ABCMdb

ABCB4 p.Arg957*

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Publications

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: 12624161 [PubMed] Gendrot C et al: "A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy."

No. Sentence Comment

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. Login to comment

PMID: 11313315 [PubMed] Jacquemin E et al: "The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood."

No. Sentence Comment

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. Login to comment

PMID: 10355502 [PubMed] Kamisako T et al: "Molecular aspects of organic compound transport across the plasma membrane of hepatocytes."

No. Sentence Comment

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. 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

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 ? Login to comment