ABCMdb

ABCB11 p.Arg1231Gln

Reviews:	p.Arg1231Gln D p.Arg1231Trp D
Predicted by SNAP2:	A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Reduced hepatic expression of farnesoid X receptor... Hum Mol Genet. 2004 Oct 15;13(20):2451-60. Epub 2004 Aug 18. Alvarez L, Jara P, Sanchez-Sabate E, Hierro L, Larrauri J, Diaz MC, Camarena C, De la Vega A, Frauca E, Lopez-Collazo E, Lapunzina P
Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1.
Hum Mol Genet. 2004 Oct 15;13(20):2451-60. Epub 2004 Aug 18., 2004-10-15 [PMID:15317749]

Abstract [show]
Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and bile salt export pump (BSEP) disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.

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44 A, R1231Q) in ABCB11 and lacked immunohistochemically demonstrable BSEP at canaliculi; MRP2 marked normally (Fig. 2). Login to comment
42 A, R1231Q) in ABCB11 and lacked immunohistochemically demonstrable BSEP at canaliculi; MRP2 marked normally (Fig. 2). Login to comment

[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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100 No spliced ABCB11 PCR product was generated for the nucleotide changes associated with T586I (c.1757CϾT; 0%; Fig. 2D) and R1231Q (c.3692GϾA; 0%; Fig. 2F). Login to comment
154 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). Login to comment
219 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. Login to comment

[hide] Morphologic findings in progressive familial intra... Am J Surg Pathol. 2011 May;35(5):687-96. Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, Miethke AG, Karpen SJ, Ferrell LD, Kim GE
Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies.
Am J Surg Pathol. 2011 May;35(5):687-96., [PMID:21490445]

Abstract [show]
Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellular cholestasis; most had canalicular bile plugs. At least 1 specimen from every patient had centrizonal/sinusoidal fibrosis, often with periportal fibrosis. Neonatal hepatitis-like features (inflammation, giant cells, necrosis) varied. In 2 of the 5 patients with paired specimens obtained >6 months apart, lobular and portal fibrosis worsened. Transmission electron microscopy (EM) in all 9 patients studied showed canalicular dilatation, microvilli loss, abnormal mitochondrial internal structure, and varying intracanalicular accumulation of finely granular bile. Canalicular staining for BSEP was absent in 10 patients and present in 2 patients, 1 of whom had intermittent symptoms. ABCB11 sequencing of all patients identified 6 novel and 10 previously described mutations, with nonsense, missense, and/or noncoding mutations in the 10 patients without immunohistochemically demonstrable BSEP. Missense and/or noncoding mutations were identified in the 2 patients with demonstrable BSEP, whose clinical course was more indolent. Mutations ending ABCB11 transcription appear linked, through hepatocellular necrosis and fibrosis, to worse outcome. In conclusion, light microscopy and electron microscopy findings in clinical PFIC2 can support diagnosis, but are variable and nonspecific. Therefore, no correlation between specific mutations and histopathology is yet possible.

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143 Immunohistochemical Findings and Genetic Abnormalities Patient BSEP Mutation Type of Mutation(s) 1 Absent c.890A>G (p.E297G)* Missense5,7,10,13,16,19,20 2 Absent c.1723C>T (p.R575X) Nonsense7,19,20 c.2178+1G>T Noncoding region20 3 Present c.1708G>A (p.A570T) Missense20 c.3634G>T (p.V1212F) Missense, predicted deleterious 4 Absent c.3164T>C (p.L1055P)* Missense, predicted deleterious 5 Absent c.3692G>A (p.R1231Q) Missense20 c.2296G>A (p.G766R) Missense20 6 Absent c.2782C>T (p.R928X) Nonsense13 c.3268C>T (p.R1090X) Nonsense5,7,13 7 Present c.3347G>A (p.G1116E) Missense, predicted deleterious IVS 23-8 G-A Noncoding region 8 Absent IVS 16-8 T>Gw Noncoding region10 9 Absent c.2944G>A (p.G982R) Missense5,7,19,20 c.2296G>A (p.G766R) Missense20 10 Absent c.2944G>A (p.G982R) Missense5,7,19,20 c.2296G>A (p.G766R) Missense20 11 Absent c.319T>C (p.C107R) Missense, predicted deleterious c.611+4A>G Noncoding region 12 Absent c.1723C>T (p.R575X) Nonsense7,19,20 c.2178+1G>T Noncoding region20 *Homozygous. Login to comment

[hide] Severe bile salt export pump deficiency: 82 differ... Gastroenterology. 2008 Apr;134(4):1203-14. doi: 10.1053/j.gastro.2008.01.038. Epub 2008 Jan 18. Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerova D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozcay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Nemeth A, Kotalova R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawlowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJ
Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.
Gastroenterology. 2008 Apr;134(4):1203-14. doi: 10.1053/j.gastro.2008.01.038. Epub 2008 Jan 18., [PMID:18395098]

Abstract [show]
BACKGROUND & AIMS: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

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150 Missense Mutations in ABCB11 Nucleotide change Predicted effect Exon CpG site Location Change in: Size Charge Hyd/Pol Shape c.149Tb0e;C p.Leu50Ser 4 No NH2 term Y Y Y c.470Ab0e;G p.Tyr157Cys 6 No TM2 Y Y Y c.725Cb0e;T p.Thr242Ile 8 No TM4 Y Y c.890Ab0e;G p.Glu297Gly 9 No IC2 Y Y Y c.908Gb0e;A p.Arg303Lys 9 No IC2 c.937Cb0e;A p.Arg313Ser 10 Yes IC2 Y Y Y Y c.980Gb0e;A p.Gly327Glu 10 No TM5 Y Y Y c.1168Gb0e;C p.Ala390Pro 11 No TM/NBF Y c.1229Gb0e;A p.Gly410Asp 12 No TM/NBF Y Y c.1238Tb0e;G p.Leu413Trp 12 No TM/NBF c.1388Cb0e;T p.Thr463Ile 13 No Adj Walker A Y Y Y c.1396Cb0e;A p.Gln466Lys 13 No Adj Walker A Y c.1409Gb0e;A p.Arg470Gln 13 Yes Adj Walker A Y c.1415Ab0e;G p.Tyr472Cys 13 No Adj Walker A Y Y Y c.1442Tb0e;A p.Val481Glu 14 No NBF1 Y Y Y c.1445Ab0e;G p.Asp482Gly 14 No NBF1 Y Y c.1460Gb0e;C p.Arg487Pro 14 Yes NBF1 Y Y Y Y c.1468Ab0e;G p.Asn490Asp 14 No NBF1 Y c.1535Tb0e;C p.Ile512Thr 14 No NBF1 Y Y Y c.1544Ab0e;C p.Asn515Thr 14 No NBF1 Y Y c.1550Gb0e;A p.Arg517His 14 Yes NBF1 Y Y c.1621Ab0e;C p.Ile541Leu 14 No NBF1 c.1622Tb0e;C p.Ile541Thr 14 No NBF1 Y Y Y c.1643Tb0e;A p.Phe548Tyr 15 No Adj ABC c.1685Gb0e;A p.Gly562Asp 15 No ABC Y Y c.1708Gb0e;A p.Ala570Thr 15 Yes ABC/Walker B Y c.1763Cb0e;T p.Ala588Val 15 No Adj Walker B Y c.2272Gb0e;C p.Gly758Arg 19 No NBF/TM Y Y Y c.2296Gb0e;A p.Gly766Arg 19 Yes TM7 Y Y Y c.2494Cb0e;T p.Arg832Cys 21 Yes IC3 Y Y Y Y c.2576Cb0e;G p.Thr859Arg 21 No IC3 Y Y Y Y c.2842Cb0e;T p.Arg948Cys 23 Yes IC4 Y Y Y Y c.2935Ab0e;G p.Asn979Asp 23 No TM11 Y c.2944Gb0e;A p.Gly982Arg 23 Yes TM11 Y Y Y c.3086Cb0e;A p.Thr1029Lys 24 No TM12 Y Y Y Y c.3329Cb0e;A p.Ala1110Glu 25 Yes Adj Walker A Y Y Y c.3382Cb0e;T p.Arg1128Cys 25 Yes Adj Walker A Y Y Y Y c.3457Cb0e;T p.Arg1153Cys 26 Yes NBF2 Y Y Y Y c.3458Gb0e;A p.Arg1153His 26 Yes NBF2 Y Y c.3460Tb0e;C p.Ser1154Pro 26 No NBF2 Y c.3628Ab0e;C p.Thr1210Pro 27 No Adj ABC Y c.3691Cb0e;T p.Arg1231Trp 27 Yes ABC/Walker B Y Y c.3692Gb0e;A p.Arg1231Gln 27 Yes ABC/Walker B Y c.3724Cb0e;A p.Leu1242Ile 27 No Walker B c.3892Gb0e;A p.Gly1298Arg 28 No NBF2 Y Y Y NOTE. Login to comment

[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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173 By the use of an in vitro minigene approach, interference with splicing was shown for c.1445A > G (p.D482G), c.1757C > T (p.T586I), c.3432C > A (p.S1144R), c.3458G > A (p.R1153H), c.3460T > C (p.S1154P), c.3691C > T (p.R1231 W) and c.3692G > A (p.R1231Q) [132]. Login to comment

[hide] Improved liver function and relieved pruritus afte... J Pediatr. 2014 May;164(5):1219-1227.e3. doi: 10.1016/j.jpeds.2013.12.032. Epub 2014 Feb 13. Naoi S, Hayashi H, Inoue T, Tanikawa K, Igarashi K, Nagasaka H, Kage M, Takikawa H, Sugiyama Y, Inui A, Nagai T, Kusuhara H
Improved liver function and relieved pruritus after 4-phenylbutyrate therapy in a patient with progressive familial intrahepatic cholestasis type 2.
J Pediatr. 2014 May;164(5):1219-1227.e3. doi: 10.1016/j.jpeds.2013.12.032. Epub 2014 Feb 13., [PMID:24530123]

Abstract [show]
To examine the effects of 4-phenylbutyrate (4PB) therapy in a patient with progressive familial intrahepatic cholestasis type 2. A homozygous c.3692G>A (p.R1231Q) mutation was identified in ABCB11. In vitro studies showed that this mutation decreased the cell-surface expression of bile salt export pump (BSEP), but not its transport activity, and that 4PB treatment partially restored the decreased expression of BSEP. Therapy with 4PB had no beneficial effect for 1 month at 200 mg/kg/day and the next month at 350 mg/kg/day but partially restored BSEP expression at the canalicular membrane and significantly improved liver tests and pruritus at a dosage of 500 mg/kg/day. We conclude that 4PB therapy would have a therapeutic effect in patients with progressive familial intrahepatic cholestasis type 2 who retain transport activity of BSEP per se.

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1 A homozygous c.3692G>A (p.R1231Q) mutation was identified in ABCB11. Login to comment
9 To test this hypothesis, we investigated the effects of 4PB therapy in a patient with PFIC2 carrying a homozygous c.3692G>A (p.R1231Q) mutation in ABCB11. Login to comment
22 She developed hepatocellular cholestasis and jaundice with normal serum gamma-glutamyl transferase (GGT) activity at the age of 2 months and was diagnosed with PFIC2 by the presence of the c.3692G>A (p.R1231Q) mutation in both alleles of ABCB11 and no detectable immunosignal for BSEP at the canalicular membrane of a liver section sample (Figure 1, A and B). Login to comment
28 In Vitro Studies pShuttle (Clontech, Palo Alto, California) containing complementary DNA (cDNA) of human BSEP with a hemagglutinin (HA) tag at the N-terminus (HA-BSEPwild type [WT] ) and that of HA-BSEPWT with the c.3692G>A (p.R1231Q) or p.T1210P mutation (HA-BSEPR1231Q and HA-BSEPT1210P ) were used for this study.8 The c.3692G>A (p.R1231Q) and p.T1210P mutations were introduced into pShuttle containing HA-BSEPWT cDNA by site-directed mutagenesis as described previously.9 HEK293T cells and McA-RH7777 cells transfected with pShuttle containing HA-BSEPWT , HA-BSEPR1231Q , or HA-BSEPT1210P cDNA, or empty vector (EV) (HA-BSEPWT , HA-BSEPR1231Q , HA-BSEPT1210P , or EV HEK293T cells and HA-BSEPWT , HA-BSEPR1231Q , HA-BSEPT1210P , or EV McA-RH7777 cells) were subjected to analysis of quantitative PCR (qPCR), cell surface biotinylation, immunofluorescence, and transport.Allinvitroexperiments were performed asdescribed previously,7,9 and a detailed description of the experiments is presented in the Appendix. Login to comment
48 The homozygous c.3692G>A (p.R1231Q) mutation in ABCB11 identified is shown by the arrowhead. Login to comment
56 HEK293T cells (top) and McA-RH7777 cells (bottom) expressing HA-BSEPWT (WT; left) or HA-BSEPR1231Q (R1231Q, right) were analyzed by confocal immunofluorescence microscopy as described in the Methods. Login to comment
64 Therefore, all encoding exons and flanking areas of both ATP8B1 and ABCB11 were sequenced, and a homozygous c.3692G>A (p.R1231Q) mutation in ABCB11 was identified, which has been reported previously in European white patients with PFIC2 (Figure 1, A).12 This result, combined with the immunosignal of ATP8B1, but not of BSEP at the canalicular membrane of liver sections (Figure 1, B), was the basis of the diagnosis of PFIC2. Login to comment
65 To characterize the effect of the c.3692G>A (p.R1231Q) mutation on BSEP, HA-BSEPWT and HA-BSEPR1231Q were expressed ectopically in HEK293T cells and McA-RH7777 cells, a rat hepatoma cell line that develops canalicular membranes through the formation of couplets as hepatocytes. Login to comment
79 These results suggest that 4PB treatment at a clinically relevant dosage for humans could increase BSEP expression at the canalicular membrane in patients with PFIC2 with the c.3692G>A (p.R1231Q) mutation in ABCB11 and, consequently, expand the capacity to secrete bile salt into bile. Login to comment
82 Therapeutic Effect of 4PB in the Patient with PFIC2 with the c.3692G>A (p.R1231Q) Mutation in ABCB11 Serum liver tests and the itching score did not improve during the period of 4PB treatment at the dosages of 200 and 350 mg/kg/day. However, the serum level of aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) started to decrease when the dosage was increased to 500 mg/kg/day. Login to comment
97 HA-BSEPWT (WT) and HA-BSEPR1231Q (R1231Q) HEK293T cells were treated with or without 1 mM 4PB for 24 hour and subjected to A, qPCR and B, cell surface biotinylation and analyzed as described in Methods. Login to comment
99 McA-RH7777 cells expressing HA-BSEPWT (WT, left) or HA-BSEPR1231Q (R1231Q, right) were treated with or without 1 mM 4PB for 24 hours and then subjected to confocal immunofluorescence microscopy as described in Figure 1, E. Login to comment
136 Analysis using an in vitro minigene system has suggested that c.3692G>A (p.R1231Q) in ABCB11 causes aberrant ABCB11 splicing.22 However, because BSEP was detected around 160 kDa, which is identical to the value in the control patients (Figure 4, C) and to the reported molecular weight,9 it is likely that the correct splicing occurred to some degree in our patient despite having c.3692G>A (p.R1231Q) in ABCB11 and its resultant protein product on the canalicular membrane was prevented from degradation by 4PB therapy. Login to comment

[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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137 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). Login to comment