ABCMdb

ABCB4 p.Ala546Asp

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Publications

PMID: 10767346 [PubMed] Dixon PH et al: "Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking."

No. Sentence Comment

44 In addition to the normal cytosine at this position, an adenine was also detected; this results in the substitution of the wild-type alanine with a mutant aspartic acid (A546D). Login to comment
69 We therefore introduced the equivalent A546D mutation into the first NBD of P-gp1 and studied the functional consequences of the change in transiently transfected mammalian cells. Login to comment
94 Evidence that A544D-P-gp1 is a trafficking mutant The finding that substitution of an aspartic acid for an alanine in a highly conserved region of NBD1 did not alter the ability of the mature protein to transport R123 was unexpected and suggested that the equivalent A546D-MDR3 protein mutant would also be functional. Login to comment
127 When considered together, these results demonstrate that not all of the mature protein is at the cell surface. These results show that the MDR3 mutation A546D causes abnormal protein glycosylation and trafficking when its equivalent is expressed in P-gp1. Login to comment
128 DISCUSSION Our analysis of the sequence of the coding region of the MDR3 gene in eight patients with ICP and raised γ-GT has revealed the presence of a mutation in exon 14 (A546D) in one individual. Login to comment
135 The occurrence of the A546D mutation, the substitution of a hydrophobic amino acid with a charged polar amino acid, in the highly conserved first NBD, suggested that this mutation would also result in loss-of-function of the MDR3 protein. Login to comment
136 In order to gain insight into the functional consequences of this mutation, we tested the effects of the equivalent mutation to A546D in P-gp1 (A544D). Login to comment
147 The A546D mutation in the MDR3 protein is likely to have a similar phenotype as there is considerable sequence identity between the proteins in this domain (87%), and because the NBDs of P-gp1 and the MDR3 protein have been shown to be functionally interchangeable (27). Login to comment
199 Study of the MDR3 protein A546D mutation in P-gp1 Plasmid pMDR-wt encodes wild-type P-gp1 with a hexa-histidine tag at the C-terminus and has been described previously (28). Login to comment
203 Site-directed mutagenesis Alignment of the amino acid sequence of human P-gp1 with the MDR3 protein identified A544 as the P-gp1 equivalent of MDR3 protein A546. Site-directed mutagenesis was used to alter codon 544 of MDR1 to encode an aspartic acid, adopting the C→A tranversion of the second position of the codon analogous to the A546D mutant of the MDR3 protein. Login to comment

PMID: 19185004 [PubMed] Delaunay JL et al: "A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature."

No. Sentence Comment

229 Dixon et al.26 have shown that the A546D mutation described in a patient with intrahepatic cholestasis of pregnancy affected the traffic of an ABCB1 mutant to the plasma membrane, but not its activity. Login to comment
230 In the work of Dixon et al.,26 ABCB1 was used as a model to reproduce the A546D ABCB4 mutation. 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

35 MDR3 mutations reported in the literature Mutation (codon) Exon Reference (R144X) 6 Gendrot et al.5 481G>A (R150K) 6 Mu¨llenbach et al.6 426-432del (132) 6 DeVree et al.13 959C>T (S320F) 9 Rosmordurc et al.,14 Pauli-Magnus et al.9 (G535D) 14 Lucena et al.7 1669 C>A (A546D) 14 Dixon et al.4 1712 del T (571) 14 Jacquemin et al.8, 15 2285 G>A (G762E) 18 Pauli-Magnus et al.9 2901 C>T (R957X) 23 DeVree et al.13 conditions included an initial denaturation step at 94 °C for 5 min, followed by 40 cycles of denaturation at 94 °C for 30 s, annealing at 55 °C for 30 s and extension at 72 °C for 30 s. Login to comment

PMID: 20799350 [PubMed] Kelly L et al: "Functional hot spots in human ATP-binding cassette transporter nucleotide binding domains."

No. Sentence Comment

50 Disease-associated nsSNPs at Three Structural Hotspots in Human ABC Transporter NBDs Gene Disease Position ARA motif ABCB11 BRIC2 A570T ABCD1 X-ALD A616V CFTR CF A559T ABCC6 PXE R765Q ABCC8 HHF1 R841G ABCC8 HHF1 R1493Q ABCC8 HHF1 R1493W ABCD1 X-ALD R617C ABCD1 X-ALD R617G ABCD1 X-ALD R617H CFTR CF R560K CFTR CF R560S CFTR CF R560T ABCA1 HDLD1 A1046D ABCB4 ICP A546D C-loop 1 motif ABCC8 HHF1 D1471H ABCC8 HHF1 D1471N CFTR CBAVD G544V ABCC8 HHF1 G1478R C-loop2 motif ABCA4 STGD1 H2128R ABCC8 HHF1 K889T ABCD1 X-ALD R660P ABCD1 X-ALD R660W ABCA1 HDLD2 M1091T ABCA4 STGD1 E2131K ABCA12 LI2 E1539K ABCA4 STGD1 and CORD3 E1122K CFTR CF L610S ABCC8 HHF1 L1543P ABCA1 Colorectal cancer sample; somatic mutation A2109T ABCC9 CMD1O A1513T ABCD1 X-ALD H667D CFTR CF A613T ABCA1 HDLD2 D1099Y ABCD1 X-ALD T668I CFTR CF D614G ABCA4 STGD1 R2139W ABCA4 STGD1 R1129C ABCA4 ARMD2, STGD1, and FFM R1129L Disease abbreviations are as follows: BRIC2, benign recurrent intrahepatic cholestasis type 2; X-ALD, X-linked adrenoleukodystrophy; CF, cystic fibrosis; PXE, Pseudoxanthoma elasticum; HHF1, familial hyperinsulinemic hypoglycemia-1; HDLD1, high density lipoprotein deficiency type 1; ICP, intrahepatic cholestasis of pregnancy; CBAVD, congenital bilateral absence of the vas deferens; STGD1, Stargardt disease type 1; HDLD2, high density lipoprotein deficiency type 2; LI2, ichthyosis lamellar type 2; CORD3, cone-rod dystrophy type 3; CMD1O, cardiomyopathy dilated type 1O; ARMD2, age-related macular degeneration type 2; FFM, fundus flavimaculatus. Login to comment

PMID: 11745043 [PubMed] Jacquemin E et al: "Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases."

No. Sentence Comment

113 Reference 37 Patient 1 No A546D Defect of trafficking 50 First WalkerB motif PFIC3, progressive familial intrahepatic cholestasis type 3; MDR3, multidrug resistance 3; ICP, intrahepatic cholestasis of pregnancy; GGT, gamma-glutamyltransferase (N, normal value is from reference 45); AA, amino acid; TMD, transmembrane domain; *, personal data (E. Jacquemin). Login to comment

PMID: 24953525 [PubMed] Falguieres T et al: "ABCB4: Insights from pathobiology into therapy."

No. Sentence Comment

104 The A546D mutation was shown to affect ABCB4 traffic [58]. Login to comment