ABCMdb

ABCB4 p.Thr775Met

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Publications

PMID: 17726488 [PubMed] Degiorgio D et al: "Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3)."

No. Sentence Comment

18 The two TMDs contain specific sites for substrate binding and translocation, whereas the two NBDs, which display a high degree of sequence similarity with the equivalent domain of ABC transporters, couple the energy obtained from ATP hydrolysis to substrate transport.8 The ICDs are deemed to be involved in mediating the coupling between NBD conformational changes and the reorientation of TM helices concomitant with substrate extrusion.9 The ABCB1 gene, one of the most extensively studied ABC transporters, is responsible for the human multidrug resistance phenotype that is a rapidly growing obstacle to the treatment of numerous infectious diseases, including human immunodeficiency10 and malaria.11 The properties of this transporter are also exploited in cancer pharmacological therapy where ABCB1 translocates the chemotherapeutic drugs and other molecules with a broad but defined specificity.12 A gene duplication of ABCB1 and additional mutations selected as advantageous have created in mammals the T715I G723E L724AfsX744 A737V G954S G762X T775M G126E S320F A840D OUT IN Linker region F357L L701P A364V NBD-NH2 terminal NBD-COOH terminal A1193T NH2 COOH 1 2 54 6 7 8 129 11 10 EC2EC1 ICD2 A250P Y279X A286V ICD1 R159X T175A ICD3 EC3 EC4 EC6EC5 ICD4 ICD6 ICD5 E888X Y403H V475A A511T E558K R590Q T593A M630V 3 S379KfsX413 P726T Figure 1 (a) Localization of the 29 mutations identified in this study in the ABCB4 protein, schematically represented in its domains. Login to comment
84 There are no PFIC3 epidemiologic data available to date; however, knowing that the number of newborns in Italy has been on average 500 000/year in the last 14 years (http://demo.istat.it/), since we observed 18 patients with ABCB4-mutated alleles born within a 14-year period (with Table 2 Mutations identified in ABCB4 Type of mutationb Exons cDNA locusa Missense Frameshift or nonsense ABCB4-predicted domain GenBank accession numberc Exon 6 c.377G4A G126E TM2 DQ861346 Exon 6 c.523A4G T175A ICD1 Exon 6 c.475C4T R159X ICD1 DQ861347 Exon 8 c.748G4C A250P ICD2 DQ861349 Exon 9 c.837T4A Y279X ICD2 DQ861348 Exon 9 c.857C4T A286V ICD2 DQ861350 Exon 9 c.959C4T S320F TM5 Exon 10 c.1069T4C F357L ICD3 DQ861351 Exon 10 c.1091C4T A364V ICD3 DQ861352 Exon 11 c.1135_1136insAA S379KfsX413 ICD3 DQ861353 Exon 11 c.1207T4C Y403H NBD-NH2 A-loop EF035007 Exon 13 c.1424T4C V475A NBD-NH2 ter DQ861354 Exon 13 c.1531G4A A511T NBD-NH2 ter DQ861355 Exon 14 c.1672G4A E558K NBD-NH2 ter DQ861356 Exon 15 c.1769G4A R590Q NBD-NH2 ter Exon 15 c.1777A4G T593A NBD-NH2 ter DQ861357 Exon 15 c.1888A4G M630V NBD-NH2 ter DQ861358 Exon 17 c.2102T4C L701P Linker region DQ861359 Exon 17 c.2144C4T T715I TM7 DQ861360 Exon 17 c.2168G4A G723E TM7 DQ861361 Exon 17 c.2169_2170insG L724AfsX744 TM7 DQ861362 Exon 17 c.2176C4A P726T TM7 DQ861363 Exon 17 c.2210C4T A737V EC4 DQ861364 Exon 18 c.2284G4T G762X TM8 DQ861365 Exon 19 c.2324C4T T775M TM8 Exon 21 c.2519C4A A840D TM9 DQ861366 Exon 21 c.2662G4T E888X ICD5 DQ861367 Exon 23 c.2860G4A G954S TM11 DQ861368 Exon 27 c.3577G4A A1193T NBD-COOH ter DQ861369 a cDNA sequence is based on reference sequence GenBank NM_018849. Login to comment

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

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
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: 21119540 [PubMed] Colombo C et al: "Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations."

No. Sentence Comment

107 Nucleotidechange (effectonprotein) Predictionscoresby PolyPhenanalysis Nucleotidechange (effectonprotein) Predictionscoresby PolyPhenanalysis Referencefor eachgenotype 1[1-I]c.475C>T(p.R159X)XUnknownUnknown20 1[1-II]c.475C>T(p.R159X)XUnknownUnknownThisstudy 2[2-I]c.523A>G(p.T175A)0.774c.1069T>C(p.F357L)þc.2324C>T(p.T775M)1.079þ0.59720 3[3-I]c.1135_1136insAA(p.S379KfsX413)Xc.2102T>C(p.L701P)2.22620 4[4-I]c.2662G>T(p.E888X)Xc.748G>C(p.A250P)Rc.1888A>G(p.M630V)1.871R1.67720 5[5-I]c.959C>T(p.S320F)1.287c.857C>T(p.A286V)1.40820 6[6-I]c.377G>A(p.G126E)1.998c.1531G>A(p.A511T)2.1720 6[6-II]c.377G>A(p.G126E)1.998c.1531G>A(p.A511T)2.1720 7[7-I]c.2176C>A(p.P726T)2.086c.1769G>A(p.R590Q)þc.2284G>T(p.G762X)2.623RX20 8[8-1]c.1091C>T(p.A364V)1.343c.2210C>T(p.A737V)0.21720 9[9-I]c.1777A>G(p.T593A)2.044UnknownUnknown20 10[10-I]c.2144C>T(p.T715I)0.383UnknownUnknown20 11[11-I]c.2519C>A(p.A840D)1.803c.1424T>C(p.V475A)2.60320 12[12-I]c.1672G>A(p.E558K)2.486c.2168G>A(p.G723E)Rc.3577G>A(p.A1193T)1.548þ2.34120 12[12-II]c.1672G>A(p.E558K)2.486c.2168G>A(p.G723E)Rc.3577G>A(p.A1193T)1.548þ2.34120 13[13-I]c.2860G>A(p.G954S)0.245c.2860G>A(p.G954S)0.24520 14[14-I]c.523A>G(p.T175A)0.774UnknownUnknown20 15[15-I]c.959C>T(p.S320F)1.287c.837T>A(p.Y279X)X20 16[16-I]c.523A>G(p.T175A)0.774UnknownUnknown20 17[17-I]c.2169_2170insG(p.L724AfsX744)Xc.2169_2170insG(p.L724AfsX744)X20 17[17-II]c.2169_2170insG(p.L724AfsX744)Xc.2169_2170insG(p.L724AfsX744)X20 18[18-I]c.1207T>C(p.Y403H)2.798c.1207T>C(p.Y403H)2.79820 19[19-I]c.208G>C(p.G70R)þc.1769G>A(p.R590Q)1.497þ2.623c.959C>T(p.S320F)1.287Thisstudy 19[19-II]c.208G>C(p.G70R)þc.1769G>A(p.R590Q)1.497þ2.623c.959C>T(p.S320F)1.287Thisstudy 19[19-III]c.208G>C(p.G70R)þc.1769G>A(p.R590Q)1.497þ2.623c.959C>T(p.S320F)1.287Thisstudy 20[20-I]c.217C>G(p.L73V)0.489UnknownUnknown22,thisstudy 21[21-I]c.959C>T(p.S320F)1.287c.959C>T(p.S320F)1.28716,thisstudy 22[22-I]c.1207T>C(p.Y403H)2.798UnknownUnknownThisstudy Xidentifiesmutationsthatpredictprematureterminationoftranslation.PolyPhenpredictionwithPSICscoredifferencesbelow1.5definebenignsubstitutions;PSICscoredifferencesencompassing between1.5and2.0(bold)definesubstitutionspossiblydamaging,whereasabove2.0(underlined)definesubstitutionsprobablydamaging. Login to comment

PMID: 19584064 [PubMed] Bacq Y et al: "ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy."

No. Sentence Comment

5 One nonsense mutation (p.Arg144Stop) and two missense mutations (p.Ser320Phe and p.Thr775Met) were revealed each in one heterozygous patient. A third missense mutation (p.Arg590Gln) was detected in three heterozygous patients and in two homozygous patients also homozygous for a particular haplotype of three single-nucleotide polymorphisms (c.175C.T, c.504T.C, c.711A.T). Login to comment
51 A missense mutation (c.2324C.T, p.Thr775Met) was detected in exon 19 in one heterozygous patient and was absent in controls. Login to comment
66 The heterozygous nonsense mutation (p.Arg144Stop) detected in one patient has previously been reported by our group.14 Three missense mutations (p.Ser320Phe, p.Arg590Gln, p.Thr775Met) were detected in this study. Login to comment
74 Furthermore, Arg590 is well conserved during evolution (fig 1), and the missense mutation p.Arg590Gln is localised in the first ATP-binding domain of the ABCB4 protein, where it substitutes a basic amino acid for a Table 3 Allele frequencies of ABCB4 genomic variants in 50 patients with intrahepatic cholestasis of pregnancy (100 chromosomes) and 107 controls (214 chromosomes) Genomic variant Exon Allele identification ICP (n (%)) Controls (n (%)) p Value Deduced effect Protein domain c.175 C.T 4 C 86 (86) 180 (84.1) 0.66 Silent T 14 (14) 34 (15.9) c.462 C.T 6 C 99 (99) 214 (100) 0.14 p.Arg144Stop (nonsense) Intracytoplasmic first loopT 1 (1) 0 (0) c.504 T.C 6 T 68 (68) 115 (53.7) 0.017 Silent C 32 (32) 99 (46.3) c.711 A.T 8 A 86 (86) 176 (82.2) 0.40 Silent T 14 (14) 38 (17.8) c.959 C.T 9 C 99 (99) 214 (100) 0.14 p.Ser320Phe (missense) TM5 T 1 (1) 0 (0) c.1769 G.A 15 G 93 (93) 213 (99.5) 0.0017 p.Arg590Gln (missense) NBD1 A 7 (7) 1 (0.5) c.1954 A.G 16 A 97 (97) 202 (94.4) 0.40 p.Arg652Gly (missense) NBD1 G 3 (3) 12 (5.6) c.2324 C.T 19 C 99 (99) 214 (100) 0.32 p.Thr775Met (missense) TM8 T 1 (1) 0 (0) ICP, intrahepatic cholestasis of pregnancy; NBD, nucleotide-binding domain; TM, transmembrane domain; n, number of chromosomes. Login to comment
77 The heterozygous status for the missense p.Thr775Met mutation that we found in one patient with ICP has been reported in a woman in a control group.16 A deleterious effect of the p.Thr775Met allele may, however, be possible because of its localisation in a transmembrane domain, which is important for substrate specificity.9 Thr775 is conserved in mammals, and a cysteine is present in fish (fig 1). Login to comment
78 The p.Thr775Met mutation leads to substitution of a small polar amino acid for a large non-polar one. Login to comment
94 Indeed, 82% of Table 4 Characteristics of eight patients with intrahepatic cholestasis of pregnancy (ICP) exhibiting ABCB4 mutations Nature of mutation (exon) Age Onset of pruritus (weeks of gestation) Total bilirubin* (N = 17 mmol/l) ALT* (N = 35 U/l) Total bile acids* (N = 6 mmol/l) GGT* (N = 15 U/l) Biliary lithiasis p.Arg144Stop:R/X (6) 23 26 36 1280 120.9 63 No p.Ser320Phe:S/F (9) 37 30 22 437 128.7 16 No p.Arg590Gln:R/Q (15) 39 30 8 73 17.7 13 No p.Arg590Gln:R/Q (15) 28 34 21 134 17.7 119 No p.Arg590Gln:Q/Q (15) 33 35 33 137 26.0 37 No p.Arg590Gln:Q/Q (15) 37 30 15 204 6.1 19 No p.Arg590Gln:R/Q (15) 24 30 14 173 78.0 20 No p.Thr775Met:T/M (19) 35 36 17 144 36.2 26 No *Maximum values during one occurrence of ICP. Login to comment