ABCB4 p.Arg957*
| ClinVar: |
c.2869C>T
,
p.Arg957*
D
, Pathogenic
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[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.Arg957* 16622704:141:346
status: NEWX
ABCB4 p.Arg957* 16622704:141:911
status: NEW[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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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.
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ABCB4 p.Arg957* 16696816:35:389
status: NEW[hide] A second heterozygous MDR3 nonsense mutation assoc... J Med Genet. 2003 Mar;40(3):e32. Gendrot C, Bacq Y, Brechot MC, Lansac J, Andres C
A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.
J Med Genet. 2003 Mar;40(3):e32., [PMID:12624161]
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128 However, clinical and epidemiological studies suggest mainly hormonal and genetic factors.1-3 7 Genetic factors have been suggested by the existence of familial cases and by the high incidence of ICP in some ethnic groups, such as the Araucanos Indians of Chile.8 The multidrug resistance 3 (MDR3, ABCB4, 171060) gene, localised on 7q21.1, was first reported to be involved in ICP by de Vree et al.9 In a large consanguineous family, subjects affected by a subtype of progressive familial intrahepatic cholestasis called PFIC3 were homozygous for a nonsense mutation in exon 23 (R957X) and women affected by ICP were heterozygous; in another family, the same authors reported a homozygous deletion of exon 6 (426-432del) in a PFIC3 patient with consanguineous, healthy parents.9 A mutation in exon 14 of MDR3 (1744delT) was identified in another large pedigree in which all PFIC patients were homozygous for the mutation and women with ICP were heterozygous.10 11 Dixon et al12 investigated eight women affected by ICP with increased serum GGT activity and no familial history of PFIC.12 A missense mutation of exon 14 (A546D) was found in one patient.
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ABCB4 p.Arg957* 12624161:128:579
status: NEW[hide] The wide spectrum of multidrug resistance 3 defici... Gastroenterology. 2001 May;120(6):1448-58. Jacquemin E, De Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, Scheffer GL, Paul M, Burdelski M, Bosma PJ, Bernard O, Hadchouel M, Elferink RP
The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood.
Gastroenterology. 2001 May;120(6):1448-58., [PMID:11313315]
Abstract [show]
BACKGROUND & AIMS: We have specified the features of progressive familial intrahepatic cholestasis type 3 and investigated in 31 patients whether a defect of the multidrug resistance 3 gene (MDR3) underlies this phenotype. METHODS: MDR3 sequencing, liver MDR3 immunohistochemistry, and biliary phospholipid dosage were performed. RESULTS: Liver histology showed a pattern of biliary cirrhosis with patency of the biliary tree. Age at presentation ranged from the neonatal period to early adulthood. Sequence analysis revealed 16 different mutations in 17 patients. Mutations were identified on both alleles in 12 patients and only on 1 allele in 5. Four mutations lead to a frame shift, 2 are nonsense, and 10 are missense. An additional missense mutation probably representing a polymorphism was found in 5 patients. MDR3 mutations were associated with abnormal MDR3 canalicular staining and a low proportion of biliary phospholipids. Gallstones or episodes of cholestasis of pregnancy were found in patients or parents. Children with missense mutations had a less severe disease and more often a beneficial effect of ursodeoxycholic acid therapy. CONCLUSIONS: At least one third of the patients with a progressive familial intrahepatic cholestasis type 3 phenotype have a proven defect of MDR3. This gene defect should also be considered in adult liver diseases.
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126 MDR3 Mutations, Immunohistochemistry, and Biliary Phospholipids in Patients With High GGT PFIC (PFIC3) Patients Exon Nucleotide mutation Amino acid change Protein consequence Family MDR3 liver Phospholipids (%) bile Homozygous Deletion/Insertion M Y M I (sister of M Y) 2 111 A Ͼ G, splice donor site, exon/intron boundary 2/3 27 Frame shift in NH2 terminus, then truncation ND Absent ND 1.6 B Ka 6 426-432 del 132 Frame shift in TMD 2, 29 novel amino acids then truncation Mother ϩ/- Father ϩ/- 1 sibling ϩ/ϩ Absent ND B Sa 14 1744 del T 571 Frame shift, 15 novel amino acids then truncation Mother ϩ/- (ICP) Father ϩ/- 3 siblings ϩ/ϩ Absent ND P G 24 2975-2984 del Compound heterozygous 981 Frame shift in TMD 12, 3 novel amino acids then truncation Mother ϩ/ϩ Father ϩ/- ND 14.9 Bo S Bo N (sister of Bo S) 16 Nonsense 1938 C Ͼ T Q636X Linker region Truncation Mother ϩ/- Father ϩ/- 2 siblings ϩ/- Absent 2 ND B Aa 23 2901 C Ͼ T R957X TMD 11 Truncation Mother ϩ/- (ICP) Father ϩ/- 4 siblings ϩ/- or ϩ/ϩ Absent ND S F 10 Missense 1069 G Ͼ T S346I Serine to isoleucine in TMD6 Mother ϩ/- Father ϩ/- Faint 1 B H 11 1216 A Ͼ G E395G Glutamate to glycine between TMD 6 and first Walker A motif ND ND ND N I 14 1653 A Ͼ T I541F Isoleucine to phenylalanine in first Walker B motif Mother ϩ/- Father ϩ/- Absent ND M M 14 1699 T Ͼ G L556R Leucine to arginine in first Walker B motif ND ND ND P G 24 2979 G Ͼ A Compound heterozygous G983S Glycine to serine in TMD 12 Mother ϩ/- Father ϩ/ϩ ND 14.9 P A 6 Heterozygous Missense 444 T Ͼ C W138R Trytophan to arginine in TMD 2 Mother ϩ/- Father ϩ/ϩ ND 6.7 M Aa 12 1302 A Ͼ G T424A Threonine to alanine in first Walker A motif ND gallbladder lithiasis in father Faint 6.3 P K 12 1307 G Ͼ A V425M Valine to methionine in first Walker A motif ND Normal ND G A 14 1723 A Ͼ G D564G Aspartate to glycine in first Walker B motif ND ND ND G M 17 2132 T Ͼ C F711S Phenylalanine to serine in TMD 7 ND ND ND L M 16 Polymorphism 1986 A Ͼ G Homozygous R652G Arginine to glycine in linker region Mother ϩ/- (suspicion of ICP) Father ϩ/- ND ND Ga M " Heterozygous " " Mother ϩ/- Father ϩ/ϩ 1 sibling ϩ/- ND 9.7 L H L F (sister of L H) " Heterozygous " " ND ND ND VH C " Heterozygous " " Mother ϩ/ϩ Father ϩ/- ND ND NOTE.
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ABCB4 p.Arg957* 11313315:126:1033
status: NEW[hide] Molecular aspects of organic compound transport ac... J Gastroenterol Hepatol. 1999 May;14(5):405-12. Kamisako T, Gabazza EC, Ishihara T, Adachi Y
Molecular aspects of organic compound transport across the plasma membrane of hepatocytes.
J Gastroenterol Hepatol. 1999 May;14(5):405-12., [PMID:10355502]
Abstract [show]
Many organic compounds are taken up from the blood by membrane transporters, taken across the sinosuidal membrane of hepatocytes and then excreted into bile via the bile canalicular membrane. The hepatic uptake of conjugated bile acids is mediated by the sodium taurocholate cotransporting polypeptide. Many organic anions and bulky organic cations are incorporated into hepatocytes by the organic anion transporting polypeptide, while small organic cations are transported by the organic cation transporter. At the canalicular membrane, organic compounds are excreted into bile by ATP-binding cassette transporters which hydrolyse ATP to ADP. Excretion of monovalent bile acids is mediated by the canalicular bile salt transporter and that of organic anions, including divalent bile acid, conjugates, are mediated by the multi-drug resistance-associated protein 2, also termed canalicular multi-specific organic anion transporter. Organic cations are excreted into bile by the multi-drug resistance gene product (MDR) 1 and phospholipids are excreted by MDR3 (mdr2 in mice and rats). The clinical syndromes associated with alterations of these transporters are also discussed.
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88 Recently, a MDR3 gene abnormality has been reported in PFIC3 (7 b.p. deletion starting at codon 132 (frameshift mutation and subsequent introduction of a stop codon) and R957X).73 It has been recently reported that simvastatin induced marked overexpression of mdr274 and, recently, we reported that this drug improves cholestasis in patients with primary biliary cirrhosis.75 These findings suggest that simvastatin may constitute a potential therapeutic agent for certain types of cholestasis with plasma phospholipid retention.
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ABCB4 p.Arg957* 10355502:88:170
status: NEW[hide] Role of multidrug resistance 3 deficiency in pedia... Semin Liver Dis. 2001 Nov;21(4):551-62. Jacquemin E
Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases.
Semin Liver Dis. 2001 Nov;21(4):551-62., [PMID:11745043]
Abstract [show]
Class III multidrug resistance P-glycoproteins, mdr2 in mice and MDR3 in humans, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an MDR3 gene defect in liver disease was initially suspected in a subtype of progressive familial intrahepatic cholestasis called PFIC3. Several MDR3 mutations have been identified in children with PFIC3 and are associated with a low level of phospholipids in bile, leading to a high biliary cholesterol saturation index. Mutations leading to a truncated protein are associated with an absence of canalicular MDR3 protein. The phenotypic spectrum of PFIC3 ranges from neonatal cholestasis to cirrhosis in young adults. There is now strong evidence that in addition to PFIC3, an MDR3 defect can be involved in intrahepatic cholestasis of pregnancy and in cholesterol gallstone disease. Therefore, at least three human liver diseases are due to a single gene deficiency. Patients with PFIC3 due to MDR3 deficiency may benefit from ursodeoxycholic acid therapy and could be good candidates for cell therapy in the future.
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109 This is likely because the cholesterol saturation index is abnormally increased in the bile of PFIC3 patients (personal communication, M. Dumont, E. Jacquemin, Hôpital Beaujon, Hôpital Bicêtre, Paris, MDR3 DEFICIENCY/JACQUEMIN 557 Table 2 Intrahepatic Cholestasis of Pregnancy and Heterozygous MDR3 Deficiency Family Mutation Protein GGT History (AA) Consequence (N < 17 U/L) References 23-25 Patient 1 PFIC3 R957X Truncation ?
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ABCB4 p.Arg957* 11745043:109:424
status: NEW