ABCMdb

ABCB4 p.Glu528Asp

ClinVar:	c.1584G>C , p.Glu528Asp N , Benign
Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (85%), F: D (91%), G: D (91%), H: D (80%), I: D (85%), K: D (91%), L: D (91%), M: D (85%), N: D (85%), P: D (91%), Q: D (95%), R: D (91%), S: D (95%), T: D (85%), V: D (85%), W: D (95%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: N, 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] Sequence analysis of bile salt export pump (ABCB11... Pharmacogenetics. 2004 Feb;14(2):91-102. Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C, Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ, Kullak-Ublick GA
Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy.
Pharmacogenetics. 2004 Feb;14(2):91-102., [PMID:15077010]

Abstract [show]
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder associated with increased risk of intrauterine fetal death and prematurity. There is increasing evidence that genetically determined dysfunction in the canalicular ABC transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) might be risk factors for ICP development. This study aimed to (i). describe the extent of genetic variability in BSEP and MDR3 in ICP and (ii). identify new disease-causing mutations. Twenty-one women with ICP and 40 women with uneventful pregnancies were recruited between April 2001 and April 2003. Sequencing of BSEP and MDR3 spanned 8-10 kb per gene and comprised the promoter region and 100-350 bp of the flanking intronic region around each exon. DNA sequencing of polymerase chain reaction fragments was performed on an ABI3700 capillary sequencer. MDR3 promoter activity of promoter constructs carrying different ICP-specific mutations was studied using reporter assays. A total of 37 and 51 variant sites were detected in BSEP and MDR3, respectively. Three non-synonymous sites in codons for evolutionarily conserved amino acids were specific for the ICP collective (BSEP, N591S; MDR3, S320F and G762E). Furthermore, four ICP-specific splicing mutations were detected in MDR3 [intron 21, G(+1)A; intron 25, G(+5)C and C(-3)G; and intron 26, T(+2)A]. Activity of the mutated MDR3 promoter was similar to that observed for the wild-type promoter. Our data further support an involvement of MDR3 genetic variation in the pathogenesis of ICP, whereas analysis of BSEP sequence variation indicates that this gene is probably less important for the development of pregnancy-associated cholestasis.

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75 Unauthorized reproduction of this article is prohibited. Table 2 MDR3 genetic variability Variant number Amplicon DNA position cDNA position Nucleotide reference Nucleotide variant AA change ICP (n ¼ 42) Control (n ¼ 80) Pro 1 amplicon -3 Intron -4 (-394) T G 0.050 0.066 Pro 2 Amplicon -3 Intron -4 (-394) insA 0.025 0.000 Pro 3 Amplicon -3 Intron -4 (-10) C T 0.028 0.000 Pro 4 Amplicon -3 Exon -3 (-410) T C Non-coding 0.053 0.066 Pro 5 Amplicon -3 Exon -3 (-358) A G Non-coding 0.026 0.000 Pro 6 Amplicon -2 Intron -3 (-31) C T 0.024 0.000 Pro 7 Amplicon -2 Exon -2 (-229) C T Non-coding 0.095 0.154 Pro 8 Amplicon -2 Intron -2 (þ234) C T 0.024 0.000 Pro 9 Amplicon -1 Intron -2 (-221) C T 0.095 0.150 Pro 10 Amplicon -1 Intron -2 (-204) A G 0.095 0.150 Pro 11 Amplicon 1 Intron -1 (-301) C G 0.167 0.225 Pro 12 Amplicon 1 Intron -1 (-292) G A 0.000 0.013 Pro 13 Amplicon 1 Intron -1 (-285) T C 0.000 0.013 Pro 14 Amplicon 1 Intron -1 (-220) C T 0.071 0.063 Pro 15 Amplicon 1 Intron -1 (-201) C G 0.167 0.138 Pro 16 Amplicon 1 Intron -1 (-184) T C 0.333 0.275 Pro 17 Amplicon 1 Exon 1 (-10) C A Non-coding 0.024 0.000 4.1. Amplicon 4 Exon 4 175 C T Syn 0.095 0.154 5.1. Amplicon 5 Intron 4 (-61) C T 0.000 0.025 5.2. Amplicon 5 Intron 5 (þ113) A G 0.167 0.213 6.1. Amplicon 6 Intron 5 (-62) AGAAA delAGAAA 0.026 0.027 6.2. Amplicon 6 Exon 6 459 T C Syn 0.026 0.000 6.3. Amplicon 6 Exon 6 504 C T Syn 0.525 0.500 6.4. Amplicon 6 Exon 6 523 A G T175A_c 0.025 0.000 8.1. Amplicon 8 Exon 8 711 A T Syn 0.167 0.213 9.1. Amplicon 9 Intron 8 (-36) T G 0.000 0.016 9.2. Amplicon 9 Exon 9 959 C T S320F_c 0.050 0.000 12.1. Amplicon 12 Intron 11 (-88) T delT 0.125 0.103 12.2. Amplicon 12 Intron 11 (-70) A G 0.000 0.015 12.3. Amplicon 12 Intron 12 (þ86) G A 0.024 0.000 12.4. Amplicon 12 Intron 12 (þ130) G T 0.067 0.227 13.1. Amplicon 13 Intron 12 (-40) G A 0.950 0.919 14.1. Amplicon 14 Intron 13 (-198) A C 0.000 0.013 14.2. Amplicon 14 Exon 14 1584 G C E528D 0.000 0.013 16.1. Amplicon 16 Exon 16 1954 A G R652G 0.100 0.163 16.2. Amplicon 16 Intron 16 (þ55) A G 0.100 0.145 17.1. Amplicon 17 Intron 17 (þ16) T C 0.975 0.879 18.1. Amplicon 18 Intron17 (-139) A G 0.024 0.000 18.2. Amplicon 18 Exon 18 2285 G A G762E_c 0.024 0.000 19.1 Amplicon 19 Exon 19 2324 C T T775M_c 0.000 0.013 20.1. Amplicon 20 Intron 20 (þ40) A G 0.100 0.176 21.1. Amplicon 21 Intron 21 (þ1) G A Splicing 0.025 0.000 21.2. Amplicon 21 Intron 21 (þ98) insTGT 0.000 0.013 21.3. Amplicon 21 Intron 21 (þ158) T C 0.150 0.064 23.1. Amplicon 23 Intron 23 (þ65) T A 0.000 0.013 25.1. Amplicon 25 Intron 25 (þ5) G C Splicing 0.029 0.000 26.1. Amplicon 26 Intron 25 (-3) C G Splicing 0.028 0.000 26.2. Amplicon 26 Intron 26 (þ2) T A Splicing 0.028 0.000 26.3. Amplicon 26 Intron 26 (þ53) A G 0.000 0.013 27.1. Amplicon 27 Intron 26 (-16) T C 0.921 0.871 28.1. Amplicon 28 Intron 27 (-72) T C 0.125 0.186 cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number NM_000443. Login to comment
109 Non-synonymous changes newly observed as singletons or doubletons in our sample set coded for the following amino acid changes: S320F, E528D, G762E and T775M. Login to comment
110 Alignment of all mammalian MDR3 sequences indicated that, with the exception of E528D and R652G, all non-synonymous coding variants were in codons for an evolutionarily conserved amino acid. Login to comment
142 Q R I K R I Q I D F H G I E H D T T E L H S I D D T L K I S E G I G D K R Q R K F F H A I L R G A V A G V T R I G G Q H L E K A Q K H L L G A E I F E YA R R T L I E G L S H A F K A H R D F H S H D Q D K H S T G A L A Q V Q G A T G T R L R S R H G A L L K R E I A E T A T S L T Q E R V Y H S E F L P Y R H S V Q K K I K D E L E A A G H E L A K A Y D A T Q G K K V Q E P I L I E A I S C Q Q R I A I E V V Q G L S L P A K L S H KL H A D T A L R T A K K A I H V V K E Y G K K F D A R V K Q Q R I L A P V F Q G G A V Q H T G H E Q H L K A A S C S S G V L L A Q L G I R H D G Y A G Q L S G G P R A H V P F G R S TT A D L L L I E I H A D L I Q I K Q A L L G V V H S F Y S L Q R E F L Q V T S K G K L H V Q H I D Q S V V E R V G D K H V V F H Y P V K E TE E D L A S T T I H R L S T A E S Y S D I D F K E L L L D G Q E A A K A A A V E L P K K Y F G H I T F E Y L A TE E V V K E S Q E R T C I V G D A L K R A H H I P I F A P L G V T K G L P K D Y F H D L E R H A T G H K P T S E L G I S S K F D G V T K T K K R K H I F R Y S D H Q L T L D K A A Q K A E G V F V D K G A T H F S S L S F H V H L L P K K H T R E E E F P I H A Y Y Y Y H T D S R G H K A I I E S K Q Q K C H I F VG P G D D A F R F C G H R F R D V G A HY L I V H G Y G H Q V F G I GE L H H P S G L G I A H A T T H G H S LFL G A G L A Y I A T L V L S P I I I G HT T V F H S I L F G A F I V G Q S A P C A F S LI L F L F I I S G F T F F L Q G F T F G F A T F V G H F V Y G S H L A F A A S Y Y L L I F I FV A F S P G L Q G I A H A T V C G A H L I A L I L S I S F H I Y A T L L L V F I A IS F G A V A LV H AG S S F G I T Q A F H Y F S Y A L L L V V A I I P V S A I V G A Q H G T G I I I S F I F V V YG I A H F Q Q F A G F I V G F I A K A Y E K D L S F A S L A E A R E A H E K G I K I K A ISAH I E E T D L D H R V T E H K K E S V K F Y V G D K A A T V A H R L S A L L EI K H P A H G H Q K S L D C L A Q V E A D F G A I V V Q G S H S S T Q H H S E F E L H R G R T T I A E E G EE H F L R S K R K L K H S Q H S T QQ QG ID A IVK K G G S L L E A T S Q D R I A I R Q P K I L L A H A V L A V E R G A G P K F D T L Q L E V A K K R I E Y A H A F H H T K D E V H C Y G R G I E E S V V G Q T S F L V P T I H L R E I Y D R H F H V I Q P Y L R Q D I I T G E D H D S T V Q L T G S G C G K S V K H L G K L V Q G S Q V T A R H V K I A V F S Y P S H D P H G E K L G K I S D H E KAGLHF QIIILS F S D I K P H H D I I D V P P V H A E L G D T E V F V I I A A G R A H A F A D P K V L K F H K T E H L R R S L Q T G A Q H IAL V I T S H A I G L L A A S H A V L V V V S Q H T F A A L S K E Y I K T175A E528D T775M R652G S Cytoplasm R T G762E S320F Extracellular K Fig. 2 Secondary structure of multidrug resistance protein 3 with non-synonymous coding region genetic variants. Login to comment

[hide] Aspects of liver pathology in adult patients with ... Virchows Arch. 2012 Mar;460(3):291-8. Epub 2012 Feb 14. Wendum D, Barbu V, Rosmorduc O, Arrive L, Flejou JF, Poupon R
Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations.
Virchows Arch. 2012 Mar;460(3):291-8. Epub 2012 Feb 14., [PMID:22331132]

Abstract [show]
The aims of this study were to describe the histological liver lesions in adult patients with MDR3/ ABCB4 mutation and to study the usefulness of MDR3 immunostaining as a diagnostic tool. All adult patients from our institution with an MDR3/ABCB4 mutation and a liver histology were included (n = 13). Eleven patients had a single heterozygous gene mutation and two patients had two heterozygous mutations. Two patients had no liver lesions. Eight patients had a mild ductular reaction and portal fibrosis. One patient had a few fibrous septa and two patients had biliary cirrhosis. In three cases intraductal lipid crystals were identified. Two patients had biliary fibroobliterative lesions with no sclerosing cholangitis on cholangiography. Biliary dysplasia was identified in hepatectomy specimens from two patients, one of whom developed an intrahepatic cholangiocarcinoma. One patient with biliary cirrhosis developed a hepatocellular carcinoma. MDR3 immunostainings performed on formalin-fixed paraffin-embedded sections showed a strong canalicular staining in all patients except in one. To conclude, the predominant histological features were ductular reaction with no or mild fibrosis without cholangitis. Liver lesions previously unreported in association with MDR3/ABCB4 gene mutations (biliary dysplasia, cholangiocarcinoma, small duct sclerosing cholangitis) were also found. Lipid crystals in bile ducts may be suggestive of MDR3/ABCB4 mutation. MDR3 immunostaining on formalin-fixed paraffin-embedded sections does not seem to be sensitive for the diagnosis of heterozygous MDR3/ABCB4 mutations.

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107 Location and nucleotide change Effect on protein Status of variant Mutation category 1 c.1328dup p.Arg444Glu fsX4, truncating Heterozygous Insertion 2 c.1584 G > C p.Glu528Asp Heterozygous Missense 3 c.101 C > T p.Thr34Met Heterozygous Missense 4 c.1553delT p.Leu518Tyr fsX16, truncating Heterozygous Deletion 5 c.139 C > G p.Arg 47 Gly Heterozygous Missense 6 c.1217 G > A p.Arg 406 Gln Heterozygous Missense c.140 G > A p.Arg47Gln Heterozygous, compound Missense 7 c.857 C > T p.Ala 286 Val Heterozygous Missense 8 c.2324 C > T p.Thr775Met Heterozygous Missense c.2836 G > A p.Ala946Thr Heterozygous Missense 9 c.523A > G p.Thr175Ala Heterozygous Missense 10 c.1005 + 5 G > A p.? Login to comment
106 Location and nucleotide change Effect on protein Status of variant Mutation category 1 c.1328dup p.Arg444Glu fsX4, truncating Heterozygous Insertion 2 c.1584 G > C p.Glu528Asp Heterozygous Missense 3 c.101 C > T p.Thr34Met Heterozygous Missense 4 c.1553delT p.Leu518Tyr fsX16, truncating Heterozygous Deletion 5 c.139 C > G p.Arg 47 Gly Heterozygous Missense 6 c.1217 G > A p.Arg 406 Gln Heterozygous Missense c.140 G > A p.Arg47Gln Heterozygous, compound Missense 7 c.857 C > T p.Ala 286 Val Heterozygous Missense 8 c.2324 C > T p.Thr775Met Heterozygous Missense c.2836 G > A p.Ala946Thr Heterozygous Missense 9 c.523A > G p.Thr175Ala Heterozygous Missense 10 c.1005 + 5 G > A p.? Login to comment

[hide] ABCB4 sequence variations in young adults with cho... Liver Int. 2009 May;29(5):743-7. Epub 2008 Oct 24. Nakken KE, Labori KJ, Rodningen OK, Nakken S, Berge KE, Eiklid K, Raeder MG
ABCB4 sequence variations in young adults with cholesterol gallstone disease.
Liver Int. 2009 May;29(5):743-7. Epub 2008 Oct 24., [PMID:19018976]

Abstract [show]
BACKGROUND AND AIMS: Mutations in the gene encoding the ABCB4 [adenosine triphosphate (ATP)-binding cassette, sub-family B (MDR/TAP), member 4] transporter lower phosphatidylcholine output into bile and contribute to cholesterol gallstone formation by decreasing the solubility of cholesterol in bile. Mutations in ABCB4 have been identified in patients with low phospholipid-associated cholelithiasis. The aim of the present study was to determine the types and frequencies of ABCB4 mutations in cholecystectomized patients aged <40 years. PATIENTS AND METHODS: Hundred and four patients (mean age 30.6 years, range 12-39) were included in the study and the ABCB4 gene was sequenced. The frequency of missense mutations found in the patient material was measured in 95 healthy controls. The potential functional implications of the ABCB4 missense variations were assessed by computerized analysis (BLOSUM62 and Grantham substitution matrices, polymorphism phenotyping and sorting intolerant from tolerant). RESULTS: One patient was heterozygous for a frameshift mutation (c.1399_1400ins10/p.Y467F fsX25). Another patient was heterozygous for a nonsense mutation (c.3136C>T/p.R1046X). These two mutations are considered detrimental to ABCB4 protein function. In addition, six missense mutations were found in the ABCB4 gene, and three of these were only present in patients. CONCLUSION: In our study, <2% of young gallstone patients were found to be heterozygous for detrimental ABCB4 mutations. The functional implication of several missense mutations remains to be clarified. Thus, mutations in the ABCB4 gene are a rare cause of gallstone disease.

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62 These were c.337A4G/p.M113L, c.523A4G/p.T175A, c.1584G4 C/ p.E528D, c.1769G4 A/p.R590Q, c.1954A4G/p.R652G and c.3318G4 C/p.Q1106H). Login to comment
65 This mutation replaces residue 528 glutamate to an aspartate (p.E528D). Login to comment
68 This may indicate that p.E528D may increase the risk for gallstone disease. Login to comment
88 Table 1. Summary of patient characteristics having ABCB4 gene variations with possible effects on the ABCB4 protein and the occurrence of these variations in healthy controls Patient (ID) (n = 104) Gender/ethnicity Age Indication for surgery Gallstone Location Nucleotide change Peptide change Status Controls (n = 95) 1-16 Female Exon 16 c.1954A 4 G p.R652G 9 17-22 Female/Norwegian 21 Choledocholithiasis Multiple, 5 mm Exon 6 c.523A 4 G p.T175A heterozygous 3 Female/Iraq 25 Cholecystolithiasis Multiple, 5-10 mm Female/Norwegian 28 Cholecystolithiasis Two, 15 mm Female/African 31 Cholecystitis Multiple, 5 mm1solitary, 20 mm Female/Norwegian 32 Cholecystolithiasis Multiple, 5 mm Female/Norwegian 34 Cholecystolithiasis Multiple, 5-10 mm 23 Female/Norwegian 32 Cholecystolithiasis Two, 20 mm Exon 14 c.1584G 4 C p.E528D heterozygous 0 24-25 Female/Norwegian 23 Cholecystolithiasis Multiple, 5 mm Exon 15 c.1769G 4 A p.R590Q heterozygous 1 Female/Norwegian 37 Cholecystolithiasis Multiple, o 5 mm 26 Female/Norwegian 40 Cholecystitis Solitary, 30 mm Exon 25 c.3136C 4 T p.R1046X heterozygous - 27 Female/Pakistani 30 Cholecystolithiasis Three, 10 mm Exon 13 c.1399_1400 ins10 p.Y467F fsX25 heterozygous - 28 Ã Female/Pakistani 32 Cholecystolithiasis Multiple, o 5 mm Exon 5 c.337A 4 G p.M113L heterozygous 0 Exon 26 c.3318G 4 C p.Q1106H 0 The variation p.R652G, considered to be without functional significance for the ABCB4 product, is shown without patient characteristics (16 patients). Login to comment
94 Grantham values range from 5 to 215; low values ( o 50) indicate chemical similarity and high values ( 4 50) indicate more radical differences) Scoring Systems for Nonsynonymous Variants Amino acid change Grantham Blosum62 SIFT PolyPhen EC/EU p.M113L 15 2 0.17 1.211 EC p.T175A 58 0 0 0.845 EC p.E528D 45 2 0.25 0.617 EC p.R590Q 43 1 0 1.951 EC p.R652G 125 À 2 0.42 1.237 EU p.Q1106H 24 0 0.03 0.185 EC Blosum62 values range from À 4 to13, with negative values indicating less acceptable and positive values indicating more acceptable substitutions. Login to comment
105 We consider the nonsynonymous variation, c.1584G 4 C (p.E528D), a potentially pathogenic mutation. Login to comment
107 This suggests that p.E528D may increase the risk for gallstone disease. Login to comment
108 However, the prediction tools PolyPhen, Grantham and BLOSUM62 indicated that p.E528D would most probably not affect the function of the ABCB4 protein (Table 3). Login to comment

[hide] Hepatobiliary phospholipid transporter ABCB4, MDR3... Dig Liver Dis. 2008 May;40(5):366-70. Epub 2007 Dec 20. Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Montagnani M, Marchesoni D, Variola A, Rosa Rizzotto E, Braghin C, Mazzella G
Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy.
Dig Liver Dis. 2008 May;40(5):366-70. Epub 2007 Dec 20., [PMID:18083082]

Abstract [show]
BACKGROUND: Intrahepatic cholestasis of pregnancy is a multifactorial disorder of pregnancy associated with a genetic background. AIM: To evaluate the genetic contribution of ABCB4, MDR3 gene in the development of intrahepatic cholestasis of pregnancy in a large cohort of Italian subjects. METHODS: This study represents an extension of a previous multicentre-prospective study including three Italian referral centres. In all, we enrolled 96 women at the 3rd trimester of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes by standard procedures. Polymerase chain reaction was used to amplify exon 14, 15 and 16 of MDR3 gene. RESULTS: We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). MDR3 gene variants in exons 14, 15 and 16 occurred in 7/96 of pregnant mothers with intrahepatic cholestasis of pregnancy (7.2%), and in none of 96 pregnant controls matched for age and parity. All seven patients had normal gamma-glutamyl transpeptidase, normal bilirubin, but high levels of both alanine transferase and serum bile acids. One had cholesterol biliary lithiasis. The outcome of pregnancy was normal in four cases (with vaginal delivery), while there was one fetal distress. CONCLUSIONS: MDR3 mutations are responsible for the development of intrahepatic cholestasis of pregnancy in only a small percentage of Italian women. Further genetic studies are warranted, however, to clarify the role of different mutations in intrahepatic cholestasis of pregnancy.

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10 We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). Login to comment
80 There is a difference, however, in the phenotypic expression of this condition by comparison Table 4 Clinical details of ICP patients with MDRR3 mutations Patient #1 E528D Patient #2 R549H Patient #3 G536R Patient #4 R590Q Patient #5 R652G Patient #6 T667I Patient #7 R652G Onset of pruritus 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester Parity 0002 0001 0001 0001 0001 0001 0001 Previous ICP No Yes Yes No No No No Peak of AST (U/L) 163 88 129 62 789 119 60 Peak of ALT (U/L) 98 121 137 88 1186 125 78 Bilirubin (mg/dL) 0.60 0.61 0.89 1.2 0.57 0.3 0.78 Peak of GGT (U/L) 8 15 19 10 25 35 5 Cholesterol lithiasis No No Yes No No No No Total bile salts (␮M/L) 3.3 6.3 10.1 60 76.3 25.3 4.0 Delivery Vaginal Vaginal Caesarean Vaginal Caesarean Caesarean Vaginal ICP, intrahepatic cholestasis of pregnancy; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Login to comment
81 There is a difference, however, in the phenotypic expression of this condition by comparison Table 4 Clinical details of ICP patients with MDRR3 mutations Patient #1 E528D Patient #2 R549H Patient #3 G536R Patient #4 R590Q Patient #5 R652G Patient #6 T667I Patient #7 R652G Onset of pruritus 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester Parity 0002 0001 0001 0001 0001 0001 0001 Previous ICP No Yes Yes No No No No Peak of AST (U/L) 163 88 129 62 789 119 60 Peak of ALT (U/L) 98 121 137 88 1186 125 78 Bilirubin (mg/dL) 0.60 0.61 0.89 1.2 0.57 0.3 0.78 Peak of GGT (U/L) 8 15 19 10 25 35 5 Cholesterol lithiasis No No Yes No No No No Total bile salts (òe;M/L) 3.3 6.3 10.1 60 76.3 25.3 4.0 Delivery Vaginal Vaginal Caesarean Vaginal Caesarean Caesarean Vaginal ICP, intrahepatic cholestasis of pregnancy; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Login to comment

[hide] Low phospholipid associated cholelithiasis: associ... Orphanet J Rare Dis. 2007 Jun 11;2:29. Rosmorduc O, Poupon R
Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene.
Orphanet J Rare Dis. 2007 Jun 11;2:29., [PMID:17562004]

Abstract [show]
Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. This syndrome is infrequent and corresponds to a peculiar small subgroup of patients with symptomatic gallstone disease. The patients with the LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree. Defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity. Intrahepatic gallstones may be evidenced by ultrasonography (US), computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography, intrahepatic hyperechogenic foci along the biliary tree may be evidenced by US, and hepatic bile composition (phospholipids) may be determined by duodenoscopy. In all cases where the ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation.

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46 To date, two of the missense mutations (Glu528Asp and Thr175Ala) detected in patients with the LPAC syndrome had been analyzed previously in a homolog of ABCB4 (Pgp now called ABCB1) in yeast [13,14]. Login to comment
50 The Glu528Asp mutation was localized close to the NBD1. Login to comment

[hide] Function and pathophysiological importance of ABCB... Pflugers Arch. 2007 Feb;453(5):601-10. Epub 2006 Apr 19. Oude Elferink RP, Paulusma CC
Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein).
Pflugers Arch. 2007 Feb;453(5):601-10. Epub 2006 Apr 19., [PMID:16622704]

Abstract [show]
Like several other ATP-binding cassette (ABC) transporters, ABCB4 is a lipid translocator. It translocates phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane of the hepatocyte. Its function is quite crucial as evidenced by a severe liver disease, progressive familial intrahepatic cholestasis type 3, which develops in persons with ABCB4 deficiency. Translocation of PC makes the phospholipid available for extraction into the canalicular lumen by bile salts. The primary function of biliary phospholipid excretion is to protect the membranes of cells facing the biliary tree against these bile salts: the uptake of PC in bile salt micelles reduces the detergent activity of these micelles. In this review, we will discuss the functional aspects of ABCB4 and the regulation of its expression. Furthermore, we will describe the clinical and biochemical consequences of complete and partial deficiency of ABCB4 function.

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141 Canalicular lipid transport defects can cause gallstone formation Cholesterol supersaturation of bile, which occurs in a large proportion of humans, leads to the formation of cholesterol Walker B; L556R 571del Truncation PFIC3 LPAC ICP 27 splice Truncation 132 del Truncation TM 2; W138R TM 12; 981 del Truncation Linker; Q636X Truncation TM 11; R957X Truncation TM 6; S346I E395G Walker B; I541F TM 12; G983S Walker A; V425M Walker A; T424A Walker B; D564G TM 7; F711S 180 del truncation 336 delT truncation Exon 22-23 del truncation F165I T175A TM 5; M301T TM 5; S320F 336 insT truncation Walker A; 432 insA truncation E528D L591Q W658stop 757 insT R788E A934T P1161S TM 5; S320F TM 8; G762ER144X Walker B; A546D Walker B; G535AALL 96 del Truncation Walker B; L556R 571del Truncation PFIC3 LPAC ICP 27 splice Truncation 132 del Truncation TM 2; W138R TM 12; 981 del Truncation Linker; Q636X Truncation TM 11; R957X Truncation TM 6; S346I E395G Walker B; I541F TM 12; G983S Walker A; V425M Walker A; T424A Walker B; D564G TM 7; F711S 180 del truncation 336 delT truncation Exon 22-23 del truncation F165I T175A TM 5; M301T TM 5; S320F 336 insT truncation Walker A; 432 insA truncation E528D L591Q W658stop 757 insT R788E A934T P1161S TM 5; S320F TM 8; G762ER144X Walker B; A546D Walker B; G535AALL 96 del Truncation Fig. 3 Summary of the known mutations and their localization in the protein, as identified in patients with PFIC type 3, LPAC syndrome (intrahepatic gallstone formation), and intrahepatic cholestasis of pregnancy (ICP). Login to comment

[hide] Intrahepatic cholestasis of pregnancy: three novel... Aliment Pharmacol Ther. 2006 Jun 1;23(11):1649-53. Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Variola A, Tommasi AM, Marchesoni D, Braghin C, Mazzella G
Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations.
Aliment Pharmacol Ther. 2006 Jun 1;23(11):1649-53., [PMID:16696816]

Abstract [show]
BACKGROUND: The aetiology of intrahepatic cholestasis of pregnancy is unknown, but more than 10 different MDR3 gene mutations have recently been identified. AIM: To evaluate the genetic contribution of the MDR3 gene in the pathogenesis of intrahepatic cholestasis of pregnancy in Italian subjects. METHODS: We performed a multicentre prospective case-control study, enrolling 80 women with intrahepatic cholestasis of pregnancy at the third trimester of pregnancy and 80 pregnant women without intrahepatic cholestasis of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes using standard procedures. The polymerase chain reaction was used to amplify exon 14 of the MDR3 gene and the polymerase chain reaction products were sequenced using a Big Dye Terminator Cycle Sequencing kit. RESULTS: Three novel non-synonymous heterozygous mutations in exon 14 were found (4%; E528D, R549H, G536R) among the 80 intrahepatic cholestasis of pregnancy patients, whereas the pregnant controls were all negative for exon 14 polymorphisms. The three patients involved had normal GGT and bilirubin, but high levels of both ALT and serum bile acids. One had cholesterol bile stones. The outcome of pregnancy was normal for two (with vaginal delivery), while foetal distress was recorded in the third. CONCLUSIONS: These three novel mutations add further information on the involvement of the MDR3 gene in intrahepatic cholestasis of pregnancy. As in other studies, we found only heterozygous mutations that could cause an impaired transport protein function, not its absence (which is responsible for more severe liver disease). Different genetic backgrounds might justify the presence of novel MDR3 gene mutations.

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6 Results Three novel non-synonymous heterozygous mutations in exon 14 were found (4%; E528D, R549H, G536R) among the 80 intrahepatic cholestasis of pregnancy patients, whereas the pregnant controls were all negative for exon 14 polymorphisms. Login to comment
69 The E528D mutation is located in the central part of the NBD1, close to the linker region. Login to comment
72 Patient #1 E528D mutation Patient #3 G536R mutation Patient #2 R549H mutation Figure 1. Login to comment
75 Clinical details of ICP patients with heterozygous mutations Patient #1 E528D Patient #2 R549H Patient #3 G536R Onset of pruritus 3rd trimester 3rd trimester 3rd trimester Parity 0002 0001 0001 Previous ICP No Yes Yes Peak of AST (U/L) 163 88 129 Peak of ALT (U/L) 98 121 137 Bilirubin (mg/dL) 0.60 0.61 0.89 Peak of GGT (U/L) 8 15 19 Cholesterol lithiasis No Yes No Total bile salts (lM/L) 3.3 6.3 10.1 Delivery Vaginal Vaginal Caesarean ICP, intrahepatic cholestasis of pregnancy; AST, aspartate aminotransferase; ALT, alanine aminotransferase. A drawback of our study lies is not having sequenced the whole MDR3 gene, as our study design only involved sequencing exon 14; may also consequently underestimate the real prevalence of MDR3 mutations in ICP patients. Login to comment

[hide] ABCB4 gene mutation-associated cholelithiasis in a... Gastroenterology. 2003 Aug;125(2):452-9. Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R
ABCB4 gene mutation-associated cholelithiasis in adults.
Gastroenterology. 2003 Aug;125(2):452-9., [PMID:12891548]

Abstract [show]
BACKGROUND & AIMS: We recently put forward arguments in favor of ABCB4 gene (adenosine triphosphate-binding cassette, subfamily B, member 4) defects as a risk factor for symptomatic cholelithiasis in adults. In this study, we characterized ABCB4 gene mutations in a series of patients with symptomatic cholelithiasis to determine the genetic basis and the clinical phenotype of ABCB4 gene mutation-associated cholelithiasis. METHODS: We analyzed the entire ABCB4 gene coding sequences in a first group of 32 patients who had a clinical history compatible with the syndrome previously described, in a second group of 28 patients who presented with a classic gallstone disease that justified a cholecystectomy, and in a third group of 33 patients without a history of cholelithiasis. RESULTS: We identified both heterozygous and homozygous ABCB4 gene point mutations in 18 of 32 (56%) patients who presented with clinical criteria of the syndrome, whereas no mutation was detected in the 2 other groups of patients (P < 0.001). Three independent clinical features were strongly associated with point mutations: recurrence of symptoms after cholecystectomy (odds ratio, 8.5); intrahepatic hyperechoic foci, intrahepatic sludge, or microlithiasis (odds ratio, 6.1); and age <40 years at the onset of symptoms (odds ratio, 3.0). ABCB4 gene point mutations were detected exclusively in the patients who showed 2 or 3 of these clinical features. CONCLUSIONS: Our results show that ABCB4 gene mutations represent a major genetic risk factor in a symptomatic and recurring form of cholelithiasis in young adults.

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68 ABCB4 Gene Mutations in Patients With LPAC Syndrome Gene position Location and nucleotide change Peptide change Protein domain Status 6 495T3A Phe165Ile First intracellular loop Heterozygous 523T3C Thr175Ala between TM2 and TM3 Heterozygous 9 902T3C Met301Thr TM5 Heterozygous 959C3T Ser320Phe TM5 Homozygous 10 1007-1015insT 355Stop TM6 Heterozygous 1007-1015delT 341Stop TM6 Heterozygous 12 1327insA 447Stop Close to NBD11 Heterozygous 14 1584G3C Glu528Asp Close to NBD11 Heterozygous 15 1772T3A Leu591Gln Third intracellular loop Homozygous 17 1973G3A Try658Stop Third intracellular loop linker domain Heterozygous 18 2270-2273insT 793Stop Fourth intracellular loop between TM8 and TM9 Heterozygous 19 2363G3T Arg788Glu Fourth intracellular loop between TM8 and TM9 Heterozygous 23 2800G3T Ala934Thr Fifth intracellular loop between TM10 and TM11 Homozygous 26 3481C3T Pro1161Ser Close to NBD2 Heterozygous NOTE. The A of ATG of the initiator Met codon was denoted as "nucleotide ϩ 1." Login to comment
96 Two of the missense mutations (Thr175Ala and Glu528Asp) detected in the patients with the LPAC syndrome were analyzed previously in yeast.23,24 The Thr175Ala mutation was localized in the first intracellular loop and resulted in a substitution in a conserved cluster of 4 amino acids at position 169-172, which is required for the adenosine triphosphatase activity of the molecule. Login to comment
99 The Glu528Asp mutation was localized close to the NBD1. Login to comment