ABCMdb

ABCB11 p.Val284Leu

Reviews:	p.Val284Ala N p.Val284Leu D
Predicted by SNAP2:	A: N (66%), C: D (59%), D: D (91%), E: D (85%), F: D (80%), G: D (80%), H: D (85%), I: N (61%), K: D (85%), L: D (85%), M: D (71%), N: D (80%), P: D (91%), Q: D (85%), R: D (85%), S: D (71%), T: D (63%), W: D (85%), Y: D (80%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D,

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[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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165 (*) The mutation V284L was found in a patient with PFIC2, whereas the SNP V284A occurs in healthy individuals trations are increased accordingly. Login to comment

[hide] Diagnosis of BSEP/ABCB11 mutations in Asian patien... J Pediatr. 2008 Dec;153(6):825-32. Epub 2008 Aug 9. Chen HL, Liu YJ, Su YN, Wang NY, Wu SH, Ni YH, Hsu HY, Wu TC, Chang MH
Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography.
J Pediatr. 2008 Dec;153(6):825-32. Epub 2008 Aug 9., [PMID:18692205]

Abstract [show]
OBJECTIVE: To determine if specific mutations were present in Asian patients with progressive familial intrahepatic cholestasis (PFIC) type 2 caused by defects in bile salt export pump (BSEP), encoded by ABCB11. STUDY DESIGN: A combination of denaturing high-performance liquid chromatography (DHPLC) and direct sequencing was used to screen ABCB11 mutations in 18 Taiwanese patients with low gamma-glutamyltransferase PFIC or benign recurrent intrahepatic cholestasis (BRIC). Polymorphisms were also analyzed in patients with PFIC (n = 21), neonatal cholestasis (n = 23), and control subjects (n = 88). RESULTS: Seven mutations in 4 of 16 patients with PFIC from different families were detected by DHPLC, including M183V, V284L, R303K, R487H, W493X, G1004D, and 1145delC. G1004D was found in a patient with BRIC. L827I was found in another patient with neonatal cholestasis. Absent or defective BSEP staining was found in the liver of patients with mutations. Polymorphisms V444A and A865V, with an allele frequencies 75.6% and 0.6%, respectively, were found in our population. No differences were found between patients with cholestasis and control subjects. CONCLUSIONS: One-fourth of Taiwanese patients with PFIC/BRIC had compound heterozygous or single heterozygous ABCB11 mutations without hot spots. All of the mutations were different from those detected in Western countries.

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3 Results Seven mutations in 4 of 16 patients with PFIC from different families were detected by DHPLC, including M183V, V284L, R303K, R487H, W493X, G1004D, and 1145delC. Login to comment
46 Age of onset Bil T (␮mol/L) Bil D (␮mol/L) GGT (U/L) AST (U/L) ALT (U/L) Liver pathology Mutations found Exon Predicted effect Outcome 1 1 mo 169.3 121.4 56 518 244 IC, GCT c.850GϾC c.1145delC 9 11 p. Val284Leu p.Ala382AlafsX16 Death, 5 y 2 1 mo 100.9 51.3 30 88 66 IC, GCT, bridging fibrosis c.850GϾC c.1145delC 9 11 p. Val284Leu p.Ala382AlafsX16 Alive 5 y, chronic cholestasis, Failure to thrive 3 2 wk 119.7 58.1 36 500 341 IC, GCT c.547AϾG c.908GϾA 7 9 p.Met183Val p.Arg303Lys Death, 8 mo 4 1 mo 179.6 138.5 68 186 150 GCT, fibrosis c.1478GϾA c.3011GϾA 14 23 p.Trp493X p.Gly1004Asp Death, 2 yr 5 birth 237.7 155.6 47 1184 653 - c.1460GϾA 14 p.Arg487His Death, 1 y 6 2 mo 360.8 251.4 132 884 352 Lobular disarray NF Death, 9 mo 7 1 mo 119.7 109.4 25 54 49 IC, bridging fibrosis NF Alive, 7 y 8 2 mo 401.9 273.6 51 251 252 GCT, cell ballooning NF Death 1 y 6mo 9 3 mo 442.9 256.5 54 556 217 - NF Death, 7 mo 10 1 mo 157.3 90.6 20 606 828 GCT, hepatocyte ballooning, confluent necrosis NF Death, 9 mo 11 1 mo 193.2 136.8 52 523 345 GCT, focal necrosis NF Death 4 mo 12 2 mo 165.9 94.1 99 298 202 GCT, portal inflammation, ductal proliferation NF Death 8 mo 13 2 wk 277.0 194.9 64 1054 825 GCT, necrosis NF OLT, 6 mo 14 2 mo 413.8 229.1 51 625 665 GCT, biliary cirrhosis NF OLT, 9 mo 15 birth 371.1 271.9 68 584 400 GCT NF Alive, 10 mo 16 birth 176.1 145.4 57 352 249 GCT, bridging fibrosis NF Death, 9 mo 17 birth 136.8 46.2 47 29 117 GCT NF Alive, 5 y 18 32 y 143.6 63.3 24 105 91 Centrilobular canalicular cholestasis, hemosiderosis c.3011GϾA 23 p.Gly1004Asp Alive, 35 y, recurrent cholestasis IC, Intrahepatic cholestasis; GCT, giant-cell transformation; OLT, orthotopic liver transplantation; NF, mutations not found. Login to comment
80 RESULTS Mutations Detected in Patients with PFIC Of 17 patients with low-GGT PFIC, mutations in ABCB11 were found in 5 patients, including a sibling pair (patients 1 and 2) with compound heterozygous c.850GϾC (p.V284L) and c.1145delC (p.Ala382AlafsX16) mutations.12 Patient 3 had compound heterozygous c.547AϾG (p.M183V)/c.908GϾA (p.R303K) mutations. Login to comment
102 Analysis of Mutations in Normal Controls All the missense mutations detected above were tested in 80 normal control subjects (160 alleles), using DHPLC for M183V (exon 7), V284L (exons 9), R303K (exon 9), R487H (exon 14), L827I (exon 21), and G1004D (exon 23). Login to comment
109 The PolyPhen results indicated that V284L and G1004D are possibly damaging, and M183V, R303K, R487H, and L827I were predicted to be benign (Table IV). Login to comment
128 Prediction of functional consequences of nonsynonymous mutations and polymorphisms in ABCB11 found in Asian patients Amino acid change SIFT PolyPhen (PSIC score) EC/EU M183V 0.02 1.45 EC V284L 0.02 1.87 EC R303K 0.00 0.38 EC V444A 0.76 0.60 EC R487H 0.01 0.65 EC L827I 0.01 1.23 EC A865V 0.10 0.76 EC G1004D 0.00 1.97 EC SIFT, Sorting intolerant from tolerant (SIFT scores Ͻ0.05 indicate evolutionarily conserved amino acids, and mutation of these residues are predicted to be deleterious); PolyPhen, polymorphism phenotyping (a PSIC score Ͻ0.5 denotes benign variants, between 1.5 and 2 is possibly damaging, and Ͼ2 is probably damaging); EC, evolutionarily conserved; EU, evolutionarily unconserved. Login to comment
135 Although the PolyPhen analysis only predicted 2 missense mutations (V284L and G1004D) to be possibly deleterious, other mutations had borderline scores. Login to comment

[hide] Prenatal diagnosis of progressive familial intrahe... J Gastroenterol Hepatol. 2008 Sep;23(9):1390-3. Chen ST, Chen HL, Su YN, Liu YJ, Ni YH, Hsu HY, Chu CS, Wang NY, Chang MH
Prenatal diagnosis of progressive familial intrahepatic cholestasis type 2.
J Gastroenterol Hepatol. 2008 Sep;23(9):1390-3., [PMID:18853996]

Abstract [show]
BACKGROUND AND AIM: Progressive familial intrahepatic cholestasis type 2 (PFIC2) results from genetic defects of the hepatobiliary bile salt export pump (BSEP, ABCB11) at chromosome 2q24. Patients with progressive cholestasis and liver cirrhosis usually need liver transplantation in the first decade. Mutations in ABCB11 are also associated with benign recurrent intrahepatic cholestasis type 2 and intrahepatic cholestasis of pregnancy in adult patients. We aimed to make the prenatal diagnosis of PFIC2. METHODS: Genetic diagnosis was performed by genomic DNA analysis. Prenatal genetic diagnosis was made by fetal amniotic DNA and chorionic DNA analysis. RESULTS: We report on two families of PFIC2 with inherited compound heterozygous mutations of ABCB11 (M183V and R303K in Family 1, V284L and 1145delC in Family 2) from the parents. An infant with heterozygous M183V mutation was later born healthy in Family 1. A fetus with compound heterozygous missense mutation V284L and 1145delC was terminated in Family 2. CONCLUSION: Prenatal diagnosis of PFIC2 was helpful to prevent further affected children in families with this fatal disease.

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6 Results: We report on two families of PFIC2 with inherited compound heterozygous mutations of ABCB11 (M183V and R303K in Family 1, V284L and 1145delC in Family 2) from the parents. Login to comment
8 A fetus with compound heterozygous missense mutation V284L and 1145delC was terminated in Family 2. Login to comment
73 In Family 2, compound heterozygous missense mutation V284L and a 1bp deletion at nucleotide 1145 at coding sequence were found in the first and second child.9 Both parents carried one mutation each (Fig. 2b). Login to comment
76 Genetic study of the fetus showed the same compound heterozygous missense mutation V284L and 1145delC mutation. Login to comment
97 (b) Cases 5, 6, 7, affected individuals with compound heterozygous V284L mutation and 1145delC. Login to comment
99 Case 9, an unaffected mother with the heterozygous V284L mutation. 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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67 ABCB11 Missense Mutations and SNPs Functionally Analyzed in This Study Exon Nucleotide Change Predicted Protein Effect Location in Protein Associated Phenotype Prevalence or Frequency* Any Defect(s) Identified Reference 4 c.149TϾC L50S NH2 term PFIC 1 family (het) Immature protein 31 5 c.270TϾC F90F EC1 SNP 2.7%-7.7% 43, 45 6 c.403GϾA E135K EC1 BRIC 1 family (het) Reduced levels of mature protein † 6 c.409GϾA E137K EC1 BRIC / ICP 1 family (het) Immature protein ‡ 7 c.500CϾT A167V TM2 PFIC 1 family (hom) Mild exon skipping beta 7 c.557AϾG E186G IC1 BRIC 2 families (both het) Moderate exon skipping; greatly reduced levels of mature protein 8, 37 7 c.580TϾC S194P IC1 SNP-PSC 1.1% 43 7 c.593TϾC L198P IC1 BRIC / ICP / DC 1 family (het) Greatly reduced levels of mature protein # 8 c.713GϾT G238V EC2 PFIC 1 family (hom) 29 8 c.725CϾT T242I TM4 PFIC 1 family (het) 31 8 c.779GϾA G260D TM4 SNP-PBC 0.8% 43 9 c.850GϾC V284L IC2 PFIC 1 family (het) No protein 28 9 c.851TϾC V284A IC2 SNP 0.5% Increased levels of mature protein 43, 45† 9 c.889GϾA E297K IC2 Prolonged NNH 1 family (het) Moderate differential splicing; immature protein ‡ 9 c. 890AϾG E297G IC2 PFIC, BRIC PFIC, 45 families (14 hom, 31 het) BRIC, 4 families (2 hom, 2 het) Greatly reduced levels of mature protein 7, 8, 12, 29-32, 35 10 c.936GϾT Q312H IC2 PFIC 1 family (het) ‡ 10 c.937CϾA R313S IC2 PFIC 1 family (het) 31 10 c.957AϾG G319G TM5 SNP 1.5 - 7.5% Mild exon skipping 42, 43, 45 10 c.980GϾA G327E TM5 PFIC 1 family (het) 31 10 c.1007GϾC C336S TM5 PFIC 1 family (het) 29 11 c.1168GϾC A390P NBF PFIC, BRIC 2 families (both het) Immature protein 31; # 12 c.1129GϾA G410D NBF PFIC 1 family (het) 31 12 c.1238TϾG L413W NBF PFIC 1 family (het) Greatly reduced levels of mature protein 31 12 c.1244GϾA R415Q NBF SNP-ICP 1.3% 42 12 c.1295GϾC R432T NBF BRIC 1 family (het) Reduced levels of mature protein 12 13 c.1331CϾT A444V NBF SNP, ICP, CC, DC, BRIC 43-60% Increased levels of mature protein 8, 28, 37, 39-45 13 c.1381AϾG K461E WA PFIC 1 family (hom) Immature protein 7 13 c.1388CϾT T463I WA PFIC 1 family (het) Mild exon skipping 31 13 c.1396CϾA Q466K Adj WA PFIC 1 family (het) 31 13 c.1409GϾA R470Q Adj WA PFIC 2 families (1 het, 1 consanguineous) Immature protein 31 14 c.1442TϾA V481E NBF1 PFIC 1 family (het) 31 14 c.1445AϾG D482G NBF1 PFIC 22 families (16 het, 6 hom) Severe differential splicing; immature protein 7, 30-32 14 c.1468AϾG N490D NBF1 PFIC 1 family (het) Greatly reduced levels of mature protein; reduction in bile salt transport 31 14 c.1493TϾC I498T NBF1 PFIC / BRIC 1 family (het) 38 14 c.1530CϾA T510T NBF1 SNP-PBC 0.7% 43 14 c.1535TϾC I512T NBF1 PFIC 1 family (het) 31 14 c.1544AϾC N515T NBF1 PFIC 1 family (het) 31, 32 14 c.1440GϾA R517H NBF1 PFIC 1 family (het) No protein 31, 32 14 c.1605CϾT A535A NBF1 SNP 0.3% Slightly reduced levels mature protein 39, 45 14 c.1621AϾC I541L NBF1 PFIC 3 families (1 het, 2 consanguineous) No protein 31-33 15 c.1643TϾA F548Y Adj ABCm PFIC 1 family (het) 31, 32 15 c.1685GϾA G562D ABCm PFIC 1 family (het) 31 15 c.1708GϾA A570T Adj ABCm/WB PFIC, BRIC PFIC, 1 family Greatly reduced levels of mature protein; reduction in bile salt transport 8, 31 Table 1. Login to comment
144 No BSEP protein, mature or immature, was observed for the mutations V284L (c.850GϾC) and A588V (c.1763CϾT; Fig. 5A) and I541L (c.1621AϾC; Fig. 5B), indicating that these variants were rapidly degraded. Login to comment
212 With respect to L1242I, disruption of a Walker B motif is predicted to cause severe functional consequences.64 No detectable protein was observed for the predicted missense mutations V284L (c.850GϾC) and A588V (c.1763CϾT; Fig. 5A). Login to comment
213 V284A enhances, whereas V284L abolishes, BSEP protein levels. Login to comment

[hide] The transporter "variome": the missing link betwee... Hepatology. 2009 Feb;49(2):352-4. Mullenbach R, Lammert F
The transporter "variome": the missing link between gene variants and bile salt transporter function.
Hepatology. 2009 Feb;49(2):352-4., [PMID:19177487]

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34 (2) Retention and degradation of the protein in the endoplasmatic reticulum (trafficking mutant, for example ABCB11 variants p.V284L and p.A588V). Login to comment

[hide] Novel ABCB11 mutations in a Thai infant with progr... World J Gastroenterol. 2009 Sep 14;15(34):4339-42. Treepongkaruna S, Gaensan A, Pienvichit P, Luksan O, Knisely AS, Sornmayura P, Jirsa M
Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis.
World J Gastroenterol. 2009 Sep 14;15(34):4339-42., 2009-09-14 [PMID:19750581]

Abstract [show]
Progressive familial intrahepatic cholestasis (PFIC) type 2 is caused by mutations in ABCB11, which encodes bile salt export pump (BSEP). We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum gamma-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11, a four-nucleotide deletion in exon 3, c.90_93delGAAA, and a single-nucleotide insertion in exon 5, c.249_250insT, were identified, with confirmation in her parents. These mutations were predicted to lead to synthesis of truncated forms of BSEP. Immunostaining and mutation analysis thus established the diagnosis of PFIC type 2.

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90 Chen et al[13] have reported seven BSEP mutations (M183V, V284L, R303K, R487H, W493X, G1004D and 1145delC) in four PFIC patients of Chinese descent; none of these mutations has been described in Caucasian patients. Login to comment

[hide] ABCB4 and ABCB11 mutations in intrahepatic cholest... Dig Liver Dis. 2013 Mar;45(3):226-32. doi: 10.1016/j.dld.2012.08.011. Epub 2012 Sep 27. Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, Ruggiero G, Zampino R, Bertolotti M, Loria P, Carulli L
ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population.
Dig Liver Dis. 2013 Mar;45(3):226-32. doi: 10.1016/j.dld.2012.08.011. Epub 2012 Sep 27., [PMID:23022423]

Abstract [show]
BACKGROUND: Genetic alterations in the ATP-binding cassette subfamily B member 4 (ABCB4) and ATP-binding cassette subfamily B member 11 (ABCB11) have been associated to the onset of intrahepatic cholestasis of pregnancy (ICP) in predisposed women. AIMS: To identify new and/or frequent ABCB4 and ABCB11 genes variants in a cohort of Italian patients with ICP and to evaluate the possible pathogenetic role for the novel mutations identified. METHODS: DNA of 33 unrelated Italian women with obstetric cholestasis were screened for mutations in the entire coding sequence of ABCB4 and ABCB11 genes. Polymerase chain reaction and automated sequencing was performed on the 27 coding exons of both genes. RESULTS: Genotyping revealed 11 mutations, 5 of whom were novel variants: 2 localized on ABCB4 (p.I587DfsX603, p.I738LfsX744) and 3 on ABCB11 (p.V284D, p.Q558H, p.P731S). The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient. CONCLUSIONS: Our data support the hypothesis of a significant involvement of ABCB4 mutations in the onset of ICP, but also confirm an important role for ABCB11 mutations in increasing the susceptibility to cholestasis of pregnancy.

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146 A further demonstration of the importance of the conservation of this valine in the evolution comes from previous evidence which identified other substitutions in the same position (p.V284L and p.V284A) [12,25,29] and analysed them by the mean of an in vitro minigene system reporting no protein formation for the variant p.V284L and an increased amount of protein for the SNP p.V284A [26]. Login to comment
147 The p.Q558H missense mutation is localised in the nucleotide binding domain1 at the level of the ABC signature motif; because this represents a functional domain, the mutation is likely to alter protein stability. Login to comment

[hide] FIC1 and BSEP defects in Taiwanese patients with c... J Pediatr. 2002 Jan;140(1):119-24. Chen HL, Chang PS, Hsu HC, Ni YH, Hsu HY, Lee JH, Jeng YM, Shau WY, Chang MH
FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels.
J Pediatr. 2002 Jan;140(1):119-24., [PMID:11815775]

Abstract [show]
To elucidate the frequency of FIC1 (ATP8B1) and BSEP (ABCB11) mutations in Taiwanese children with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase (GGT) levels, we assessed 13 unrelated patients with infantile onset chronic intrahepatic cholestasis. Liver complementary DNA sequencing was performed in 7 infants for mutation analyses of FIC1 and BSEP genes. Two distinct liver histologic features were found. Group 1 (n = 5) was characterized by bland cholestasis and group 2 (n = 8) by giant cell transformation. Group 2 patients were associated with higher transaminase levels, alpha-fetoprotein levels, and early mortality. Novel FIC1 mutations were found in all 4 patients tested in group 1, including a 74-bp deletion, a 98-bp deletion, a nonsense, and 2 missense mutations. BSEP mutations were found in 2 of the 3 patients in group 2, including 2 missense mutations and a 1-bp deletion. Phenotypic characterization is useful to differentiate FIC1- from BSEP-related disease.

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52 onset/sex Symptoms follow-up Outcome features Genotype 1 1 mo/F Persistent JD, intractable 6 y Liver Hepatocellular FIC1: heterozygous pruritus, hepatomegaly, transplantation cholestasis, lobular deletion at mild diarrhea in infancy at 5.5 y disarray, Byler`s bile, nucleotide positions cirrhosis at 556~628; heterozygous hepatectomy nonsense mutation Q1131X 2 1 mo/F Persistent JD, rickets, 3.5 y Alive, growth Bland cholestasis, FIC1: homozygous pruritus, failure retardation fine granular bile missense mutation to thrive R296C 3 8 mo/M Mild JD, chronic 3 y Alive, progressive Cholestasis, FIC1: homozygous diarrhea in infancy JD, growth mild fibrosis missense mutation retardation I694N 4 1 mo/M JD, rickets 14 mo Alive Cholestasis, ND moderate fibrosis 5 1 mo/M Persistent JD 17 mo Biliary diversion Cholestasis, FIC1: heterozygous at 1 y, portal fibrosis, deletion at nucleotide moderate JD Byler`s bile position 185~282 6 Birth/F Progressive JD, 14 mo Death GCT, feathery FIC1 and BSEP: variceal bleeding degeneration no mutation 7 1 mo/F Persistent JD, 21 mo Alive, mild JD, GCT, pericellular BSEP: heterozygous severe pruritus, severe pruritus fibrosis 1 bp deletion at position chronic diarrhea 1145, and heterozygous V284L mutation 8 1 mo/F Progressive JD, 10 mo Alive, GCT, portal fibrosis BSEP: homozygous failure to thrive moderate JD G1004D mutation 9 1 mo/M Progressive JD, 4 mo Death GCT, fibrosis ND hepatic failure 10 Birth/F Progressive JD, 5 mo Death GCT, fibrosis ND hepatic failure 11 1.5 mo/M Progressive JD, 12 mo Death GCT ND hepatic failure 12 1 mo/M Progressive JD, 5 mo Death GCT, portal fibrosis ND hepatic failure 13 Birth/M Progressive JD, 15 mo Liver GCT, fibrosis ND failure to thrive, transplantation hepatic failure at 1 y All patients except 9 and 10 were of Chinese descent. Login to comment
78 A heterozygous 850G࢐C (V284L), and a heterozygous 1-bp deletion at position 1145 was found in 1 patient. Login to comment
80 The V284L missense mutation was in the intracellular loop between transmembrane spans 4 and 5. Login to comment
111 The BSEP (ABCB11) mutation V284L found in case 7 was in the vicinity of common European mutation E297G.7 No common mutations were shared among our patients, indicating that these mutations did not come from 123 Group 1 Group 2 P (n = 5) (n = 8) value Peak bilirubin (<17.1 &#b5;mol/L) 277 615 .059 (Range) (137-573) (180-1094) Peak AST (<60 U/L) 137 876 .002* (Range) (50-384) (504-1530) Peak ALT (<50 U/L) 74 471 .001* (Range) (24-174) (237-847) Serum GGT (<94 U/L) 24 55 .018* (Range) (14-41) (23-98) Serum bile acid (<10 &#b5;mol/L) 180 71 .001* (Range) (139-214) (16-127) Serum cholesterol (<200 U/L) 103 196 .207 (Range) (74-134) (47-438) Serum triglyceride (<200 U/L) 206 209 .966 (Range) (106-323) (38-448) AFP SD score 0.57 8.76 .007* (Range) (0-1.36) (2.4-16.2) Group 1, Patients with bland cholestasis in histology; Group 2, patients with giant cell transformation in histologic features. 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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185 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. Login to comment