ABCMdb

ABCB11 p.Arg303Lys

Reviews:	p.Arg303Lys D p.Arg303Gly D
Predicted by SNAP2:	A: D (53%), C: D (59%), D: D (75%), E: D (66%), F: D (71%), G: D (66%), H: N (53%), I: D (59%), K: N (82%), L: D (59%), M: N (57%), N: N (53%), P: D (75%), Q: N (57%), S: N (57%), T: N (53%), V: D (63%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: N, 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] 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
88 R303K had been reported in 1 family of Central Asian/Arab background.13 R487H had previously been reported to occur in a Japanese patient.11 No mutational hot spots were identified in our patients. 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
105 R303K and R487H had previously been reported to occur in patients with PFIC, further supporting their disease-causing roles.11,13 Figure 1. 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
122 In our study, G1004D was found in 1 patient with PFIC and in 1 patient with BRIC.12 R303K, which was found in our patient, had been reported in a family of central Asian/Arab background.13 Further investigations are therefore required to confirm whether these mutations are found more commonly in Asian patients. 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

[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
66 In Family 1, compound heterozygous missense mutations M183V and R303K were found in the patient. Login to comment
71 Genetic analysis from amniotic DNA showed a heterozygous mutation of M183V, but not R303K. Login to comment
96 (a) Case 1, an affected male with compound heterozygous M183V and R303K mutations; cases 2 and 4, an unaffected sibling and mother with a heterozygous M183V mutation; case 3, an unaffected father with a heterozygous R303K mutation. 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] ABCB11 gene mutations in Chinese children with pro... Liver Int. 2010 Jul;30(6):809-15. Epub 2009 Oct 21. Liu LY, Wang ZL, Wang XH, Zhu QR, Wang JS
ABCB11 gene mutations in Chinese children with progressive intrahepatic cholestasis and low gamma glutamyltransferase.
Liver Int. 2010 Jul;30(6):809-15. Epub 2009 Oct 21., [PMID:19845854]

Abstract [show]
BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe autosomal recessive liver disorder of childhood that can cause cholestasis and progress to end-stage liver disease. ABCB11 gene mutations causing PFIC2 have been reported in some population groups, but not in mainland Chinese. AIMS: To elucidate the existence of and characterize ABCB11 gene mutations in mainland Chinese with progressive intrahepatic cholestasis and low gamma glutamyltransferase (GGT). METHODS: Twenty-four children presenting with progressive intrahepatic cholestasis and low GGT were admitted to a tertiary paediatric hospital in eastern China from January 2004 to July 2007. All encoding exons and flanking areas of the ABCB11 gene were sequenced. Hepatic histopathology results were obtained by review of the medical record. RESULTS: Twelve novel mutations of ABCB11 gene were found in seven patients: three nonsense mutations, six missense mutations, two splicing mutations and one intronic mutation. Giant cell transformation of hepatocytes was demonstrated in all the four patients with ABCB11 mutations and four of 12 patients without mutations in coding sequences of ABCB11 gene who received liver needle biopsy. CONCLUSIONS: ABCB11 gene mutations play an important role in Chinese patients with progressive intrahepatic cholestasis and low GGT. The characteristics of ABCB11 gene mutations in Chinese are different from other population groups. Histological examination may be helpful in diagnosis of PFIC2.

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87 All of them, except for R303K, were different from those reported in other population groups. Login to comment
119 R303K found in Central Asian, Arab and Taiwan Chinese is shown in green. Login to comment

[hide] PFIC2 and ethnicity-specific bile salt export pump... Liver Int. 2010 Jul;30(6):777-9. Epub 2010 Mar 8. Ananthanarayanan M, Li Y
PFIC2 and ethnicity-specific bile salt export pump (BSEP, ABCB11) mutations: where do we go from here?
Liver Int. 2010 Jul;30(6):777-9. Epub 2010 Mar 8., [PMID:20214736]

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28 Mutations reported in this study except one (R303K) were unique to this population Liver International (2010) c 2010 John Wiley & Sons A/S 777 Liver International ISSN 1478-3223 group. 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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220 Four different changes occurred at, or adjacent to, the 5= splice site of intron 9: R303K, c.908af9;1delG,1,33 c.908af9;1Gb0e;T,28 and c.908af9;1Gb0e;A. 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