ABCB11 p.Ala1228Val
| Reviews: |
p.Ala1228Val
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| Predicted by SNAP2: | C: N (72%), D: D (80%), E: D (80%), F: D (80%), G: D (63%), H: D (75%), I: D (71%), K: D (75%), L: D (75%), M: D (66%), N: D (71%), P: D (80%), Q: D (71%), R: D (75%), S: N (66%), T: D (53%), V: D (71%), W: D (80%), Y: D (80%), |
| Predicted by PROVEAN: | 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, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] BSEP and MDR3 haplotype structure in healthy Cauca... Hepatology. 2004 Mar;39(3):779-91. Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ
BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis.
Hepatology. 2004 Mar;39(3):779-91., [PMID:14999697]
Abstract [show]
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned approximately 10,000 bp including promoter and coding regions as well as 50-350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC.
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No. Sentence Comment
72 and A1228V.
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ABCB11 p.Ala1228Val 14999697:72:4
status: NEW73 Alignment of all mammalian BSEP sequences indicated that 5 of the 6 nonsynonymous coding variants were in codons for an evolutionarily conserved amino acid (S194P, V284A, V444A, R698H, and A1228V) (Table 2).
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ABCB11 p.Ala1228Val 14999697:73:189
status: NEW84 One variant (T851C 3 V284A) was only found in the control group, 3 were specific to PBC patients (G779A 3 G620D, C1530A and C3683T 3 A1228V), and 1 to PSC patients (T580C 3 S194P).
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ABCB11 p.Ala1228Val 14999697:84:133
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.Ala1228Val 17051391:160:335
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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131 - 25 3383 G→A Arg1128His BRIC2 [45] - 25 3457 C→T Arg1153Cys PFIC2 [35] rs1521808 26 3556 G→A Glu1186Lys - [102] - 26 3683 C→T Ala1228Val - [44] - 27 3767 - 3768 X→C Frame shift at position 1256 PFIC2 [35] - 27 3803 G→A Arg1268Gln PFIC2 [35] Intron 4 3 A→C - PFIC2 [43] Table 2.
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ABCB11 p.Ala1228Val 17181454:131:155
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.Ala1228Val 19101985:68:2918
status: NEW