ABCMdb

ABCB4 p.Arg590Gln

ClinVar:	c.1769G>A , p.Arg590Gln ? , Conflicting interpretations of pathogenicity
Predicted by SNAP2:	A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (91%), I: D (95%), K: D (85%), L: D (95%), M: D (91%), N: D (91%), P: D (95%), Q: D (95%), S: D (95%), T: D (91%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Molecular characterization and structural implicat... Eur J Hum Genet. 2007 Dec;15(12):1230-8. Epub 2007 Aug 29. Degiorgio D, Colombo C, Seia M, Porcaro L, Costantino L, Zazzeron L, Bordo D, Coviello DA
Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3).
Eur J Hum Genet. 2007 Dec;15(12):1230-8. Epub 2007 Aug 29., [PMID:17726488]

Abstract [show]
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal-recessive disorder due to mutations in the ATP-binding cassette, subfamily B, member 4 gene (ABCB4). ABCB4 is the liver-specific membrane transporter of phosphatidylcholine, a major and exclusive component of mammalian bile. The disease is characterized by early onset of cholestasis with high serum gamma-glutamyltranspeptidase activity, which progresses into cirrhosis and liver failure before adulthood. Presently, about 20 distinct ABCB4 mutations associated to PFIC3 have been described. We report the molecular characterization of 68 PFIC3 index cases enrolled in a multicenter study, which represents the largest cohort of PFIC3 patients screened for ABCB4 mutations to date. We observed 31 mutated ABCB4 alleles in 18 index cases with 29 distinct mutations, 25 of which are novel. Despite the lack of structural information on the ABCB4 protein, the elucidation of the three-dimensional structure of bacterial homolog allows the three-dimensional model of ABCB4 to be built by homology modeling and the position of the mutated amino-acids in the protein tertiary structure to be located. In a significant fraction of the cases reported in this study, the mutation should result in substantial impairment of ABCB4 floppase activity. The results of this study provide evidence of the broad allelic heterogeneity of the disease, with causative mutations spread along 14 of the 27 coding exons, but with higher prevalence on exon 17 that, as recently shown for the closely related paralogous ABCB1 gene, could contain an evolutionary marker for mammalian ABCB4 genes in the seventh transmembrane segment.

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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
102 Table 3) includes seven cases: p.Y403H, p.V475A, p.A511T, p.E558K, p.R590Q, p.T593A and p.A1193T. Login to comment

[hide] BSEP and MDR3 haplotype structure in healthy Cauca... Hepatology. 2004 Mar;39(3):779-91. Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ
BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis.
Hepatology. 2004 Mar;39(3):779-91., [PMID:14999697]

Abstract [show]
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned approximately 10,000 bp including promoter and coding regions as well as 50-350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC.

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116 Four variant sites (T927C, A1099G 3 I367V, G1769A 3 R590Q, and A3296G 3 E1099G) were only found in the control group, 4 were specific to PBC patients (C217G 3 L73V, A728C 3 D243A, A1304C 3 K435T, and A3751C 3 K1251Q), while 1 was PSC-specific (C1633T 3 R545C). Login to comment

[hide] Genetic variability, haplotype structures, and eth... Drug Metab Dispos. 2006 Sep;34(9):1582-99. Epub 2006 Jun 8. Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, Kerb R
Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).
Drug Metab Dispos. 2006 Sep;34(9):1582-99. Epub 2006 Jun 8., [PMID:16763017]

Abstract [show]
Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.

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177 Amino Acid Change Scoring Systems for Nonsynonymous Variants Grantham SIFT PolyPhen Blosum62 EC/EU MDR3 D87E 45 1.00 0.48 2 EC P95S 74 0.48 0.87 -1 EC T175A 58 0.01 0.72 -1 EC I367V 29 0.23 0.96 3 EC E450G 98 0.01 0.13 -2 EC R590Q 43 0.01 2.51 1 EC R652G 125 0.36 1.47 -2 EU E1099G 98 0.04 1.58 -2 EC BSEP I206V 29 1.00 0.23 3 EU V284A 64 0.13 0.43 -2 EC R299K 26 1.00 0.38 2 EU V444A 64 0.63 0.78 -2 EC R616G 125 0.01 3.16 -2 EC T619A 58 0.00 1.78 -1 EC M677V 21 0.29 0.82 1 EU R698H 29 0.30 0.57 0 EC A865V 64 0.02 1.12 0 EC R958Q 43 0.04 0.24 1 EU neutral mutation model (Tajima, 1989). Login to comment
296 Although experimentally not validated, we conclude that the amino acid changes p.R590Q, p.E1099G (ABCB4), p.R616G, and p.T619A (ABCB11) are the strongest candidates to alter protein function and subsequently biliary excretion (Table 5). Login to comment
63 The numbers 1 to 42 in the variant ID column indicate all variants included in haplotype analysis and linkage disequilibrium estimation. Variant ID 5Ј Sequence Genetic Variation 3Ј Sequence Region Amino Acid Change CA KO JA Total n % n % n % n % 43 TCAATGCAC g.-7676AϾT GTCTCACAA PromA 110 0.9 96 0.0 88 0.0 294 0.3 44 CTACCCTCT g.-7554TϾC CAATGCCTC PromA 110 0.9 96 0.0 88 0.0 294 0.3 45 GAGTGAAGT g.-7253GϾA TAGAAATCT PromA 106 0.0 96 1.0 94 0.0 296 0.3 46 AATTTAGAA g.-7114AϾT ACTCAATAG PromA 108 0.0 96 1.0 94 0.0 298 0.3 1 AAGAGGAAA g.-7094GϾC TTTCTTGTA PromA 108 13.0 96 30.2 94 24.5 298 22.1 47 CAAGAATTT g.-6816CϾT ATTAGGCAA PromA 102 0.0 96 1.0 92 0.0 290 0.3 48 GAGAGAGAG g.-6639AϾC GAGCTGAAT PromA 110 0.9 90 0.0 92 0.0 292 0.3 49 GAGAGAGAG g.-6637_-6636 delAG CTGAATCAG PromA 110 0.0 90 1.1 92 0.0 292 0.3 2 GTGCCTTTG g.-6588GϾT GTGTGCTGG PromA 110 2.7 88 0.0 92 2.2 290 1.7 3 AAAGAAGAA g.-6540CϾT GAAACCAAA PromA 108 14.8 86 26.7 90 27.8 284 22.5 4 TTAGTGACC g.-6325AϾG AAAGTTTGG PromA 108 17.6 90 31.1 92 26.1 290 24.5 5 ATTCTTTTT g.-6014GϾT TACAAACCC PromA 108 16.7 94 28.7 88 26.1 290 23.4 50 ACTGGTGCT g.-5941GϾA TGGGCACTA PromA 108 0.0 94 0.0 88 1.1 290 0.3 6 TGAAGTCAC g.-5859GϾA TGGCCAGAG PromA 108 16.7 94 28.7 88 26.1 290 23.4 7 ATGAGATGA g.-5717TϾC ATATATGTG PromA 110 0.0 92 1.1 86 3.5 288 1.4 8 CCTTCTTTA g.-5610TϾC ATGCCTAAA PromA 110 100.0 96 100.0 94 97.9 300 99.3 9 TAAGTGTGG g.-5570GϾC CAGCAATTA PromA 110 12.7 96 29.2 94 24.5 300 21.7 51 TACTCTCAC g.-5509GϾA GCTCTTATG PromA 110 0.0 96 1.0 94 0.0 300 0.3 10 CTCTCTTGT g.-5236CϾT TGAGTAATA PromA 108 15.7 90 27.8 94 26.6 292 22.9 52 GAGGATAAA g.-2551AϾT AAGAAAGAT PromB 126 0.0 88 0.0 90 1.1 304 0.3 11 AGCCTTACA g.-2478TϾG CAATGCATA PromB 126 4.8 88 0.0 90 2.2 304 2.6 12 GAAGGAATT g.-1921TϾC GGGTTGATT PromB/Exon -3 122 4.9 92 0.0 82 1.2 296 2.4 53 GAAGAGAAT g.-1899CϾA CTCATGGTC PromB/Exon -3 122 0.8 92 0.0 82 0.0 296 0.3 13 ATCCTAATA g.-1603AϾT CACCCTTAT PromB 128 0.0 94 2.1 86 1.2 308 1.0 14 TTTATAGAT g.-1584CϾT CAATGACTG PromB/Exon -2 118 11.0 94 29.8 74 23.0 286 20.3 54 ACACCAGGG g.-1510TϾG CCACCCAGC PromB 126 0.0 94 1.1 68 0.0 288 0.3 15 CTTATACCA g.-1484TϾC GCTCTGCTT PromB 126 0.0 94 1.1 68 5.9 288 1.7 55 TTTGAAAGT g.-1146CϾT TCCGGTTTC PromB 126 0.0 92 1.1 82 0.0 300 0.3 16 TGGTAGGAG g.-1031CϾT AGAGACAAT PromB 126 11.1 92 30.4 82 24.4 300 20.7 56 GAGACAATT g.-1020CϾG AATACAGAC PromB 126 0.0 92 1.1 82 0.0 300 0.3 17 ATTCAATAC g.-1014AϾG GACAGAAGT PromB 126 13.5 92 30.4 82 24.4 300 21.7 18 GAACTGGGG g.-682AϾC TGCGGAAGC PromB/Exon -1 124 1.6 70 0.0 64 0.0 258 0.8 19 AGGCTCCAG g.-495CϾG CTGATCTCG PromB 126 17.5 86 29.1 84 28.6 296 24.0 20 GCGCCCCGG g.-414CϾT GGCAAGAGC PromB 126 4.8 86 3.5 84 6.0 296 4.7 21 GGCAGGCTG g.-395CϾG GCCCCTGGC PromB 126 13.5 86 3.5 84 6.0 296 8.4 22 GCCCGCGCC g.-378TϾC AGCCTGGGG PromB 126 26.2 86 27.9 84 20.2 296 25.0 57 GCGTTTCCC g.-292GϾT GGCCGGACG PromB 128 0.0 96 0.0 92 1.1 316 0.3 58 CCGGACGCG g.-280CϾA GTGGGGGGC PromB 126 0.8 86 0.0 84 0.0 296 0.3 59 CCCTGCCAG g.-186AϾG CACGCGCGA PromB/Exon 1 128 0.0 96 1.0 92 0.0 316 0.3 23 TGCCCCCGG g.-75GϾT CCCCGCGAC PromB 128 0.0 96 0.0 92 1.1 316 0.3 24 TTTATGTCG g.12597CϾT TGGGTACCA Exon 4 L59L 126 12.7 96 25.0 94 21.3 316 19.0 60 CAAATTTGT g.12680TϾG GATACTGCA Exon 4 V86V 126 0.0 96 0.0 94 1.1 316 0.3 61 ATTTGTTGA g.12683TϾG ACTGCAGGA Exon 4 D87E 126 0.0 96 0.0 94 1.1 316 0.3 62 TTCTCCTTT g.12705CϾT CAGGTAAGC Exon 4 P95S 126 0.0 96 0.0 94 1.1 316 0.3 63 TAGCTTTCA g.20782TϾG ACATTTAAA Intron 4 114 0.0 88 1.1 70 0.0 272 0.4 25 TTTTAAAAA g.20813CϾT CTGGCAATG Intron 4 116 3.4 90 1.1 70 0.0 276 1.8 26 TCACCTATT g.21044AϾG TTATCATTT Intron 5 122 16.4 52 15.4 46 32.6 220 19.5 27 AAAAGAAAA g.22281_22284delGAAAA AAGAAAAGA Intron 5 126 7.9 88 0.0 84 0.0 298 3.4 28 TGACATCAA g.22490CϾT GACACCACT Exon 6 N168N 126 42.9 88 37.5 90 44.4 304 47.7 29 GAACTCAAT g.22509AϾG CGCGGCTAA Exon 6 T175A 126 3.2 88 0.0 90 0.0 304 1.3 64 CTCTGCAGC g.23831CϾT GTTTGGGCA Exon 7 A232A 128 0.0 94 0.0 90 1.1 312 0.3 65 AAGGGTTGA g.25313CϾG CAGAGTGCC Intron 7 124 0.8 96 0.0 90 0.0 310 0.3 30 TGTCCAGAT g.25376AϾT CTCTCGGCA Exon 8 I237l 126 15.1 96 27.1 90 27.8 312 22.4 66 GTTAATATA g.28354TϾC GCATCATAT Exon 9 Y309Y 128 0.8 96 0.0 92 0.0 316 0.3 67 GCATATGTG g.30584AϾG TCTTTGATA Exon 10 I367V 118 0.8 92 0.0 92 0.0 302 0.3 68 TAATATTTA g.31823TϾG AGGAATTCC Intron 11 128 0.0 96 0.0 92 1.1 316 0.3 31 ACTTTTTTT g.31941delT CAAATTTCA Intron 11 128 7.0 96 3.1 94 1.1 318 4.1 69 ACCCTGATG g.32140AϾG GGGCACAGT Exon 12 E450G 128 0.0 96 1.0 94 0.0 318 0.3 70 ACAAATTTG g.32232CϾT GTGTGAATC Intron 12 128 0.0 96 1.0 94 0.0 318 0.3 32 GGCAATGCC g.32277GϾT ATGGATAAT Intron 12 124 6.5 96 3.1 94 3.2 314 4.5 33 CAGCTATTA g.35024AϾG ATGGTTAAA Intron 12 124 95.2 94 70.2 94 72.3 312 80.8 71 ACAGGTAAA g.35273GϾA CCTCTGATA Intron 13 126 0.0 96 0.0 94 1.1 316 0.3 72 AGTGTGCCA g.43862AϾG TACTGTAAC Intron 14 122 0.8 88 0.0 72 0.0 282 0.4 34 TGTGCCAAT g.43864AϾG CTGTAACCC Intron 14 124 0.0 88 1.1 72 2.8 284 1.1 73 TAGCACACC g.43938GϾA ACTGTCTAC Exon 15 R590Q 124 0.8 88 0.0 74 0.0 286 0.3 35 GCTGCCACT g.48606AϾG GAATGGCCC Exon 16 R652G 124 7.3 86 2.3 74 1.4 284 4.2 36 GCTACAATT g.48771AϾG TTGAAATTC Intron 16 114 5.3 86 2.3 70 1.4 270 3.3 37 TTGCAAACA g.51576CϾT CACATAACA Intron 17 122 95.1 70 74.3 80 71.3 272 82.7 38 TTACATAAC g.56969AϾG TGGTTTTAG Intron 20 126 6.3 60 3.3 66 1.5 252 4.4 74 ATATTTTAC g.58304TϾC GTATTAATG Intron 21 124 0.0 96 0.0 92 1.1 212 0.3 39 CTGTATTAA g.58312TϾC GTCTAGAAC Intron 21 122 4.1 96 1.0 92 1.1 310 2.3 75 AAAGGAGGC g.63395delT GAAGAGATG Intron 22 124 0.8 92 0.0 94 0.0 310 0.3 76 AATATTAAG g.63598AϾT TTATTCTAT Intron 23 124 0.0 92 1.1 94 0.0 310 0.3 40 ATGGTCAAG g.68988AϾG AGCAAAGAA Exon 26 E1099G 112 1.8 92 0.0 84 0.0 288 0.7 41 TATTTATAA g.72169TϾC TTGGTTAAC Intron 26 122 91.8 90 65.6 92 75.0 304 78.9 42 GTAACATTT g.73092TϾC CAAATTTAC Intron 27 124 7.3 94 1.1 86 1.2 304 3.6 n, number of alleles analyzed (number of subjects times 2). 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111 Five rare missense mutations occurred once as single heterozygotes (singletons) in exon 4 (c.261TϾC and c.283CϾT), exon 10 (c.1099AϾG), exon 12 (c.1349AϾG), and exon 15 (c.1769GϾA), resulting in the amino acid changes p.I367V, p.R590Q, p.D87E, p.P95S, and p.E450G. Login to comment

[hide] Mutations and polymorphisms in the bile salt expor... Pharmacogenet Genomics. 2007 Jan;17(1):47-60. Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, Kullak-Ublick GA, Meier PJ, Pauli-Magnus C
Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
Pharmacogenet Genomics. 2007 Jan;17(1):47-60., [PMID:17264802]

Abstract [show]
OBJECTIVES: Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms. METHODS: ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay. RESULTS: Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional. CONCLUSION: In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.

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149 Of the coding region changes, eight have previously been described in healthy Caucasians, including three synonymous and two nonsynonymous changes (synonymous: exon 4: 175C > T, exon 6: 504C > T, exon 8: 711A > T; nonsynonymous: exon 6: 523A > G-T175A, exon 15: 1769G > A-R590Q and exon 16: 1954A > G-R652G). Login to comment
163 The estimated IC50 was 50 and 60 mmol/l for reference BSEP Fig. 4 Extracellular I764L T175A R652G R590Q Cytoplasm L1082Q Secondary structure of multidrug resistance protein 3 (MDR3) with nonsynonymous coding region variants. Login to comment

[hide] Prolonged cholestasis triggered by hepatitis A vir... Ann Hepatol. 2012 Sep;11(5):710-4. Krawczyk M, Grunhage F, Langhirt M, Bohle RM, Lammert F
Prolonged cholestasis triggered by hepatitis A virus infection and variants of the hepatocanalicular phospholipid and bile salt transporters.
Ann Hepatol. 2012 Sep;11(5):710-4., [PMID:22947535]

Abstract [show]
Hepatitis A virus (HAV) infection resolves in most patients uneventfully within weeks from the onset of the disease. In rare cases, however, it may relapse or cause prolonged cholestasis. Here we present a case of a 36-year-old female patient who developed severe pruritus and jaundice three weeks after initially uncomplicated hepatitis A. A relapse of the infection was excluded. Since therapy with colestyramin, antihistaminics, naloxon and ursodeoxycholic acid (UDCA) did not improve symptoms, we decided to perform plasma absorption and to start rifampicin therapy. Under these measures, pruritus and jaundice, as well as serum bilirubin levels improved gradually and after four plasmapheresis sessions we were able to discharge the patient. Genetic testing showed the presence of two procholestatic polymorphisms, the c.3084 [GG] variant within the gene encoding the hepatocanalicular bile salt transporter ABCB11 and the c.711 [AT] variant of the phosphatidylcholine floppase ABCB4. We speculate that this compound ABCB4-ABCB11 genotype led to a severe intrahepatic cholestasis in the setting of HAV infection. In conclusion, our case suggests that polymorphisms within the hepatocanalicular transporters may contribute to a more pronounced course of HAV infection. Although dedicated studies in large cohorts of patients are needed to confirm this observation, we speculate that patients carrying procholestatic hepatobiliary transporter variants may benefit from vaccination against hepatitis A.

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58 To detect genetic factors contributing to severe phenotype, we genotyped procholestatic mutations and polymorphisms in the ABCB4 (p.R590Q, c.711A>T), ABCB11 (p.E297G, p.A444V, p.D482G, c.3084A>G), ATP8B1 (p.N45T, p.E429A, p.I661T) and FXR (c.-1 G>T) genes. The genotyping was performed using PCR-based assays with 5`-nuclease and fluorescence detection (TaqMan). Login to comment
57 To detect genetic factors contributing to severe phenotype, we genotyped procholestatic mutations and polymorphisms in the ABCB4 (p.R590Q, c.711A>T), ABCB11 (p.E297G, p.A444V, p.D482G, c.3084A>G), ATP8B1 (p.N45T, p.E429A, p.I661T) and FXR (c.-1 G>T) genes. The genotyping was performed using PCR-based assays with 5`-nuclease and fluorescence detection (TaqMan). Login to comment

[hide] Clinical features and genotype-phenotype correlati... J Pediatr Gastroenterol Nutr. 2011 Jan;52(1):73-83. Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, Motta V, Consonni D, Maggiore G
Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations.
J Pediatr Gastroenterol Nutr. 2011 Jan;52(1):73-83., [PMID:21119540]

Abstract [show]
OBJECTIVES: The aim of the study was to estimate the frequency of ABCB4 mutations among children with chronic intrahepatic cholestasis with elevated gamma-glutamyl-transpeptidase (gamma-GT) activity and to characterize the genotypes with respect to severity of symptoms, response to ursodeoxycholic acid therapy, and outcome. PATIENTS AND METHODS: Molecular analysis of ABCB4 in 133 Italian children was performed, and ABCB4 mutations were classified as disease-causing mutations or benign substitutions according to the prediction algorithm PolyPhen. RESULTS: : Twenty-eight patients were identified carrying 31 mutations (20 disease causing). Twenty patients carried 2 mutated alleles and 8 only 1. At presentation (1-204 months), 20 children were symptomatic with jaundice and/or pruritus, whereas in 8 biochemical cholestasis was a fortuitous finding. Cirrhosis developed in 15 and 6 progressed to terminal liver failure. Disease-causing mutations on both alleles were found to be associated with reduced liver expression of ABCB4 protein, lack of response to ursodeoxycholic acid therapy, and progression to cirrhosis and end-stage liver disease, whereas mild genotypes, including single heterozygous mutations, were generally associated with less severe disease and, often, absence of symptoms. CONCLUSIONS: ABCB4 mutations are responsible for a chronic liver disease in more than one-third of patients with chronic intrahepatic cholestasis and elevated gamma-GT activity. In patients with severe ABCB4 genotype, the disease is often progressive with risk of developing cirrhosis and liver failure during the first 2 decades of life. Patients with mild genotypes, including single heterozygous mutations, have variable expressions of liver disease that may be influenced by comorbidity factors and modulated by still unknown genetic modifiers.

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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

[hide] ABCB4 gene mutations and single-nucleotide polymor... J Med Genet. 2009 Oct;46(10):711-5. Epub 2009 Jul 6. Bacq Y, Gendrot C, Perrotin F, Lefrou L, Chretien S, Vie-Buret V, Brechot MC, Andres CR
ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy.
J Med Genet. 2009 Oct;46(10):711-5. Epub 2009 Jul 6., [PMID:19584064]

Abstract [show]
AIM: To evaluate the nature and frequency of ATP-binding cassette subfamily B member 4 (ABCB4) gene variants in a series of French patients with intrahepatic cholestasis of pregnancy (ICP). METHODS: In this prospective study, the entire ABCB4 gene coding sequence was analysed by DNA sequencing in 50 unrelated women with ICP defined by pruritus and raised serum alanine aminotransferase activity or bile acid concentration, with recovery after delivery. Genomic variants detected in patients with ICP were sought in 107 control pregnant women. Patients with ICP and controls were of Caucasian origin. RESULTS: Eight genomic variants were observed. 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). The chromosomal frequency of the p.Arg590Gln variant was significantly different between the ICP and control group (7.0% vs 0.5%; p = 0.0017; OR 16.03, 95% CI 1.94 to 132.16). An association was also found between allele T of the c.504T>C silent nucleotide polymorphism and ICP (68.0% vs 53.7%; p = 0.017; OR 1.83, 95% CI 1.08 to 3.11). The chromosomal frequency of the p.Arg652Gly variant did not differ between the ICP and control group (p = 0.40). CONCLUSIONS: This study shows that 16% of Caucasian patients with ICP bear ABCB4 gene mutations, and confirms the significant involvement of this gene in the pathogenesis of this complex disorder.

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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
6 The chromosomal frequency of the p.Arg590Gln variant was significantly different between the ICP and control group (7.0% vs 0.5%; p = 0.0017; OR 16.03, 95% CI 1.94 to 132.16). Login to comment
48 A nonsense mutation (nucleotide position from ATG, c.462C.T; amino acid position, p.Arg144Stop) was detected in exon 6 in one heterozygous patient.14 A missense mutation (c.959C.T, p.Ser320Phe) was detected in exon 9 in one heterozygous patient. A missense mutation (c.1769G.A, p.Arg590Gln) was detected in exon 15 in two homozygous and three heterozygous patients with ICP and in one heterozygous control. Login to comment
49 The two p.Arg590Gln:Q/Q homozygous patients were also homozygous for a particular haplotype of three single-nucleotide polymorphisms (SNPs) (haplotype T-C-T of c.175C.T, c.504T.C, c.711A.T). Login to comment
50 The distribution of allele frequencies of this p.Arg590Gln mutation was significantly different between the ICP and control groups (7.0% vs 0.5%; p = 0.0017; odds ratio 16.03, 95% CI 1.94 to 132.16). 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
70 The allele distribution of p.Arg590Gln detected in exon 15 was significantly different between patients with ICP and controls. Login to comment
71 We found two women homozygous for p.Arg590Gln in the ICP group and none in the control group. Login to comment
72 These two patients, with no known history of consanguinity, were also homozygous for the same rare ABCB4 haplotype, and two of the three patients who were heterozygous for p.Arg590Gln were also heterozygous for this haplotype. Login to comment
73 This haplotype reveals a probable founder effect for this p.Arg590Gln mutation. 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
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

[hide] A new splicing site mutation of the ABCB4 gene in ... Dig Liver Dis. 2009 Sep;41(9):671-5. Epub 2009 Mar 3. Tavian D, Degiorgio D, Roncaglia N, Vergani P, Cameroni I, Colombo R, Coviello DA
A new splicing site mutation of the ABCB4 gene in intrahepatic cholestasis of pregnancy with raised serum gamma-GT.
Dig Liver Dis. 2009 Sep;41(9):671-5. Epub 2009 Mar 3., [PMID:19261551]

Abstract [show]
BACKGROUND: Intrahepatic cholestasis of pregnancy is a liver disorder with a multifactorial etiology characterized by maternal pruritus, abnormal liver function tests and increased fetal risk. The main biochemical finding is the increase in total serum bile acid concentrations. In a subgroup of women, the serum gamma-glutamyl transpeptidase level is also increased. There is evidence that dysfunction of the ABCB4 gene might play a role in intrahepatic cholestasis of pregnancy development. AIM: To investigate the role of the ABCB4 gene in Italian women with intrahepatic cholestasis of pregnancy and raised gamma-glutamyl transpeptidase by, analyzing the complete coding sequence and mRNA splicing products. METHODS: Among 299 women with intrahepatic cholestasis of pregnancy, 10 showing raised gamma-glutamyl transpeptidase were enrolled in this study. DNA and RNA were extracted from peripheral blood mononuclear cells using standard procedures. The 27 coding exons and the promoter region were amplified by polymerase chain reaction and analyzed by sequencing. Reverse transcript-polymerase chain reaction analysis of ABCB4 mRNA and cDNA analysis were also performed. RESULTS: A novel splicing mutation that causes a truncated protein of 249 amino acid was identified in a woman who had the highest serum levels of gamma-glutamyl transpeptidase, alkaline phosphatase, bile acids, and the highest pruritus score. We identified also one already described p.R590Q mutation in a woman who had significantly higher serum levels of alkaline phosphatase, aspartate, and alanine aminotransferase. CONCLUSIONS: Our study demonstrates that splicing mutations in the ABCB4 gene can cause ICP in women with high gamma-glutamyl transpeptidase and thus a complete analysis of coding sequence and cDNA products is required.

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10 We identified also one already described p.R590Q mutation in a woman who had significantly higher serum levels of alkaline phosphatase, aspartate, and alanine aminotransferase. Login to comment
67 Patients Involved regions Nucleotide positiona Reference nucleotide Nucleotide variant Effect on proteinb GenBank accession numberc 9d Promoter c.-495 C G 3, 9 Promoter c.-378 T C 2 Exon 4 c.175 C T p.L59L 2, 3, 4, 5d , 7, 9, 10 Exon 6 c.504 T C p.N168N 9 Intron 7 c.709-2 A G p.I237VfsX250 EU142941 2, 7 Exon 8 c.711 A T p.I237I 2, 7 Intron 8 c.834-66 G T 7 Intron 11 c.1231-81 T delT 2 Exon 15 c.1769 G A p.R590Q 7 Exon 16 c.1954 A G p.R652G 7 Intron 16 c.2064+55 A G 2 Intron 17 c.2211+16 T C 7 Intron 20 c.2478+40 A G 7 Intron 20 c.2479-67 G delG 7 Intron 21 c.2682+22 T C EU142942 7 Intron 21 c.2683-197 T C 7 Intron 27 c.3655-72 T C In bold the two mutations which were most likely to cause an impairment of about 50% of the ABCB4 floppase activity in ICP patients n. 2 and n. 9. a Nucleotide A of the ATG of the initiator Met codon is position +1 of cDNA sequence (reference sequence GenBank NM 018849); b The protein GenBank reference number is NP 061337. c GenBank accession number of the new sequences identified in this study. Login to comment
94 The second mutation is the missense p.R590Q, detected in the heterozygous state of the ICP patient n. 2 (ICP2), who presented with occasional pruritus, significantly higher serum levels of alkaline phosphatase, aspartate, and alanine aminotransferase (Table 1). Login to comment
95 The p.R590Q mutation is located in the nucleotide binding domain 1 (NBD1) of the ABCB4 protein and was not present in any of the 43 control women. Login to comment
113 The mutation is localized in exon 15 and causes significant changes, with respect to polarity (p.R590Q) in the very well conserved NBD1 region of the protein. Login to comment
116 Furthermore, in our previous detailed molecular ABCB4 analysis of children with PFIC3 phenotype [13], the p.R590Q has been ascribed to the mutation responsible for substantial impairment of ABCB4 floppase activity. Login to comment
96 The p.R590Q mutation is located in the nucleotide binding domain 1 (NBD1) of the ABCB4 protein and was not present in any of the 43 control women. Login to comment
114 The mutation is localized in exon 15 and causes significant changes, with respect to polarity (p.R590Q) in the very well conserved NBD1 region of the protein. Login to comment
117 Furthermore, in our previous detailed molecular ABCB4 analysis of children with PFIC3 phenotype [13], the p.R590Q has been ascribed to the mutation responsible for substantial impairment of ABCB4 floppase activity. Login to comment

[hide] ABCB4 sequence variations in young adults with cho... Liver Int. 2009 May;29(5):743-7. Epub 2008 Oct 24. Nakken KE, Labori KJ, Rodningen OK, Nakken S, Berge KE, Eiklid K, Raeder MG
ABCB4 sequence variations in young adults with cholesterol gallstone disease.
Liver Int. 2009 May;29(5):743-7. Epub 2008 Oct 24., [PMID:19018976]

Abstract [show]
BACKGROUND AND AIMS: Mutations in the gene encoding the ABCB4 [adenosine triphosphate (ATP)-binding cassette, sub-family B (MDR/TAP), member 4] transporter lower phosphatidylcholine output into bile and contribute to cholesterol gallstone formation by decreasing the solubility of cholesterol in bile. Mutations in ABCB4 have been identified in patients with low phospholipid-associated cholelithiasis. The aim of the present study was to determine the types and frequencies of ABCB4 mutations in cholecystectomized patients aged <40 years. PATIENTS AND METHODS: Hundred and four patients (mean age 30.6 years, range 12-39) were included in the study and the ABCB4 gene was sequenced. The frequency of missense mutations found in the patient material was measured in 95 healthy controls. The potential functional implications of the ABCB4 missense variations were assessed by computerized analysis (BLOSUM62 and Grantham substitution matrices, polymorphism phenotyping and sorting intolerant from tolerant). RESULTS: One patient was heterozygous for a frameshift mutation (c.1399_1400ins10/p.Y467F fsX25). Another patient was heterozygous for a nonsense mutation (c.3136C>T/p.R1046X). These two mutations are considered detrimental to ABCB4 protein function. In addition, six missense mutations were found in the ABCB4 gene, and three of these were only present in patients. CONCLUSION: In our study, <2% of young gallstone patients were found to be heterozygous for detrimental ABCB4 mutations. The functional implication of several missense mutations remains to be clarified. Thus, mutations in the ABCB4 gene are a rare cause of gallstone disease.

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62 These were c.337A4G/p.M113L, c.523A4G/p.T175A, c.1584G4 C/ p.E528D, c.1769G4 A/p.R590Q, c.1954A4G/p.R652G and c.3318G4 C/p.Q1106H). Login to comment
79 The variant c.1769G4 A in exon 19 results in the amino acid change p.R590Q (argini- ne4 glutamine). Login to comment
88 Table 1. Summary of patient characteristics having ABCB4 gene variations with possible effects on the ABCB4 protein and the occurrence of these variations in healthy controls Patient (ID) (n = 104) Gender/ethnicity Age Indication for surgery Gallstone Location Nucleotide change Peptide change Status Controls (n = 95) 1-16 Female Exon 16 c.1954A 4 G p.R652G 9 17-22 Female/Norwegian 21 Choledocholithiasis Multiple, 5 mm Exon 6 c.523A 4 G p.T175A heterozygous 3 Female/Iraq 25 Cholecystolithiasis Multiple, 5-10 mm Female/Norwegian 28 Cholecystolithiasis Two, 15 mm Female/African 31 Cholecystitis Multiple, 5 mm1solitary, 20 mm Female/Norwegian 32 Cholecystolithiasis Multiple, 5 mm Female/Norwegian 34 Cholecystolithiasis Multiple, 5-10 mm 23 Female/Norwegian 32 Cholecystolithiasis Two, 20 mm Exon 14 c.1584G 4 C p.E528D heterozygous 0 24-25 Female/Norwegian 23 Cholecystolithiasis Multiple, 5 mm Exon 15 c.1769G 4 A p.R590Q heterozygous 1 Female/Norwegian 37 Cholecystolithiasis Multiple, o 5 mm 26 Female/Norwegian 40 Cholecystitis Solitary, 30 mm Exon 25 c.3136C 4 T p.R1046X heterozygous - 27 Female/Pakistani 30 Cholecystolithiasis Three, 10 mm Exon 13 c.1399_1400 ins10 p.Y467F fsX25 heterozygous - 28 Ã Female/Pakistani 32 Cholecystolithiasis Multiple, o 5 mm Exon 5 c.337A 4 G p.M113L heterozygous 0 Exon 26 c.3318G 4 C p.Q1106H 0 The variation p.R652G, considered to be without functional significance for the ABCB4 product, is shown without patient characteristics (16 patients). Login to comment
94 Grantham values range from 5 to 215; low values ( o 50) indicate chemical similarity and high values ( 4 50) indicate more radical differences) Scoring Systems for Nonsynonymous Variants Amino acid change Grantham Blosum62 SIFT PolyPhen EC/EU p.M113L 15 2 0.17 1.211 EC p.T175A 58 0 0 0.845 EC p.E528D 45 2 0.25 0.617 EC p.R590Q 43 1 0 1.951 EC p.R652G 125 À 2 0.42 1.237 EU p.Q1106H 24 0 0.03 0.185 EC Blosum62 values range from À 4 to13, with negative values indicating less acceptable and positive values indicating more acceptable substitutions. Login to comment

[hide] ABCB4 heterozygous gene mutations associated with ... Gastroenterology. 2008 Jul;135(1):131-41. Epub 2008 Mar 26. Ziol M, Barbu V, Rosmorduc O, Frassati-Biaggi A, Barget N, Hermelin B, Scheffer GL, Bennouna S, Trinchet JC, Beaugrand M, Ganne-Carrie N
ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults.
Gastroenterology. 2008 Jul;135(1):131-41. Epub 2008 Mar 26., [PMID:18482588]

Abstract [show]
BACKGROUND & AIMS: Adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) mutations have not been investigated in patients with unexplained cholestasis. We aimed to investigate ABCB4 mutations in adult patients with unexplained anicteric cholestasis and to describe liver injury associated with ABCB4 mutations. METHODS: Between February 2004 and March 2007, all adults with unexplained cholestasis despite multiple investigations including liver biopsy and 124 healthy volunteers had ABCB4 sequencing. Fibrosis, bile duct lesions, inflammatory infiltrate, activation of myofibroblasts and multidrug-resistant P-glycoprotein 3 (MDR3) immunostaining were assessed on patients' liver biopsy specimens. RESULTS: Thirty-two patients were included (23 females, 16-69 years of age). Eight different ABCB4 heterozygous mutations were found in 11 patients (34%). Seven of these mutations (exons 4, 6, 14, 18, 23) were never detected in the control group. One mutation (exon 15) was detected in 4 patients (12.5%) and 4 controls (3%). At the time of liver biopsy, the main clinical and biologic characteristics were similar in the 32 patients regardless of ABCB4 mutation. The histologic pattern in patients with a mutation consisted of portal fibrosis with ductular reaction and strong macrophagic infiltrate of portal tracts without significant periportal and lobular necroinflammatory lesions or cholangitis. Fibrosis score and macrophagic infiltration of portal tracts were significantly increased in patients with ABCB4 mutation (P = .01). Absence or reduced MDR3 canalicular immunostaining was demonstrated in all patients with ABCB4 mutations tested. CONCLUSIONS: Heterozygous ABCB4 mutations were detected in 34% of adults with unexplained cholestasis, for the most part without biliary symptoms, and could result in significant liver fibrosis.

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56 As described in Figure 1, 3 (T175A, R590Q, A934T) have been previously described in patients with LPAC or ICP.8,13 Conversely, 5 (R47X, V526F, A539T, R545G, I738L) have not been previously described.20 The frequency of each mutation is indicated in Figure 1. Login to comment
59 The c.1769GϾA (R590Q) mutation in exon 15 Table 2. Login to comment
92 1615GϾA A539T Missense 15 c. 1769GϾA R590Q 5 F 47 No - No No Missense 23 c. Login to comment
93 2800GϾT A934T 6 F 18 Yes (18 y) No No Yesb Missense 15 c. 1769GϾA R590Q 7 M 28 No - No - Missense 18c c. 2212AϾC I738L 8 F 52 Yes (51 y) Yes No No Missense 15 c. 1769GϾA R590Q 9 F 57 No - No No Missense 15 c. 1769GϾA R590Q 10 F 48 Yes (32 y) Yes Yes No Missense 14c c. Login to comment
94 1633AϾG R545G 11 M 29 No - No - Missense 14c c. Login to comment
143 LPAC criteria and of 33 patients with various chronic liver disease.8 Only 1 previously reported mutation (R590Q) observed in 4 patients was also detected in 4 controls, raising the question of its relevance in the pathogenesis of the liver disease. Login to comment
144 The c.1769GϾA (R590Q) mutation in exon 15 has already been described as a genetic variability but predicted to have functional consequences.22 Second, 3 out of the 8 mutations have been previously reported in LPAC or ICP as shown in Figure 1. Login to comment
57 As described in Figure 1, 3 (T175A, R590Q, A934T) have been previously described in patients with LPAC or ICP.8,13 Conversely, 5 (R47X, V526F, A539T, R545G, I738L) have not been previously described.20 The frequency of each mutation is indicated in Figure 1. Login to comment
60 The c.1769Gb0e;A (R590Q) mutation in exon 15 Table 2. Login to comment
145 The c.1769Gb0e;A (R590Q) mutation in exon 15 has already been described as a genetic variability but predicted to have functional consequences.22 Second, 3 out of the 8 mutations have been previously reported in LPAC or ICP as shown in Figure 1. Login to comment

[hide] Hepatobiliary phospholipid transporter ABCB4, MDR3... Dig Liver Dis. 2008 May;40(5):366-70. Epub 2007 Dec 20. Floreani A, Carderi I, Paternoster D, Soardo G, Azzaroli F, Esposito W, Montagnani M, Marchesoni D, Variola A, Rosa Rizzotto E, Braghin C, Mazzella G
Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy.
Dig Liver Dis. 2008 May;40(5):366-70. Epub 2007 Dec 20., [PMID:18083082]

Abstract [show]
BACKGROUND: Intrahepatic cholestasis of pregnancy is a multifactorial disorder of pregnancy associated with a genetic background. AIM: To evaluate the genetic contribution of ABCB4, MDR3 gene in the development of intrahepatic cholestasis of pregnancy in a large cohort of Italian subjects. METHODS: This study represents an extension of a previous multicentre-prospective study including three Italian referral centres. In all, we enrolled 96 women at the 3rd trimester of pregnancy. Genomic DNA was extracted from peripheral venous blood leucocytes by standard procedures. Polymerase chain reaction was used to amplify exon 14, 15 and 16 of MDR3 gene. RESULTS: We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). MDR3 gene variants in exons 14, 15 and 16 occurred in 7/96 of pregnant mothers with intrahepatic cholestasis of pregnancy (7.2%), and in none of 96 pregnant controls matched for age and parity. All seven patients had normal gamma-glutamyl transpeptidase, normal bilirubin, but high levels of both alanine transferase and serum bile acids. One had cholesterol biliary lithiasis. The outcome of pregnancy was normal in four cases (with vaginal delivery), while there was one fetal distress. CONCLUSIONS: MDR3 mutations are responsible for the development of intrahepatic cholestasis of pregnancy in only a small percentage of Italian women. Further genetic studies are warranted, however, to clarify the role of different mutations in intrahepatic cholestasis of pregnancy.

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10 We found 3 non-synonymous heterozygous mutations in exon 14 (E528D, R549H, G536A), 1 in exon 15 (R590Q) and 2 in exon 16 (R652G, T6671). Login to comment
54 The median peak serum transaminases were 114.6 U/L (range 42-1117) and 164.5 U/L (range 47-1186) for AST Table 2 Clinical details of the patients with ICP N = 96 (%) Median age (range) 34 years (19-47) Parity 0001 68 70.8 0002 22 22.9 0003 6 6.3 Family history of ICP 8 8.3 Median AST (U/L; range) 114.6 (42-1117) Median ALT (U/L; range) 164.5 (47-1186) 10.4 Median total bile salts (␮M; range) 14.35 (3-115) Total bile salts >40 ␮M 10 10.4 Median total bilirubin (mg/dL) 0.61 (0.23-2.35) Abnormal bilirubin 10 11.4 Median serum GGT (U/L; range) 20.5 (4-147) Abnormal serum GGT 11 Normal values: AST, aspartate aminotransferase <40 U/L; ALT, alanine transferase <45 U/L; total bile salts <2 ␮M. Table 3 Polymorphisms of exons 14, 15 and 16 found in the study population cDNA (exon) N refer N var AA change 1584 (14) G C E528D 1606 (14) G A G536R 1646 (14) G A R549H 1769 (15) G A R590Q 1954 (16) A G R652G 2000 (16) C T T667I andALTrespectively.Eighty-sixpatientshadbilirubinwithin the normal range, while 10 (10.4%) had a slight rise in total bilirubin (2-3 mg/dL). Login to comment
57 Sequence analysis of exon 15 showed an heterozygous mutation in codon 590 with a consequent substitution of the wild-type arginine with glutamine (R590Q). Login to comment
58 Sequence analysis of exon 16 showed 2 mutations: (1) AGA-GGA mutation in codon 652, resulting in the substitution of the wild-type arginine with a mutant glycine (R652G); (2) ACT-ATT mutation in codon 667 with a substitution of the wild-type threonine with a mutant isoleucine (T667I). Login to comment
80 There is a difference, however, in the phenotypic expression of this condition by comparison Table 4 Clinical details of ICP patients with MDRR3 mutations Patient #1 E528D Patient #2 R549H Patient #3 G536R Patient #4 R590Q Patient #5 R652G Patient #6 T667I Patient #7 R652G Onset of pruritus 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester Parity 0002 0001 0001 0001 0001 0001 0001 Previous ICP No Yes Yes No No No No Peak of AST (U/L) 163 88 129 62 789 119 60 Peak of ALT (U/L) 98 121 137 88 1186 125 78 Bilirubin (mg/dL) 0.60 0.61 0.89 1.2 0.57 0.3 0.78 Peak of GGT (U/L) 8 15 19 10 25 35 5 Cholesterol lithiasis No No Yes No No No No Total bile salts (␮M/L) 3.3 6.3 10.1 60 76.3 25.3 4.0 Delivery Vaginal Vaginal Caesarean Vaginal Caesarean Caesarean Vaginal ICP, intrahepatic cholestasis of pregnancy; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Login to comment
55 Table 3 Polymorphisms of exons 14, 15 and 16 found in the study population cDNA (exon) N refer N var AA change 1584 (14) G C E528D 1606 (14) G A G536R 1646 (14) G A R549H 1769 (15) G A R590Q 1954 (16) A G R652G 2000 (16) C T T667I andALTrespectively.Eighty-sixpatientshadbilirubinwithin the normal range, while 10 (10.4%) had a slight rise in total bilirubin (2-3 mg/dL). Login to comment
81 There is a difference, however, in the phenotypic expression of this condition by comparison Table 4 Clinical details of ICP patients with MDRR3 mutations Patient #1 E528D Patient #2 R549H Patient #3 G536R Patient #4 R590Q Patient #5 R652G Patient #6 T667I Patient #7 R652G Onset of pruritus 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester 3rd trimester Parity 0002 0001 0001 0001 0001 0001 0001 Previous ICP No Yes Yes No No No No Peak of AST (U/L) 163 88 129 62 789 119 60 Peak of ALT (U/L) 98 121 137 88 1186 125 78 Bilirubin (mg/dL) 0.60 0.61 0.89 1.2 0.57 0.3 0.78 Peak of GGT (U/L) 8 15 19 10 25 35 5 Cholesterol lithiasis No No Yes No No No No Total bile salts (òe;M/L) 3.3 6.3 10.1 60 76.3 25.3 4.0 Delivery Vaginal Vaginal Caesarean Vaginal Caesarean Caesarean Vaginal ICP, intrahepatic cholestasis of pregnancy; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Login to comment

[hide] ABCB4 gene mutations and primary sclerosing cholan... Gastroenterology. 2004 Apr;126(4):1220-2; author reply 1222-3. Rosmorduc O, Hermelin B, Boelle PY, Poupon RE, Poupon R, Chazouilleres O
ABCB4 gene mutations and primary sclerosing cholangitis.
Gastroenterology. 2004 Apr;126(4):1220-2; author reply 1222-3., [PMID:15057773]

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55 However, as this mutation affected nonconserved amino acids (Arg590Gln) between the human ABCB4 gene and its rodent homologs, it was not considered as a disease-causing mutation. Login to comment

[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]

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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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63 However, because these mutations affected nonconserved amino acids between the human ABCB4 gene and its rodent homologs, they were not considered as DCMs.13, 14 They were localized in the third intracellular loop and in the fourth extracellular loop of the protein (e.g., Arg590Gln and Gly742Ser). Login to comment

[hide] Prevalence of low phospholipid-associated cholelit... Dig Liver Dis. 2013 Nov;45(11):915-9. doi: 10.1016/j.dld.2013.04.002. Epub 2013 May 16. Condat B, Zanditenas D, Barbu V, Hauuy MP, Parfait B, El Naggar A, Collot V, Bonnet J, Ngo Y, Maftouh A, Dugue L, Balian C, Charlier A, Blazquez M, Rosmorduc O
Prevalence of low phospholipid-associated cholelithiasis in young female patients.
Dig Liver Dis. 2013 Nov;45(11):915-9. doi: 10.1016/j.dld.2013.04.002. Epub 2013 May 16., [PMID:23684896]

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BACKGROUND AND AIMS: We evaluated the prevalence of low phospholipid-associated cholelithiasis, a specific form of cholelithiasis associated with at least 2 of the 3 following criteria: first symptoms before the age of 40; intrahepatic comet tail artefacts, sludge or microlithiasis on ultrasound imaging; and recurrence of symptoms after cholecystectomy. METHODS: We prospectively studied the cases of 60 consecutive female patients under 30 with symptomatic cholelithiasis. RESULTS: A diagnosis of low phospholipid-associated cholelithiasis was made in 14/60 patients (23%). The molecular analysis showed ABCB4 (n=4) and ABCB11 (n=4) gene mutations. Low phospholipid-associated cholelithiasis was frequently observed in non-overweight patients [13/27 (48%)], was present in most patients whose biliary symptoms occurred before the age of 18 [7/10 (70%)] and was often associated with cholangitis or acute pancreatitis [9/14 (64%), p<0.05] while "common" cholelithiasis was mainly associated with cholecystitis [16/46 (35%), p<0.05]. CONCLUSION: Nearly one quarter of the female patients under the age of 30 admitted for symptomatic cholelithiasis had low phospholipid-associated cholelithiasis; particularly if body weight was normal, the symptoms began before the age of 18 or in the presence of severe biliary complications.

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61 Heterozygous ABCB4 gene mutations were detected in 4 patients (29%): a point mutation in the coding region (NP 000434.1: p.Arg590Gln; p.Asn510Ser) in 2 cases, a sequence variation of a RNAn splicing site (c.3486+10 dupA) whose effect on the protein is unknown in one case and a deletion of exon 10, resulting in the absence of 38 amino acids, a region carrying the entire 6th transmembrane domain of the protein (NP 000434, p.Val336 Asn373del) in one case. Login to comment
62 Molecular analysis of the ABCB11 gene also showed variants in 4 patients (29%): a homozygous known polymorphic mutation (NP 003733: p.Val444Ala) in three cases and a heterozygous point mutation (NP 003733: p.Val43Ile) reported as a tolerated variant by protein prediction software in one case. Login to comment
101 [18] 1 Exon 10 c.1006-162 1119+706del p.Val336 Asn373del Absence of 6th transmembrane domain [12] 1 Exon 13 c.1529A>G HTZ p.Asn510Ser HTZ Missense; IC3 Domain; deleterious according to SIFT None 1 Exon 15 c.1769G>A HTZ p.Arg590Gln HTZ Missense IC3 Domain; deleterious according to SIFT; rs45575636 [19] Exon involved NM 003742.2 (ABCB11) NP 003733 (BSEP) Consequences Bibliography 1 Exon 4 c.127G>A HTZ p.Val43Ile HTZ Missense; N-Ter Domain; tolerated according to SIFT None 3 Exon 13 c.1331T>C HMZ p.Val444Ala HMZ Missense IC3 Domain; tolerated according to SIFT; rs2287622 [14] Table 3 Characteristics of patients with low phospholipid associated cholelithiasis with and without ABCB4 or ABCB11 mutations. Login to comment
102 [18] 1 Exon 10 c.1006-162 1119+706del p.Val336 Asn373del Absence of 6th transmembrane domain [12] 1 Exon 13 c.1529A>G HTZ p.Asn510Ser HTZ Missense; IC3 Domain; deleterious according to SIFT None 1 Exon 15 c.1769G>A HTZ p.Arg590Gln HTZ Missense IC3 Domain; deleterious according to SIFT; rs45575636 [19] Exon involved NM 003742.2 (ABCB11) NP 003733 (BSEP) Consequences Bibliography 1 Exon 4 c.127G>A HTZ p.Val43Ile HTZ Missense; N-Ter Domain; tolerated according to SIFT None 3 Exon 13 c.1331T>C HMZ p.Val444Ala HMZ Missense IC3 Domain; tolerated according to SIFT; rs2287622 [14] Table 3 Characteristics of patients with low phospholipid associated cholelithiasis with and without ABCB4 or ABCB11 mutations. Login to comment

[hide] Analysis of functional variants reveals new candid... Psychiatry Res. 2015 Jun 30;227(2-3):363-5. doi: 10.1016/j.psychres.2015.03.018. Epub 2015 Mar 27. Mezzavilla M, Ulivi S, Bianca ML, Carlino D, Gasparini P, Robino A
Analysis of functional variants reveals new candidate genes associated with alexithymia.
Psychiatry Res. 2015 Jun 30;227(2-3):363-5. doi: 10.1016/j.psychres.2015.03.018. Epub 2015 Mar 27., [PMID:25882097]

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In this study we explored the possible association between 36,915 functional variants and alexithymia, a personality trait characterized by the inability to identify and describe emotions and feelings. From our analysis, variants in the genes ABCB4, TP53AIP1, ARHGAP32 and TMEM88B were identified linked to the alexithymia phenotype.

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50 We found the following variants: rs45575636 on the ABCB4 gene (p-Value&#bc;2.6e08), a missense variant which determines arginine substitution into a glutamine (NP_000434.1: p.Arg590Gln); rs45575636 and rs35942033 SNPs on TP53AIP1 and ARHGAP32 genes respectively (p-Value&#bc;3.2e07), and finally rs144957058 on TMEM88B gene (p-Value&#bc;1.0e06). Login to comment

[hide] ABCB4 mutations in adult patients with cholestatic... J Gastroenterol. 2015 Sep 1. Degiorgio D, Crosignani A, Colombo C, Bordo D, Zuin M, Vassallo E, Syren ML, Coviello DA, Battezzati PM
ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression.
J Gastroenterol. 2015 Sep 1., [PMID:26324191]

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BACKGROUND: The ABCB4 gene encodes the MDR3 protein. Mutations of this gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3) in children, but their clinical relevance in adults remains ill defined. The study of a well-characterized adult patient series may contribute to refining the genetic data regarding cholangiopathies of unknown origin. Our aim was to evaluate the impact of ABCB4 mutations on clinical expression of cholestasis in adult patients. METHODS: We consecutively evaluated 2602 subjects with hepatobiliary disease. Biochemical evidence of a chronic cholestatic profile (CCP) with elevated serum gamma-glutamyltransferase activity or diagnosis of intrahepatic cholestasis of pregnancy (ICP) and juvenile cholelithiasis (JC) were inclusion criteria. The personal/family history of additional cholestatic liver disease (PFH-CLD), which includes ICP, JC, or hormone-induced cholestasis, was investigated. Mutation screening of ABCB4 was carried out in 90 patients with idiopathic chronic cholestasis (ICC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ICP, and JC. RESULTS: Eighty patients had CCP. PSC and ICC patients with PFH-CLD had earlier onset of disease than those without it (p = 0.003 and p = 0.023, respectively). The mutation frequency ranged from 50 % (ICP, JC) to 17.6 % (PBC). Among CCP patients, presence or absence of PFH-CLD was associated with ABCB4 mutations in 26.8 vs 5.1 % (p = 0.013), respectively; in the subset of ICC and PSC patients, the corresponding figures were 44.4 vs 0 % (p = 0.012) and 28.6 vs 8.7 % (p = 0.173). CONCLUSIONS: Cholangiopathies attributable to highly penetrant ABCB4 mutant alleles are identifiable in a substantial proportion of adults that generally have PFH-CLD. In PSC and ICC phenotypes, patients with MDR3 deficiency have early onset of disease.

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70 A more significant effect is attributable to the five mutations (Figs. 2, 3, residues in red) ascribed to type A [p.(A511T), p.(R545C), p.(R590Q), p.(E616K), p.(G811R)]. Login to comment
72 CCP chronic cholestatic profile, NCCP patients without chronic cholestatic profile, PBC primary biliary cirrhosis, PSC primary sclerosing cholangitis, ICP intrahepatic cholestasis of pregnancy, JC juvenile cholelithiasis, AIH autoimmune hepatitis, OS overlap syndrome between AIH and PBC or PSC, ICC idiopathic chronic cholestasis; a with (n = 14) or without (n = 23) other cholangiopathies in the personal/family history (see ''Methods``), b with (n = 9) or without (n = 15) other cholangiopathies in the personal/family history (see ''Methods``), c with (n = 2) or without (n = 2) other cholangiopathies in the personal/family history (see ''Methods``) Table 1 Heterozygous nucleotide changes within the ABCB4 gene identified in 18 adult patients with cholangiopathies and predicted impact on MDR3 Nucleotide changea Involved regions Type of mutation Mutant protein Location on the protein Degree of conservationb Reference genotypesc c.217C[G Exon 4 Missense p.(L73V) TM1 B 7, 21 c.475C[T Exon 6 Non-sense p.(R159X) ICD1 X 8, 14 c.523A[G Exon 6 Missense p.(T175A) ICD1 B 18, 21, 8, 25, 14 c.959C[T Exon 9 Missense p.(S320F) TM5 B 18, 8, 14 c.1529A[G Exon 13 Missense p.(N510S) N-ter NBD B 14 c.1531G[A Exon 13 Missense p.(A511T) N-ter NBD A 8, 14 c.1633C[T Exon 14 Missense p.(R545C) N-ter NBD A 21 c.1769G[A Exon 15 Missense p.(R590Q) N-ter NBD A 8, 13, 14, 25 c.1846G[A Exon 15 Missense p.(E616K) N-ter NBD A This study (JN392435) c.1901G[A Exon 16 Missense p.G634E Linker region B This study (JN392436) c.2431G[C Exon 20 Missense p.(G811R) ICD4 A This study (JN392437) c.2544_2548delATCAT Exon 21 Frameshift p.(S849YfsX24) TM9 X This study (JN392438) c.2576T[G Exon 21 Missense p.(L859W) TM10 B This study (JN392439) c.2844G[C Exon 23 Missense p.(M948I) TM11 B This study (JN392440) c.3541C[T Exon 27 Non-sense p.(Q1181X) C-ter NBD X This study (JN392441) TM transmembrane domain, ICD intracellular domain, N-ter NBD N-terminal nucleotide binding domain, C-ter NBD C-terminal nucleotide binding domain a The mutations were numbered according to GenBank NM_018849 and NP_061337. Login to comment
81 L73V T175A S320F N510S A511T R590Q E616K R545C G634E G811R L859W M948I ...69_SGLPLMMIV_77... ...69_SGLPLMMIV_77... ...66_SGLPLMMIV_74... ...66_SGLPLMMIV_74... ...69_SGLPLMMIV_77... ...69_SGLPLMMIV_77... ...67_SGLPLMMIV_75..... ...63_AGLPLMMLV_71... ...92_LGFPIMTIL_100.. ...59_MSEPLMTVV_67... ...77_GFAMPALTI_85... ...79_ASFPIMSIL_87... ..107_LGMPLMSLV_115.. ...89_AGLPLMSIL_97... ...39_ASDTFMLSL_47... ...39_ASDTFMLSL_47... ...39_AADTYMISL_47... ...28_GIPMLIPLL_36... 171_TELNTRLTD_179... 171_TELNTRLTD_179... 168_TELNTRLTD_176... 168_TELNTRLTD_176... 171_TELNTRLTD_179... 171_TELNTRLTD_179... 169_TELNTRLTD_177... 169_GELNTRLTD_177... 180_GEVVGRMSG_188... 146_GEAASRISA_154.. 164_GEVVGRMSG_172.. 167_GEVVGRMSG_175.. 197_GEITTRITT_205.. 193_GTLATKLFD_201.. 122_GTLLSRITY_130... 122_GTLLSRITY_130... 122_GGLLSRITY_130... 118_GQVISRVIN_126... 586_VIAHRLSTV_594... 586_VIAHRLSTV_594... 583_VIAHRLSTI_591... 583_VIAHRLSTV_591... 586_VIAHRLSTI_594... 586_VIAHRLSTI_594... 584_VIAHRLSTI_592... 584_VIAHRLSTV_592... 595_VVAHRLSTV_603... 561_IVAHRLSTI_569... 579_VIAHRLTTI_587... 582_IVAHRLSTV_590... 621_VIAHRLSTI_629... 608_IIAHRLSTI_616... 534_VIAHRLSTI_542... 534_VIAHRLSTI_542... 534_VIAHRLSTI_542... 531_IVAHRLSTI_539... 316_FWYGSTLVI_324... 316_FWYGSTLVI_324... 313_FWYGSTLVI_321... 313_FWYGSTLVI_321... 316_FWYGSTLVI_324... 316_FWYGSTLVI_324... 314_FWYGSTLVI_322... 314_FWYGTTLVL_322... 325_VWYGGKMIL_333... 291_FWYGAKLVI_299... 309_LWYGSKLVL_317... 312_IWFGGKMIL_320... 342_FWEGGRLLH_350... 338_FYIGVGWVH_346... 267_LYAASFPSV_275... 267_LYAASFPSV_275... 267_LFLASVDSI_275... 263 IGVGAYLAI 271... 506_VKEANAYEFI_515... 506_VKEANAYEFI_515... 503_VKEANAYDFI_512... 503_VKEANAYDFI_512... 506_VKEANAYEFI_515... 504_VKEANAYEFI_513... 504_VKDANAYEFI_513... 504_VKEANAYDFI_513... 515_TELANASKFI_524... 481_AELANAANFI_490... 499_AYLANAARFI_508... 502_TELANAAKFI_511... 541_AKLANAYDFI_550... 528_CKMANAEKFI_537... 454_ARMAYAMDFI_463... 454_ARMAYAMDFI_463... 454_ARQAHAMEFI_463... 451_AKMANAHDFI_460... 541_IAIARALVR_549... 541_IAIARALVR_549... 538_IAIARALVR_546... 538_IAIARALVR_546... 541_IAIARALVR_549... 541_IAIARALVR_549... 539_IAIARALVR_547... 539_IAIARALVR_547... 550_IAVARAILK_558... 516_IAIARAILK_524... 534_VAIARAILK_542... 537_IAIARAILK_545... 576_IAIARAVIS_584... 563_IAIARALVR_571... 489_IAIARALLR_497... 489_IAIARALLR_497... 489_VAIARALLR_497... 486_LSIARIFLN_494... ...612_GSHSELMKK_620... ...612_GSHSELMKK_620... ...609_GSHSELMKK_617... ...609_GSHSELIKK_617... ...612_GSHGELMKK_620... ...612_GNHRELMKK_620... ...610_GSHNELMKK_618... ...610_GNHDELMKE_618... ...621_GSHSELLRD_629... ...587_GSHDELIKD_595... ...605_GTHFDLVQR_613... ...608_GSHSELLKD_616... ...647_GSHNELLDL_655... ...634_GDHRALMAQ_642... ...560_GTHNDLLEH_568... ...560_GTHSELLAQ_568... ...560_GRHADLLAQ_568... ...557_GTHRELIAK_565... 630_MQTSGSQIQ_638... 630_MQTSGSQIQ_638... 627_MQTAGSQIL_635... 627_MQTSGSQIL_635... 630_TQISGSQIQ_638... 630_MQTSGNQTQ_638... 628_MQTSGNQIQ_636... 628_MQTAGNEVE_636... 640_LQEDTKQTE_648... 620_SEVSTSRLK_628... 624_LQEMHQPPP_632... 627_LQEVNKESK_635... 666_QKLSGGEKD_674... 652_AQTFTDAVD_660... 578_MQFGQ----_582... 578_MQFGQ----_582... 578_IQFGE----_582... 575_IQNL-----_578... 807_KNSTGALST_815... 807_KNSTGALST_815... 804_KNSTGALST_812... 806_KNSTGALST_814... 804_KNSTGALST_812... 809_KNSTGALST_817... 806_KNSTGALST_814... 808_KNTTGALTT_816... 825_ENSSGAIGA_833... 797_SHSSGSLGA_805... 835_ENSSGALGA_843... 822_EHSSGAIGA_830... 891_ENTVGAITT_899... 849_QNASGKIST_857... 118_KQSTGTLLS_126... 118_KQSTGTLLS_126... 118_QESTGGLLS_126... 114_NNQVGQVIS_122... 855_QLTLLLLAV_863.... 855_QLTLLLLAV_863.... 852_QLTLLLLSV_860.... 854_QLTLLLLSV_862.... 852_QLTLLLLSV_860.... 857_QLTLLLLVV_865.... 854_QLTLLLLSV_862.... 856_QLTLLLLAI_864.... 873_QLAFIVLAM_881.... 845_KLTLTIMCP_853.... 883_QLALLVLAL_891.... 870_QLALVILVL_878.... 939_KLGLVTLST_947... 897_QMALLIIAI_905.... 166_QLSIILIVL_174.... 166_QLSIILVVL_174.... 166_QLSLVLIVV_174.... 162_KLTLAALFI_170.... 944_SQAFMYFSY_952... 944_SQAFMYFSY_952... 941_SQAFMYFSY_949... 943_SQAFMYFSY_951... 941_SQAFMYFSY_949... 946_SQAFMYFSY_954... 943_SQAFMYFSY_951... 945_TQAMMYFSY_953... 962_SFFVLFSSY_970... 940_SYLMVYLTY_948... 972_SNFVLFGSY_980... 959_SFFLLFSVY_967... 1028_AQGVTFLIN_1036.. 986_ASSVLYLLN_994... 255_IQLIASLAL_263... 255_IQLIASLAL_263... 255_IQMIASLAL_263... 251_INTVTDIGP_259... Hs_MDR3 Pt_MDR3 Mm_MDR3 Rn_MDR3 Bt_MDR3 Cf_MDR3 Md_MDR3 Hs_MDR1 At_MDR Os_MDR Sm_MDR Ptr_MDR Sp_MDR Ce_P-gly Esch-coli_Msba Salm-typh_Msba Vibrio-ch_Msba Staph-au_Sav1866 Hs_MDR3 Pt_MDR3 Mm_MDR3 Rn_MDR3 Bt_MDR3 Cf_MDR3 Md_MDR3 Hs_MDR1 At_MDR Os_MDR Sm_MDR Ptr_MDR Sp_MDR Ce_P-gly Esch-coli_Msba Salm-typh_Msba Vibrio-ch_Msba Staph-au_Sav1866 Fig. 2 Multiple sequence alignment of 18 ABC proteins concerning the amino acid sequences around the 12 ABCB4 missense mutations identified in this study. Login to comment
99 When the 19 patients affected by PBC, AIH, or OS, in whom PFH-CLD was among the enrollment criteria, were excluded from the analysis, the S320F L859W L73V M948I N-ter T175A G811R R545C A511T N510S R590Q E616K G634E C-ter Fig. 3 Ribbon representation of the three-dimensional structure of human MDR3. Login to comment
139 Sex Main diagnosis Age at onset (years) Heterozygous mutation Radical mutationc Concomitant cholangiopathy Notes 20 M PSC 47 p.(G634E) No 39 M PSC 27 p.(R159X) Yes JC 40 M PSC 30 p.(R590Q) Yes JC 24a,b F PSC 23 p.(A511T) ? Login to comment
141 p.(S320F) Yes JC/HIC 16 F PSC 55 p.(R590Q) Yes 7 M ICC 16 p.(R545C) Yes JC Father of patient 72 18a,b M ICC 34 p.(S849YfsX24) Yes JC Family history of JC 49 F ICC 32 p.(G811R) Yes ICP/JC Family history of JC 72 F ICC 12 p.(R545C) Yes ICP/JC Daughter of patient 72 68 F PBC 31 p.(T175A) No ICP 73a F PBC 58 p.(R590Q) Yes JC 75 F PBC 64 p.(L73V) No JC 38 M JC 18 p.(S320F) No 55 M JC 26 p.(Q1181X) Yes 81 F JC 39 p.(R590Q) ? Login to comment