiol. 2007 Nov;293(5):C1709-16. Epub 2007 Sep 13. Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL
Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases.
Am J Physiol Cell Physiol. 2007 Nov;293(5):C1709-16. Epub 2007 Sep 13., [PMID:17855769]
Abstract [show]
Human BSEP (ABCB11) mutations are the molecular basis for at least three clinical forms of liver disease, progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), 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 PFIC2 mutations (D482G, E297G) with two BRIC2 mutations (A570T and R1050C) and one ICP mutation (N591S) with regard to the subcellular localization, maturation, and function of the rat Bsep protein. Bile salt transport was retained in all but the E297G mutant. Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK293 cells compared with wild-type (WT) Bsep in the following order: WT > N591S > R1050C approximately A570T approximately E297G >> D482G. 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 D482G protein in HEK293 cells. These results suggest that the clinical phenotypes of PFIC2, BRIC2, 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.
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No. Sentence Comment
9 Therefore we compared the effect of two PFIC2 mutations (D482G, E297G) with two BRIC2 mutations (A570T and R1050C) and one ICP mutation (N591S) with regard to the subcellular localization, maturation, and function of the rat Bsep protein.
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ABCB11 p.Arg1050Cys 17855769:9:107
status: NEW11 Mutant proteins were expressed at reduced levels on the plasma membrane of transfected HEK293 cells compared with wild-type (WT) Bsep in the following order: WT Ͼ N591S Ͼ R1050C ϳ A570T ϳ E297G ϾϾ D482G.
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ABCB11 p.Arg1050Cys 17855769:11:183
status: NEW45 All point mutations (D482G, E297G, A570T, R1050C, N591S) were introduced with the QuickChange Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA).
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ABCB11 p.Arg1050Cys 17855769:45:42
status: NEW64 PFIC2 (D482G, E297G), BRIC2 (A570T, R1050C), and ICP (N591S) mutations that are investigated in this study are indicated in italics.
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ABCB11 p.Arg1050Cys 17855769:64:36
status: NEW94 Sf9 cells infected with recombinant virus (mock, WT, D482G, E297G, A570T, R1050C, and N591S) were harvested, and cell membranes were prepared as described previously (23).
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ABCB11 p.Arg1050Cys 17855769:94:74
status: NEW107 The subcellular distributions of D482G, E297G, A570T, R1050C, and N591S were examined first because intracellular accumulation of misfolded proteins has been shown for many diseases.
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ABCB11 p.Arg1050Cys 17855769:107:54
status: NEW118 The level of cell surface expression of Bsep protein was quantitated by densitometry and determined to be in the following order: WT (100%) Ͼ N591S (75.6 Ϯ 15.6%) Ͼ E297G (38.5 Ϯ 12.6%) ϳ R1050C (35.6 Ϯ 14.5%) ϳ A570T (29.5 Ϯ 8.8%) ϾϾ D482G (5.7 Ϯ 2.3%).
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ABCB11 p.Arg1050Cys 17855769:118:218
status: NEW120 The total expression (cell surface and intracellular proteins) also showed changes similar to those in cell surface expression: WT (100%) Ͼ N591S (73.5 Ϯ 4.3%) Ͼ E297G (33.7 Ϯ 20.4%) ϳ R1050C (26.7 Ϯ 16.0%) ϳ A570T (11.9 Ϯ 5.2%) ϾϾ D482G (2.5 Ϯ 2.0%) (Fig. 4B).
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ABCB11 p.Arg1050Cys 17855769:120:215
status: NEW150 The membrane vesicles expressing D482G, A570T, R1050C, or N591S showed similar levels of taurocholate uptake compared with WT Bsep.
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ABCB11 p.Arg1050Cys 17855769:150:47
status: NEW155 Cells were transiently transfected with pEGFPN1 (control), rat Bsep-GFP [wild type (WT)], D482G-GFP, E297G-GFP, A570T-GFP, R1050C-GFP, and N591S-GFP constructs.
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ABCB11 p.Arg1050Cys 17855769:155:123
status: NEW164 A PFIC2 mutation (D482G) is highly unstable (ϳ5% of WT), while the BRIC2 variants A570T and R1050C are expressed at the plasma membrane at intermediate levels (ϳ25% of WT).
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ABCB11 p.Arg1050Cys 17855769:164:98
status: NEW169 Cells were transfected with rat Bsep-GFP (WT), D482G-GFP, E297G-GFP, A570T-GFP, R1050C-GFP, and N591S-GFP constructs and were examined for GFP by confocal laser microscopy.
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ABCB11 p.Arg1050Cys 17855769:169:80
status: NEW171 D482G, E297G, A570T, and R1050C mutants partially colocalized with recycling endosome marker Rab11.
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ABCB11 p.Arg1050Cys 17855769:171:25
status: NEW176 D4, D482G; E2, E297G; A5, A570T; R10, R1050C; N5, N591S.
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ABCB11 p.Arg1050Cys 17855769:176:38
status: NEW183 P Ͻ 0.05, D482G, E297G, A570T, R1050C, and N591S compared with WT control.
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ABCB11 p.Arg1050Cys 17855769:183:37
status: NEW229 A: immunoblot of the isolated Sf9 cell membrane proteins with anti-Bsep polyclonal antibody: GFP control expressed in HEK293 cells, WT expressed in HEK293 cells, rat liver homogenate (L), pFastBac1-Gus control (C), wild type (WT), D482G (D4), E297G (E2), A570T (A5), R1050C (R10), N591S (N5).
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ABCB11 p.Arg1050Cys 17855769:229:267
status: NEW231 B: TCA (200 M) stimulates and orthovanadate inhibits ATPase activity in membrane vesicles containing comparable levels of WT or D482G, E297G, A570T, R1050C, and N591S mutant Bsep.
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ABCB11 p.Arg1050Cys 17855769:231:157
status: NEW[hide] Phenotypic differences in PFIC2 and BRIC2 correlat... Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G58-67. Epub 2007 Oct 18. Kagawa T, Watanabe N, Mochizuki K, Numari A, Ikeno Y, Itoh J, Tanaka H, Arias IM, Mine T
Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells.
Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G58-67. Epub 2007 Oct 18., [PMID:17947449]
Abstract [show]
Progressive familial cholestasis (PFIC) 2 and benign recurrent intrahepatic cholestasis (BRIC) 2 are caused by mutations in the bile salt export pump (BSEP, ABCB11) gene; however, their prognosis differs. PFIC2 progresses to cirrhosis and requires liver transplantation, whereas BRIC2 is clinically benign. To identify the molecular mechanism(s) responsible for the phenotypic differences, eight PFIC2 and two BRIC2 mutations were introduced in rat Bsep, which was transfected in MDCK II cells. Taurocholate transport activity, protein expression, and subcellular distribution of these mutant proteins were studied in a polarized MDCK II monolayer. The taurocholate transport activity was approximately half of the wild-type (WT) in BRIC2 mutants (A570T and R1050C), was substantially less in two PFIC2 mutants (D482G and E297G), and was almost abolished in six other PFIC2 mutants (K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X). Bsep protein expression levels correlated closely with transport activity, except for R1057X. The half-life of the D482G mutant was shorter than that of the WT (1.35 h vs. 3.49 h in the mature form). BRIC2 mutants and three PFIC mutants (D482G, E297G, and R1057X) were predominantly distributed in the apical membrane. The other PFIC2 mutants remained intracellular. The R1057X mutant protein was stably expressed and trafficked to the apical membrane, suggesting that the COOH-terminal tail is required for transport activity but not for correct targeting. In conclusion, taurocholate transport function was impaired in proportion to rapid degradation of Bsep protein in the mutants, which were aligned in the following order: A570T and R1050C > D482G > E297G > K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X. These results may explain the phenotypic difference between BRIC2 and PFIC2.
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13 The taurocholate transport activity was approximately half of the wild-type (WT) in BRIC2 mutants (A570T and R1050C), was substantially less in two PFIC2 mutants (D482G and E297G), and was almost abolished in six other PFIC2 mutants (K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X).
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ABCB11 p.Arg1050Cys 17947449:13:109
status: NEW19 In conclusion, taurocholate transport function was impaired in proportion to rapid degradation of Bsep protein in the mutants, which were aligned in the following order: A570T and R1050C Ͼ D482G Ͼ E297G Ͼ K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X.
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ABCB11 p.Arg1050Cys 17947449:19:180
status: NEW139 The positions of 8 PFIC2 mutations (E297G, K461E, D482G, G982R, R1057C, R1153C, 3767-3768insC, and R1268Q) and 2 BRIC2 mutations (A570T and R1050C) are indicated by ଝ and ଙ, respectively.
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ABCB11 p.Arg1050Cys 17947449:139:140
status: NEW166 In contrast, two BRIC2 mutants exhibited considerable transport activity (A570T: 52.2 Ϯ 13.0%, R1050C: 58.7 Ϯ 9.9% of the WT).
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ABCB11 p.Arg1050Cys 17947449:166:101
status: NEW170 A570T and R1050C Fig. 2.
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ABCB11 p.Arg1050Cys 17947449:170:10
status: NEW184 Subcellular distribution study revealed that E297G, R1057X, A570T, and R1050C mutants were predominantly located along the apical membrane, whereas the other PFIC2 mutants (K461E, G982R, R1153C, R1268Q, and 3767-3768insC) remained intracellular (Fig. 7).
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ABCB11 p.Arg1050Cys 17947449:184:71
status: NEW185 In summary, BRIC2 mutants (A570T and R1050C) were expressed substantially, trafficked correctly, and maintained half of transport activity.
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ABCB11 p.Arg1050Cys 17947449:185:37
status: NEW286 TC transport activity was 50-60% in BRIC2 mutants (A570T and R1050C) and 0-30% in PFIC2 mutants.
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ABCB11 p.Arg1050Cys 17947449:286:61
status: NEW290 From the view of maintenance of TC transport activity, the mutants could be aligned in the following order: A570T and R1050C Ͼ D482G Ͼ E297G Ͼ K461E, G982R, R1153C, R1268Q, 3767-3768insC, and R1057X.
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ABCB11 p.Arg1050Cys 17947449:290:118
status: NEW[hide] Update on progressive familial intrahepatic choles... J Pediatr Gastroenterol Nutr. 2008 Mar;46(3):241-52. Alissa FT, Jaffe R, Shneider BL
Update on progressive familial intrahepatic cholestasis.
J Pediatr Gastroenterol Nutr. 2008 Mar;46(3):241-52., [PMID:18376240]
Abstract [show]
Three distinct forms of familial intrahepatic cholestasis are the result of mutations in the ATP8B1, ABCB11, and ABCB4 genes. The pathophysiologies of the latter 2 of these diseases are well characterized and are the result of abnormalities in canalicular excretion of bile acids and phospholipids, respectively. The molecular pathophysiology of the systemic disease associated with mutations in ATP8B1 remains unclear. In all of these diseases, wide variations in clinical phenotypes have been observed. The variability can be ascribed at least in part to predicted genotype:phenotype correlations. Disease- and genotype-specific prognoses and therapeutic approaches may exist, although much more information needs to be ascertained before clinicians can confidently make decisions based on genetic information.
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194 Even more subtle mutations of ABCB11 were described in patients with an intermittent form of disease (BRIC2; see below), these mutations include E186G, A570T, T923P, A926P, R1050C, R1128H, V444A, and E297G.
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ABCB11 p.Arg1050Cys 18376240:194:173
status: NEW[hide] Missense mutations and single nucleotide polymorph... Hepatology. 2009 Feb;49(2):553-67. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ
Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing.
Hepatology. 2009 Feb;49(2):553-67., [PMID:19101985]
Abstract [show]
The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. Conclusion: This work is a comprehensive analysis of 80% of ABCB11 missense mutations and single-nucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency.
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68 Continued Exon Nucleotide Change Predicted Protein Effect Location in Protein Associated Phenotype Prevalence or frequency* Any Defect(s) Identified Reference BRIC, 1 family (both hom) 15 c.1757CϾT T586I Adj WB BRIC 1 family (het) No splicing † 15 c.1763CϾT A588V Adj WB PFIC 2 families (both het) No protein 31, 32 15 c.1772AϾG N591S Adj WB SNP-ICP 2.6% 42 15 c.1779TϾA S593R NBF1 PFIC 1 family (het) 29 15 c.1791GϾT V597V NBF1 SNP 2.6% 42 16 c.1880TϾC I627T IC3 PFIC 1 family (het) ‡ 16 c.1964CϾT T655I IC3 BRIC / ICP / DC 1 family (het) Reduced levels of mature protein ‡ 17 c.2029AϾG M677V IC3 SNP 1.6-5.6% 39, 42-45 18 c.2093GϾA R698H IC3 SNP 0.3 - 0.8% 43, 45 18 c.2125GϾA E709K IC3 SNP-PFIC 1 family (het) ‡ 18 c.2130TϾC P710P IC3 SNP-PBC 0.5 - 3.1% 43 20-21 c.2412AϾC A804A TM8 SNP 1.1% 45 20-21 c.2453AϾT Y818F IC4 SNP-PFIC 2 families (hom) Reduced levels of mature protein ‡ 20-21 c.2494CϾT R832C IC4 PFIC 2 families (1 het, 1 consanguineous) Moderate differential splicing 31, 32 20-21 c.2576CϾG T859R IC4 PFIC 1 family (het) 31 22 c.2767AϾC T923P IC5 BRIC 1 family (het) 8 22 c.2776GϾC A926P IC5 BRIC 1 family (het) Mild exon skipping 8 23 c.2842CϾT R948C IC5 PFIC 2 families (both het) Immature protein 31 23 c.2935AϾG N979D TM11 PFIC 1 family (consanguineous) 31 23 c.2944GϾA G982R TM11 PFIC 4 families (1 hom, 1 consanguineous, 2 het) Immature protein 7, 29, 31 23 c.3011GϾA G1004D EC6 PFIC 1 family (hom) 28 24 c.3084AϾG A1028A TM12 SNP-PBC 39.86 - 56.3% Severe exon skipping 8, 43, 45 24 c.3148CϾT R1050C C term BRIC 2 familes (1 hom, 1 het) Immature protein 8 25 c.3329CϾA A1110E Adj WA PFIC 2 familes (both het) Mild exon skipping; immature protein 31 25 c.3346GϾC G1116R WA PFIC / BRIC 1 family (consanguineous) Mild exon skipping ‡ 25 c.3382CϾT R1128C NBF2 PFIC 1 family (consanguineous) Mild exon skipping; immature protein 31 25 c.3383GϾA R1128H NBF2 BRIC 1 family (hom) Mild exon skipping; greatly reduced levels of mature protein 8 26 c.3432CϾA S1144R NBF2 PFIC 1 family (het) Severe differential splicing 29 26 c.3457CϾT R1153C NBF2 PFIC 4 families (2 consanguineous, 2 het) Immature protein 7, 31, 36 26 c.3458GϾA R1153H NBF2 PFIC 4 families (2 consanguineous, 2 het) Severe differential splicing; immature protein 31 26 c.3460TϾC S1154P NBF2 PFIC 1 family (het) Severe differential splicing 31 26 c.3556GϾA E1186K NBF2 SNP 1%-10% Mild exon skipping ‡ 26 c.3589_3590 delCTinsGG L1197G NBF2 BRIC 1 family (het) † 27 c.3628AϾC T1210P Adj ABCm PFIC 1 family (hom) Immature protein 31 27 c.3631AϾG N1211D Adj ABCm SNP-PFIC 1 family (het) ‡ 27 c.3669GϾC E1223D ABCm Prolonged NNH 1 family (het) ‡ 27 c.3683CϾT A1228V Adj ABCm/WB SNP-PBC 0.8% 43 27 c.3691CϾT R1231W Adj ABCm/WB PFIC 1 family (het) Severe exon skipping; immature protein 30, 31 27 c.3692GϾA R1231Q Adj ABCm/WB PFIC 2 families (1 consanguineous, 1 het) No splicing; immature protein 31, 34 27 c.3724CϾA L1242I WB PFIC 1 family (het) 31 28 c.3892GϾA R1268Q¶ NBF2 PFIC 1 family (hom) Immature protein 7 *Prevalence or frequency is quoted depending on how data were presented in the original publication(s).
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ABCB11 p.Arg1050Cys 19101985:68:1688
status: NEW154 The following mutations showed an enrichment of mature BSEP: R1153H (c.3458GϾA; Fig. 6B), R1128C (c.3382CϾT), R1128H (c.3383GϾA), R1231Q (c.3692GϾA), R1050C (c.3148CϾT; Fig. 6C) and R1268Q (c.3892GϾA), A570T (c.1708GϾA), and E297K (c.889GϾA; Fig. 6D).
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ABCB11 p.Arg1050Cys 19101985:154:174
status: NEW219 These include the PFIC-associated mutations E297G (c.890AϾG; Fig. 6A), R1128C (c.3382CϾT) and R1231Q (c.3692GϾA; Fig. 6C), and R1268Q (c.3892GϾA; Fig. 6.d), the BRIC-associated mutations R1128H (c.3383GϾA) and R1050C (c.3148CϾT; Fig. 6C), and E297K (c.889GϾA; Fig. 6D), as well as A570T (c.1708GϾA), which can be associated with either form of disease.
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ABCB11 p.Arg1050Cys 19101985:219:240
status: NEW[hide] The bile salt export pump: clinical and experiment... Semin Liver Dis. 2010 May;30(2):125-33. Epub 2010 Apr 26. Lam P, Soroka CJ, Boyer JL
The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease.
Semin Liver Dis. 2010 May;30(2):125-33. Epub 2010 Apr 26., [PMID:20422495]
Abstract [show]
The primary transporter responsible for bile salt secretion is the bile salt export pump (BSEP, ABCB11), a member of the ATP-binding cassette (ABC) superfamily, which is located at the bile canalicular apical domain of hepatocytes. In humans, BSEP deficiency results in several different genetic forms of cholestasis, which include progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), as well as other acquired forms of cholestasis such as drug-induced cholestasis (DIC) and intrahepatic cholestasis of pregnancy (ICP). Because bile salts play a pivotal role in a wide range of physiologic and pathophysiologic processes, regulation of BSEP expression has been a subject of intense research. The authors briefly describe the molecular characteristics of BSEP and then summarize what is known about its role in the pathogenesis of genetic and acquired cholestatic disorders, emphasizing experimental observations from animal models and cell culture in vitro systems.
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49 Similar to the results of immunofluorescence studies in liver tissue from PFIC2 patients,47 when PFIC2 human mutations were expressed in model mammalian cell lines (MDCK, HEK293, HepG2), the proteins failed to reach or be maintained at the cell surface.54-57 When BSEP mutations that cause PFIC2 (D482G, E297G), BRIC2 (A590T, R1050C), and ICP (N591S) were compared, the clinical severity of these mutations tended to correlate inversely with the amount of protein expressed on the cell surface.
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ABCB11 p.Arg1050Cys 20422495:49:326
status: NEW[hide] The bile salt export pump (BSEP) in health and dis... Clin Res Hepatol Gastroenterol. 2012 Dec;36(6):536-53. doi: 10.1016/j.clinre.2012.06.006. Epub 2012 Jul 12. Kubitz R, Droge C, Stindt J, Weissenberger K, Haussinger D
The bile salt export pump (BSEP) in health and disease.
Clin Res Hepatol Gastroenterol. 2012 Dec;36(6):536-53. doi: 10.1016/j.clinre.2012.06.006. Epub 2012 Jul 12., [PMID:22795478]
Abstract [show]
The bile salt export pump (BSEP) is the major transporter for the secretion of bile acids from hepatocytes into bile in humans. Mutations of BSEP are associated with cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 2 (PFIC-2), benign recurrent intrahepatic cholestasis type 2 (BRIC-2) and genetic polymorphisms are linked to intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). Detailed analysis of these diseases has considerably increased our knowledge about physiology and pathophysiology of bile secretion in humans. This review focuses on expression, localization, and function, short- and long-term regulation of BSEP as well as diseases association and treatment options for BSEP-associated diseases.
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182 Mutations such as p.E186G, p.E297G, p.R432T, p.A570T, p.T923P, p.A926P, p.G1004D, p.R1050C and p.R1128H have been described in BRIC-2 patients [137,140-142] (Table 1).
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ABCB11 p.Arg1050Cys 22795478:182:84
status: NEW185 PFIC BRIC/NFC ICP Other liver diseases Genetic variants without disease association Missense mutations M1V C336S D549V L1055P E135K E137K T87R V43I S701P G19R W342G G556R C1083Y E137K L198P M123T S56L L712L L50S A382G G562D A1110E E186G E297G S194P Q121K A865D M62K R387H A570T S1114R L198P R415Q L198P R128H A865G C68Y A390P L581F G1116E E297G V444A G260D I206V S874P C107R G410D A588V G1116F G374S D482G E297K V284A I939M I112T L413W S593R G1116R A390P N591S V444A G295C R958Q W114R I420T I627T S1120N R432T T655I T510T G295R F959C Y157C D440E E636G R1128C V444A T655I G295S F959V A167T G455E R698C S1144R I498T D676Y R299K T965S A167V K461E S699P R1153C A570T P710P R303K F971L I182K T463I E709K R1153H T586I L827I L339V F971Y M183T Q466K G758R S1154P G648V G855R H423R L1006F M183V R470Q G766R N1173D T655I E1186K V444A N1009H G188W Y472C Y818F T1210P T923P V444D K1145N M217R V481E R832C N1211D A926P V444G I1183T R223C D482G R832H V1212F R948C A459V S226L R487H T859R R1231Q G1004D I468I G238V R487P A865V R1231W R1050C R487L T242I N490D Q869P L1242I G1116R Q546K A257G I498T G877R D1243G R1128H Q558H V284L G499E S901R R1268Q L1197G E592Q E297G I512T R948C A1283V R1231Q V597M R303G N515T N979D G1292V R616G R303K R517H G982R G1298R T619A Q312H F540L G1004D M677L R313S I541L T1029K M677V G327E I541T G1032R R696Q W330R F548Y A1044P R698H Nonsense mutations (premature stop-codons) S25X Y472X Y772X R1090X E96X W493X Q791X V1147X W330X R520X R928X Q1215X Y354X I528X Y1041X R1235X R415X R575X R1057X E1302X R470X Q702X Q1058X Table 1 (Continued) PFIC BRIC/NFC ICP Other liver diseases Genetic variants without disease association Splice site mutations 76 + 3G > T 908 + 1delG 2178 + 1G > T 3057-2A > G Q159Q 77-1G > C 908 + 1G > T 2179-2A > G 3213 + 1delG Q361Q 99-1G > T 908 + 1G > A 2343 + 1G > T 3213 + 4A > G 150 + 3A > C 1435-13 -8del 2343 + 2T > C 3213 + 5G > A 390-1G > A 2012-8T > G 2611-2A > T 611 + 1G > A 2178 + 1G > A R1001R Deletions/insertions/frame shifts Q101Dfs8X L380Wfs18X G648Vfs5X Q1058Hfs38X F959Hfs1X T127Hfs6X A382 A388del K700Sfs12X I1061Vfs34X F959Gfs48X N199Ifs14X P456Pfs24X T919del L1165del L232Cfs9X H484Rfs5X K930Efs92X A1192Efs50X R303Sfs17X I528Sfs21X K930Efs79X T1256Tfs40X V368Rfs27X I610Qfs45X K969 K972del Synonymous variants without disease association R33R F90F L232L I416I G557G I876I A1028A K1145K D36D I134I Y269Y G418G V597V G937G K1070K R52R S136S Q312Q F427F A804A Y981Y T1086T D58D V195V G319G E395E A535A G817G G1004G A1110A The overview shows ࣈ 290 known variants of BSEP on the protein level, except splice site mutations, which are shown on cDNA level.
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ABCB11 p.Arg1050Cys 22795478:185:1019
status: NEW[hide] Biosynthesis and trafficking of the bile salt expo... Mol Aspects Med. 2014 Jun;37:3-14. doi: 10.1016/j.mam.2013.05.001. Epub 2013 May 15. Soroka CJ, Boyer JL
Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.
Mol Aspects Med. 2014 Jun;37:3-14. doi: 10.1016/j.mam.2013.05.001. Epub 2013 May 15., [PMID:23685087]
Abstract [show]
The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter.
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145 We examined differences in protein maturation, plasma membrane localization and transport activity in mutants of rat Bsep representing two PFIC2 (D482G and E297G), two BRIC2 (A570T and R1050C) and one ICP (N591) mutation (Lam et al., 2007).
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ABCB11 p.Arg1050Cys 23685087:145:185
status: NEW[hide] Genetic variations of bile salt transporters. Drug Discov Today Technol. 2014 Jun;12:e55-67. doi: 10.1016/j.ddtec.2014.03.006. Kubitz R, Droge C, Kluge S, Stindt J, Haussinger D
Genetic variations of bile salt transporters.
Drug Discov Today Technol. 2014 Jun;12:e55-67. doi: 10.1016/j.ddtec.2014.03.006., [PMID:25027376]
Abstract [show]
Bile salt transporters directly or indirectly influence biological processes through physicochemical or signalling properties of bile salts. The coordinated action of uptake and efflux transporters in polarized epithelial cells of the liver, biliary tree, small intestine and kidney determine bile salt concentrations in different compartments of the body. Genetic variations of bile salt transporters lead to clinical relevant phenotypes of varying severity ranging from a predisposition for drug-induced liver injury to rapidly progressing end-stage liver disease. This review focuses on the impact of genetic variations of bile salt transporters including BSEP, NTCP, ASBT and OSTalpha/beta and discusses approaches for transporter analysis.
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100 For example, the two 'BRIC-2 mutations` p.A570T and p.R1050C had lower expression levels than the 'ICP mutation` p.N591S, but higher expression levels as compared to the PFIC-2 mutations p.D482G and p.E297G [59].
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ABCB11 p.Arg1050Cys 25027376:100:54
status: NEW137 BSEP/Bsep NTCP ASBT Exon skipping E186G G1116R G319G R1128C T463I R1128H A926P E1186K A1028Aa R1231W A1110E Aberrant splicing E297K R1153H R832C S1154P S1144R No splice product T586I R1231Q Reduced plasma membrane expression E135K A570T I223T E297Gb N591Sb V444A R1050C Intracellular retention Y818F G982R Reduced or absent bile salt transport A570T R432T A64T K314E V98Ic M264V I206V Q558H I223T C144Y P290S E297Gb N591Sb S267F L243P G374S E1186K I279T T262M a A1028A induces significant exon skipping in vitro but probably not in vivo (unpublished data; Dro &#a8;ge, Ha &#a8;ussinger, Kubitz).
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ABCB11 p.Arg1050Cys 25027376:137:263
status: NEW[hide] Autoimmune BSEP disease: disease recurrence after ... Clin Rev Allergy Immunol. 2015 Jun;48(2-3):273-84. doi: 10.1007/s12016-014-8457-4. Kubitz R, Droge C, Kluge S, Stross C, Walter N, Keitel V, Haussinger D, Stindt J
Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis.
Clin Rev Allergy Immunol. 2015 Jun;48(2-3):273-84. doi: 10.1007/s12016-014-8457-4., [PMID:25342496]
Abstract [show]
Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. The three subtypes of PFIC are defined by the involved genes: PFIC-1, PFIC-2, and PFIC-3 are due to mutations of P-type ATPase ATP8B1 (familial intrahepatic cholestasis 1, FIC1), the ATP binding cassette transporter ABCB11 (bile salt export pump, BSEP), or ABCB4 (multidrug resistance protein 3, MDR3), respectively. All transporters are localized in the canalicular membrane of hepatocytes and together mediate bile salt and phospholipid transport. In some patients with PFIC-2 disease, recurrence has been observed after LTX, which mimics a PFIC phenotype. It could be shown by several groups that inhibitory anti-BSEP antibodies emerge, which most likely cause disease recurrence. The prevalence of severe BSEP mutations (e.g., splice site and premature stop codon mutations) is very high in this group of patients. These mutations often result in the complete absence of BSEP, which likely accounts for an insufficient auto-tolerance against BSEP. Although many aspects of this "new" disease are not fully elucidated, the possibility of anti-BSEP antibody formation has implications for the pre- and posttransplant management of PFIC-2 patients. This review will summarize the current knowledge including diagnosis, pathomechanisms, and management of "autoimmune BSEP disease."
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112 Following this report, similar observations were published (1) K930Efs79X wtBSEP (2) (3) (4) R1050C (7) D482G G374S (6) (5) c.150+3A>C (8) G982R Fig. 2 Different effects of genetic ABCB11 variants on processing and function of BSEP.
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ABCB11 p.Arg1050Cys 25342496:112:93
status: NEW