ABCB4 p.Phe165Ile
| Predicted by SNAP2: | A: D (91%), C: D (85%), D: D (95%), E: D (95%), G: D (95%), H: D (75%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (91%), W: D (91%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: 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: N, |
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[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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No. Sentence Comment
49 The Phe165Ile mutation was localized in the same part of this intracellular loop and may therefore give rise to a similar defect.
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ABCB4 p.Phe165Ile 17562004:49:4
status: NEW[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).
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ABCB4 p.Phe165Ile 16622704:141:535
status: NEWX
ABCB4 p.Phe165Ile 16622704:141:1100
status: NEW[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."
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ABCB4 p.Phe165Ile 12891548:68:143
status: NEW98 The Phe165Ile mutation was localized in the same part of this intracellular loop and might thereby give rise to a similar defect.
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ABCB4 p.Phe165Ile 12891548:98:4
status: NEW[hide] Functional Characterization of ABCB4 Mutations Fou... Korean J Physiol Pharmacol. 2013 Dec;17(6):525-30. doi: 10.4196/kjpp.2013.17.6.525. Epub 2013 Dec 16. Kim TH, Park HJ, Choi JH
Functional Characterization of ABCB4 Mutations Found in Low Phospholipid-Associated Cholelithiasis (LPAC).
Korean J Physiol Pharmacol. 2013 Dec;17(6):525-30. doi: 10.4196/kjpp.2013.17.6.525. Epub 2013 Dec 16., [PMID:24381502]
Abstract [show]
Multidrug resistance 3 (MDR3) is expressed on the canalicular membrane of the hepatocytes and plays an important role in protecting the liver from bile acids. Altered ABCB4 gene expression can lead to a rare hepatic disease, low phospholipid-associated cholelithiasis (LPAC). In this study, we characterized 3 ABCB4 mutations in LPAC patients using various in vitro assay systems. We first measured the ability of each mutant to transport paclitaxel and then the mechanisms by which these mutations might change MDR3 transport activity were determined using immunoblotting, cell surface protein biotinylation, and immunofluorescence. Through a membrane vesicular transport assay, we observed that the uptake of paclitaxel was significantly reduced in membrane vesicles expressing 2 ABCB4 mutations, F165I and S320F. Both mutants showed significantly decreased total and cell surface MDR3 expression. These data suggest two missense mutations of ABCB4 may alter function of MDR3 and ultimately can be determined as LPAC-causing mutations.
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No. Sentence Comment
8 Through a membrane vesicular transport assay, we observed that the uptake of paclitaxel was significantly reduced in membrane vesicles expressing 2 ABCB4 mutations, F165I and S320F.
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ABCB4 p.Phe165Ile 24381502:8:165
status: NEW26 In this study, we selected 3 novel missense mutations of ABCB4 that were first reported by Rosmorduc et al. [3] and F165I 5`-AGG AAA TAG GAT GGA TTG ACA TCA ATG ACA-3` M301T 5`-GCA AAC ATT TCC ACG GGT ATT GCC TTS CTG-3` S320F 5`-AGG ACA CAA ATC AGA CAG CAT CAA AGG GAA-3` The SNP sites were marked by bold-faced letters with underlines.
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ABCB4 p.Phe165Ile 24381502:26:118
status: NEW56 RESULTS Mutations of ABCB4 examined in this study To perform a molecular characterization of ABCB4 muta- cDNA position Amino acid substitution Predicted domain a c.495T&#ff1e;A F165I ICD1 c.902T&#ff1e;C M301T TM5 c.959C&#ff1e;T S320F TM5 Position of each mutant was based upon the translational start site.
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ABCB4 p.Phe165Ile 24381502:56:180
status: NEW80 The ABCB4 mutant, F165I might be located in the ICD1, while other two mutants, M301T and S320F are located in the TM5 [3].
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ABCB4 p.Phe165Ile 24381502:80:18
status: NEW84 To exclude ATPase activity by other endogenous ABC transporters including MDR1, values for transport activity were obtained by subtracting the uptake in empty vector-transfected cells from that in cells transfected with ABCB4 reference or mutant-bearing vectors, at each corresponding paclitaxel concentration. The uptake of paclitaxel Vmax (nmol mg &#ff0d;1 per min) Km (mM) Vmax/Km ratio (nmol mg&#ff0d;1 min &#ff0d;1 per mM) Reference 28.98&#b1;1.565 1.114&#b1;0.1391 27.13&#b1;5.232 F165I 16.82&#b1;1.565* 1.028&#b1;0.1189 15.56&#b1;4.658* M301T 23.23&#b1;0.8641 1.206&#b1;0.2875 20.60&#b1;5.628 S320F 18.55&#b1;2.726* 1.185&#b1;0.1064 15.99&#b1;3.736* Data (mean&#b1;SD) are from 5 separate experiments.
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ABCB4 p.Phe165Ile 24381502:84:489
status: NEW92 was significantly reduced in membrane vesicles expressing 2 ABCB4 mutations, F165I and S320F.
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ABCB4 p.Phe165Ile 24381502:92:77
status: NEW95 We observed that the average values of Vmax/Km for F165I and S320F were significantly reduced compared to that of the ABCB4 reference.
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ABCB4 p.Phe165Ile 24381502:95:51
status: NEW100 The 2 mutations, F165I and S320F that showed decreased transport activities as compared to the reference, had significantly decreased MDR3 expression as compared to reference.
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ABCB4 p.Phe165Ile 24381502:100:17
status: NEW102 Then, we investigated MDR3 expression levels of these mutants on the plasma membrane by cell surface biotinylation and observed that those of F165I and S320F were significantly decreased by 31%, compared to that of the reference (Fig. 2B).
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ABCB4 p.Phe165Ile 24381502:102:142
status: NEW103 The results from immunoblotting or cell surface biotinylation experiments could explain the reason of altered transport activities of ABCB4 mutants, F165I and S320F; the decreased transport activities of these mutants were due to the reduced expression of functional MDR3 on the plasma membrane.
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ABCB4 p.Phe165Ile 24381502:103:149
status: NEW106 The subcellular expression of M301T was comparable with that of the reference while the co-localization of F165I and S320F with plasma membrane was decreased.
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ABCB4 p.Phe165Ile 24381502:106:107
status: NEW115 Through a membrane vesicular transport assay using paclitaxel, we found that 2 mutants, F165I and S320F, showed significantly decreased transport activity compared to the reference (Fig. 1).
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ABCB4 p.Phe165Ile 24381502:115:88
status: NEW116 F165I and S320F are located in the ICD1 and TM5 of MDR3, respectively, that might be involved in coupling the energy from ATP hydrolysis to substrate transport and the conformational change involved in substrate extrusion, respectively [3,15].
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ABCB4 p.Phe165Ile 24381502:116:0
status: NEW120 The reduced transport function of F165I and S320F mutants also might be due to the decreased expression of functional MDR3 on the plasma membrane (Fig. 2).
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ABCB4 p.Phe165Ile 24381502:120:34
status: NEW125 2 mutants, F165I and S320F, examined in this study also showed decreased transport activity and protein expression, although the extent of reduction was less than that of I541F.
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ABCB4 p.Phe165Ile 24381502:125:11
status: NEW