ABCMdb

ABCB4 p.Glu528Asp

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PMID: 15077010 [PubMed] Pauli-Magnus C et al: "Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy."

No. Sentence Comment

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

PMID: 22331132 [PubMed] Wendum D et al: "Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations."

No. Sentence Comment

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

PMID: 19018976 [PubMed] Nakken KE et al: "ABCB4 sequence variations in young adults with cholesterol gallstone disease."

No. Sentence Comment

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

PMID: 18083082 [PubMed] Floreani A et al: "Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy."

No. Sentence Comment

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

PMID: 17562004 [PubMed] Rosmorduc O et al: "Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene."

No. Sentence Comment

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

PMID: 16622704 [PubMed] Oude Elferink RP et al: "Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein)."

No. Sentence Comment

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

PMID: 16696816 [PubMed] Floreani A et al: "Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations."

No. Sentence Comment

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

PMID: 12891548 [PubMed] Rosmorduc O et al: "ABCB4 gene mutation-associated cholelithiasis in adults."

No. Sentence Comment

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