ABCMdb

ABCB11 p.Gly877Arg

Reviews:	p.Gly877Arg D
Predicted by SNAP2:	A: D (53%), C: D (66%), D: D (85%), E: D (85%), F: D (85%), H: D (91%), I: D (80%), K: D (91%), L: D (80%), M: D (80%), N: D (80%), P: D (85%), Q: D (85%), R: D (91%), S: D (71%), T: D (75%), V: D (80%), W: D (91%), Y: D (91%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: 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] DHPLC screening for mutations in progressive famil... J Hum Genet. 2010 May;55(5):308-13. Epub 2010 Apr 23. Shapiro R, Anikster Y, Yardeni T, Korem S, Hartman K, Shamir R, Broide E, Levine A, Bujanover Y, Bercovich D
DHPLC screening for mutations in progressive familial intrahepatic cholestasis patients.
J Hum Genet. 2010 May;55(5):308-13. Epub 2010 Apr 23., [PMID:20414253]

Abstract [show]
Progressive familial intrahepatic cholestasis (PFIC) is a group of rare heterogeneous autosomal recessive disorders characterized by metabolic defects in biliary proteins involved in the formation and transfer of bile acids in the liver. The genotype-phenotype correlation is not always clear. Mutations in the ATP8B1, BSEP and MDR3 genes have been associated with PFIC1, PFIC2 and PFIC3, respectively. This study sought to characterize the molecular genetic basis for PFIC subtypes in Israel. It was conducted on 14 children with PFIC and their families; 10 with a PFIC1 or PFIC2 phenotype and 4 with a PFIC3 phenotype. Using denaturing high-performance liquid chromatography (DHPLC), five different mutations were identified in four affected families: three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and one heterozygous mutation in ATP8B1 (R600W, in a family with the PFIC1/PFIC2 phenotype). The cause of PFIC was identified in 20% of the families tested. These findings indicate the probable involvement of additional genes in PFIC and the need for further studies to determine whether the abnormality lies on the RNA or protein level. A better understanding of the phenotype-genotype correlation in PFIC will lead to improved diagnoses and treatments.

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5 Using denaturing high-performance liquid chromatography (DHPLC), five different mutations were identified in four affected families: three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and one heterozygous mutation in ATP8B1 (R600W, in a family with the PFIC1/PFIC2 phenotype). Login to comment
64 Family 2 was found to harbor a novel mutation, G877R-g2755a, in a homozygous state (Figure 3). Login to comment
69 In addition, DNA screening for MDR3 mutations in families 11, 12 and 13 yielded one heterozygous novel splice-site Table 2 Results from the screening of the five candidate genes Family DNA ATP8B1 BSEP MDR3 FXR NTCP 1 1-patient WT WT - WT WT 1-M WT WT - WT WT 2 2-patient WT G877R - WT WT 2-M WT G877R/N - WT WT 3 3-patient WT G19R/N; S226L/N - WT WT 3-B WT S226L/N - WT WT 3-patient WT G19R/N; S226L/N - WT WT 3-M WT S226L/N - WT WT 3-F WT G19R/N - WT WT 4 4-patient WT WT - WT WT 4-M WT WT - WT WT 4-B WT WT - WT WT 5 5-patient W.T WT - WT WT 5-patient WT WT - WT WT 5-M WT WT - WT WT 5-F WT WT - WT WT 6 6-patient WT WT - WT WT 6-M WT WT - WT WT 6-F WT WT - WT WT 7 7-patient WT WT - WT WT 7-patient WT WT - WT WT 7-M WT WT - WT WT 8 8-patient WT WT - WT WT 8-M WT WT - WT WT 9 9-patient R600W/N WT - WT WT 9-F WT WT - WT WT 9-M R600W/N WT - WT WT 9-S R600W/N WT - WT WT 9-S WT WT - WT WT 10 10-patient WT WT - WT WT 10-F WT WT - WT WT 11 11-patient - - WT WT - 11-M - - WT WT - 11-F - - WT WT - 12 12-patient - - IVS14+6t/c/N WT - 12-F - - W.T WT - 13 13-patient - - WT WT - 13-M - - WT WT - 13-F - - WT WT - 14 14-patient - - WT WT - 14-M - - WT WT - 14-F - - WT WT - 14-B - - WT WT - 14-S - - WT WT - Abbreviations: B, brother; BSEP, bile salt export pump; F, father; FXR, farnesoid X receptor; M, mother; NTCP, Na+-dependent taurocholic co-transporting polypeptide; S, sister; WT, wild type. Login to comment
73 In total, five mutations were discovered in the ATP8B, BSEP and MDR3 genes; that is, three novel mutations in BSEP (G19R-g181c, S226L-c803t and G877R-g2755a), one novel mutation in MDR3 (IVS14+6 t/c) and only one heterozygous mutation in ATP8B1 (R600W). Login to comment
75 The patients from family 3 were compound heterozygotes for two mutations in BSEP-G19R and S226L-and the patient from family 2 had a hemizygous mutation in BSEP-G877R. Login to comment
76 S226L and G877R are missense mutations at the conserved and active sites of the proteins (ConSeq; http://conseq.tau.ac.il; Figure 5), and G19R is located at the N-terminal region of the BSEP protein. Login to comment
105 G877R-Hetrozigote G877R -Homozygote unknown Figure 3 Sequence analysis of the G877R (2755g4a) missense mutations of the BSEP gene in family 2. Login to comment
116 The two mutations (S226L and G877R) are in the functional regions of the protein. 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