ABCMdb

PMID: 23022423

Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, Ruggiero G, Zampino R, Bertolotti M, Loria P, Carulli L
ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population.
Dig Liver Dis. 2013 Mar;45(3):226-32. doi: 10.1016/j.dld.2012.08.011. Epub 2012 Sep 27., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCB11 p.Gln558His ABCB11 p.Val284Asp ABCB11 p.Pro731Ser Results: Genotyping revealed 11 mutations, 5 of whom were novel variants: 2 localized on ABCB4 (p.I587DfsX603, p.I738LfsX744) and 3 on ABCB11 (p.V284D, p.Q558H, p.P731S). Login to comment 5 ABCB11 p.Val284Asp The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Login to comment 6 ABCB4 p.Asn510Ser Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient. Login to comment 69 ABCB4 p.Thr175Ala ABCB4 p.Leu73Val ABCB4 p.Asn510Ser The p.L73V, the p.T175A and the p.N510S were previously described in literature [12,24]. Login to comment 70 ABCB4 p.Thr175Ala ABCB4 p.Leu73Val ABCB4 p.Asn510Ser The p.L73V, the p.T175A and the p.N510S were previously described in literature [12,24]. Login to comment 86 ABCB4 p.Asn510Ser Sequence analysis showed a heterozygous missense mutation in exon 13 localized at codon 510 (p.N510S) of the MDR3 protein. Login to comment 87 ABCB4 p.Asn510Ser ABCB4 p.Asn510Ser The PSIC score reports the p.N510S mutation as probably damaging for the protein function. Login to comment 88 ABCB4 p.Asn510Ser The PSIC score reports the p.N510S mutation as probably damaging for the protein function. Login to comment 91 ABCB11 p.Gln558His ABCB11 p.Val284Asp ABCB11 p.Pro731Ser ABCB11 mutation analysis Among the six variants identified in the coding sequence of the ABCB11 gene, three (p.V284D, p.Q558H, p.P731S) were new mutations. Login to comment 92 ABCB11 p.Asp482Gly ABCB11 p.Arg698His ABCB11 p.Gln558His ABCB11 p.Glu135Lys ABCB11 p.Val284Asp ABCB11 p.Pro731Ser Variants p.E135K, p.D482G and p.R698H were reported in previous studies [12,25-28]. Login to comment 93 ABCB11 p.Asp482Gly ABCB11 p.Arg698His ABCB11 p.Glu135Lys Variants p.E135K, p.D482G and p.R698H were reported in previous studies [12,25-28]. Login to comment 94 ABCB11 p.Val284Asp The first novel variant (c.851 T > A), localized in exon 6 at position 284 of BSEP protein (p.V284D), was identified in a 30 years old patient (n.7). Login to comment 95 ABCB11 p.Val284Asp The first novel variant (c.851 T > A), localized in exon 6 at position 284 of BSEP protein (p.V284D), was identified in a 30 years old patient (n.7). Login to comment 101 ABCB11 p.Asp482Gly ABCB11 p.Arg698His ABCB11 p.Gln558His ABCB11 p.Glu135Lys ABCB4 p.Thr175Ala ABCB4 p.Leu73Val ABCB11 p.Val284Asp ABCB11 p.Pro731Ser ABCB4 p.Asn510Ser Nucleotide change and effect on protein Location PSIC scores by PolyPhen-2 analysis Reference 1 c.217 C > G (p. L73V) Exon 4 0.489 [12] 2 c.523 A > G (p.T175A) Exon 6 0.774 [12] 3 c.1529 A > G (p.N510S) Exon 13 2.075 [24] 4 c.1758 1759 ins G (p.I587DfsX603) Exon 15 X This study 5 c.2211(+1) G > T (p.I738LfsX744) 5 Intron 17 X This study ABCB11 mutations 6 c.403 G > A (p.E135K) Exon 6 0.502 [26] 7 c.852 T > A (p.V284D) Exon 9 2.175 This study 8 c.1445 A > G (p.D482G) Exon 14 1.364 [26-28] 9 c.1674 G > C (p.Q558H) Exon 15 1.383 This study 10 c.2093 G > A (p.R698H) Exon 18 0.821 [12,25] 11 c.2191 C > T (p. P731S) Exon 19 0.851 This study New mutations are shown in bold. Login to comment 102 ABCB11 p.Asp482Gly ABCB11 p.Arg698His ABCB11 p.Gln558His ABCB11 p.Glu135Lys ABCB4 p.Thr175Ala ABCB4 p.Leu73Val ABCB11 p.Val284Asp ABCB11 p.Pro731Ser ABCB4 p.Asn510Ser Nucleotide change and effect on protein Location PSIC scores by PolyPhen-2 analysis Reference 1 c.217 C > G (p. L73V) Exon 4 0.489 [12] 2 c.523 A > G (p.T175A) Exon 6 0.774 [12] 3 c.1529 A > G (p.N510S) Exon 13 2.075 [24] 4 c.1758 1759 ins G (p.I587DfsX603) Exon 15 X This study 5 c.2211(+1) G > T (p.I738LfsX744) 5 Intron 17 X This study ABCB11 mutations 6 c.403 G > A (p.E135K) Exon 6 0.502 [26] 7 c.852 T > A (p.V284D) Exon 9 2.175 This study 8 c.1445 A > G (p.D482G) Exon 14 1.364 [26-28] 9 c.1674 G > C (p.Q558H) Exon 15 1.383 This study 10 c.2093 G > A (p.R698H) Exon 18 0.821 [12,25] 11 c.2191 C > T (p. P731S) Exon 19 0.851 This study New mutations are shown in bold. Login to comment 106 ABCB11 p.Gln558His Sequence analysis of DNA identified a missense mutation on exon 15 (p.Q558H). Login to comment 107 ABCB11 p.Gln558His ABCB11 p.Pro731Ser The last new variant (p.P731S) on exon 19 was identified in a 35 years old patient. Login to comment 108 ABCB11 p.Pro731Ser The last new variant (p.P731S) on exon 19 was identified in a 35 years old patient. Login to comment 110 ABCB11 p.Asp482Gly ABCB11 p.Glu135Lys ABCB11 p.Glu135Lys The already described mutations p.E135K and p.D482G are associated with two similar phenotypes (Table 4), except for the higher levels of serum bile acids in the patient carrying the p.E135K variant. Login to comment 111 ABCB11 p.Asp482Gly ABCB11 p.Glu135Lys ABCB11 p.Glu135Lys The already described mutations p.E135K and p.D482G are associated with two similar phenotypes (Table 4), except for the higher levels of serum bile acids in the patient carrying the p.E135K variant. Login to comment 112 ABCB11 p.Arg698His Finally, the variant p.R698H is referred as a polymorphism [12,25], however it was not detected in any of the 100 control subjects screened in our study. Login to comment 113 ABCB11 p.Arg698His Finally, the variant p.R698H is referred as a polymorphism [12,25], however it was not detected in any of the 100 control subjects screened in our study. Login to comment 127 ABCB4 p.Thr175Ala ABCB4 p.Leu73Val ABCB4 p.Asn510Ser The first novel mutation detected on the ABCB4 gene is a frameshift mutation (p.I587DfsX603) and predicts the formation of Table 3 Clinical details of patients with ABCB4 mutations. Parameters Patient 1 L73V Patient 2 T175A Patient 3 N510S Patient 4 I587DfsX603 Patient 5 I738LfsX744 Onset of pruritus 3rd trimester 3rd trimester 3rd trimester 3rd trimester 2nd trimester Parity 3 2 2 2 1 Previous ICP Yes No Yes Yes Yes Peak of AST (U/L) 82 79 133 204 43 Peak of ALT (U/L) 123 156 238 382 76 Peak of Bilirubin (mg/dL) 0.14 0.81 Nd 2.8 2.07 Peak of GGT (U/L) 6 25 Nd 67 54 Total bile acids (òe;mol/L) 28.7 41 128 Nd 114.5 Delivery Caesarean section (37w+5 )a Caesarean section (36w)a Caesarean section (39w)a Caesarean section (32w)a Caesarean section (33w+4 )a Cholelithiasis No No No Yes No UDCA therapy Yes No No No Yes AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: ॹ-glutamyl transpeptidase; Nd: not determined. a Caesarean section due to pregnancy complications related to ICP (foetal distress and/or intolerable pruritus and/or persistent elevation of AST and ALT). Login to comment 128 ABCB4 p.Thr175Ala ABCB4 p.Leu73Val ABCB4 p.Asn510Ser The first novel mutation detected on the ABCB4 gene is a frameshift mutation (p.I587DfsX603) and predicts the formation of Table 3 Clinical details of patients with ABCB4 mutations. Parameters Patient 1 L73V Patient 2 T175A Patient 3 N510S Patient 4 I587DfsX603 Patient 5 I738LfsX744 Onset of pruritus 3rd trimester 3rd trimester 3rd trimester 3rd trimester 2nd trimester Parity 3 2 2 2 1 Previous ICP Yes No Yes Yes Yes Peak of AST (U/L) 82 79 133 204 43 Peak of ALT (U/L) 123 156 238 382 76 Peak of Bilirubin (mg/dL) 0.14 0.81 Nd 2.8 2.07 Peak of GGT (U/L) 6 25 Nd 67 54 Total bile acids (òe;mol/L) 28.7 41 128 Nd 114.5 Delivery Caesarean section (37w+5 )a Caesarean section (36w)a Caesarean section (39w)a Caesarean section (32w)a Caesarean section (33w+4 )a Cholelithiasis No No No Yes No UDCA therapy Yes No No No Yes AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: ॹ-glutamyl transpeptidase; Nd: not determined. a Caesarean section due to pregnancy complications related to ICP (foetal distress and/or intolerable pruritus and/or persistent elevation of AST and ALT). Login to comment 129 ABCB11 p.Asp482Gly ABCB11 p.Arg698His ABCB11 p.Gln558His ABCB11 p.Glu135Lys ABCB11 p.Val284Asp ABCB11 p.Pro731Ser Table 4 Clinical details of patients with ABCB11 mutations. Parameters Patient 6 E135K Patient7 V284D Patient 8 D482G Patient 9 Q558H Patient 10 R698H Patient 11 P731S Onset of pruritus 3rd trimester 2nd trimester 3rd trimester 2nd trimester 2nd trimester 3rd trimester Parity 2 1 2 2 2 2 Previous ICP Yes Yes Yes No Yes Yes Peak of AST (U/L) 24 92 29 125 244 105 Peak of ALT (U/L) 26 215 37 315 514 198 Peak of Bilirubin (mg/dL) 0.53 0.49 Nd 0.36 0.3 0.46 Peak of GGT (U/L) 7 25 Nd 23 14 16 Total bile acids (òe;mol/L) 93.6 112.4 28 Nd 20.4 23.4 Delivery Induction of labour (36w+4 )a Caesarean section (38w)a Induction of labour (38w+4 )a Caesarean section (36w)a Caesarean section (38w)a Induction of labour (38w) Cholelithiasis No No No No No No UDCA therapy Yes Yes No Yes Yes Yes AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: ॹ-glutamyl transpeptidase; Nd: not determined. a Caesarean section or induction of labour due to pregnancy complications related to ICP (foetal distress and/or intolerable pruritus and/or persistent elevation of AST and ALT). Login to comment 130 ABCB11 p.Asp482Gly ABCB11 p.Arg698His ABCB11 p.Gln558His ABCB11 p.Glu135Lys ABCB11 p.Val284Asp ABCB11 p.Pro731Ser Table 4 Clinical details of patients with ABCB11 mutations. Parameters Patient 6 E135K Patient7 V284D Patient 8 D482G Patient 9 Q558H Patient 10 R698H Patient 11 P731S Onset of pruritus 3rd trimester 2nd trimester 3rd trimester 2nd trimester 2nd trimester 3rd trimester Parity 2 1 2 2 2 2 Previous ICP Yes Yes Yes No Yes Yes Peak of AST (U/L) 24 92 29 125 244 105 Peak of ALT (U/L) 26 215 37 315 514 198 Peak of Bilirubin (mg/dL) 0.53 0.49 Nd 0.36 0.3 0.46 Peak of GGT (U/L) 7 25 Nd 23 14 16 Total bile acids (òe;mol/L) 93.6 112.4 28 Nd 20.4 23.4 Delivery Induction of labour (36w+4 )a Caesarean section (38w)a Induction of labour (38w+4 )a Caesarean section (36w)a Caesarean section (38w)a Induction of labour (38w) Cholelithiasis No No No No No No UDCA therapy Yes Yes No Yes Yes Yes AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: ॹ-glutamyl transpeptidase; Nd: not determined. a Caesarean section or induction of labour due to pregnancy complications related to ICP (foetal distress and/or intolerable pruritus and/or persistent elevation of AST and ALT). Login to comment 137 ABCB11 p.Val444Ala Moreover, the remarkable increase in patient`s serum bile acids could be explained considering that a decrease in the flippase activity of MDR3 might induce a modification in the lipid composition of the canalicular membrane, consequently altering BSEP function; besides, the presence of the p.V444A polymorphism in one allele of the ABCB11 gene might play an additional role. Login to comment 138 ABCB11 p.Val444Ala ABCB4 p.Asn510Ser The missense variant p.N510S was found for the first time in a patients with ICP in this study. Login to comment 139 ABCB4 p.Asn510Ser The missense variant p.N510S was found for the first time in a patients with ICP in this study. Login to comment 143 ABCB11 p.Pro731Ser Variant p.P731S, classified as benign by PolyPhen-2 algorithm, is associated with a mild cholestatic phenotype. Login to comment 144 ABCB11 p.Pro731Ser Variant p.P731S, classified as benign by PolyPhen-2 algorithm, is associated with a mild cholestatic phenotype. Login to comment 145 ABCB11 p.Val284Asp The p.V284D mutation determines a substitution of a valine with an aspartic acid; the different nature of the aminoacids and its localization in the intracellular loop between transmembrane domain 4 and 5 might lead to an alteration in protein conformation and/or function. Login to comment 146 ABCB11 p.Val284Ala ABCB11 p.Val284Ala ABCB11 p.Val284Leu ABCB11 p.Val284Leu ABCB11 p.Val284Asp A further demonstration of the importance of the conservation of this valine in the evolution comes from previous evidence which identified other substitutions in the same position (p.V284L and p.V284A) [12,25,29] and analysed them by the mean of an in vitro minigene system reporting no protein formation for the variant p.V284L and an increased amount of protein for the SNP p.V284A [26]. Login to comment 147 ABCB11 p.Val284Ala ABCB11 p.Val284Ala ABCB11 p.Val284Leu ABCB11 p.Val284Leu ABCB11 p.Gln558His The p.Q558H missense mutation is localised in the nucleotide binding domain1 at the level of the ABC signature motif; because this represents a functional domain, the mutation is likely to alter protein stability. Login to comment 148 ABCB11 p.Gln558His The p.Q558H missense mutation is localised in the nucleotide binding domain1 at the level of the ABC signature motif; because this represents a functional domain, the mutation is likely to alter protein stability. Login to comment 150 ABCB11 p.Val444Ala Our study also takes into consideration a possible involvement of some polymorphisms in the development of ICP: variants p.V444A (c.1331 T > C) and p.A1028A (c.3084 A > G) in ABCB11 and variant p.N168N (c.504 C > T) in ABCB4 are frequently present in our patients (88%, 76% and 79%, respectively). Login to comment 151 ABCB11 p.Val444Ala ABCB11 p.Val444Ala Variant p.V444A is localised in a functional domain (nucleotide binding domain 1) of the protein and it was correlated, in previous reports in the literature, with a considerable number of possible BSEP alterations [30]. Login to comment 152 ABCB11 p.Val444Ala Variant p.V444A is localised in a functional domain (nucleotide binding domain 1) of the protein and it was correlated, in previous reports in the literature, with a considerable number of possible BSEP alterations [30]. Login to comment 156 ABCB11 p.Val444Ala Anyway, considering the V444A polymorphism, we cannot exclude it could represent a susceptibility factor for ICP, as it was associated with 9 of the 11 mutations identified and it was found in 30 of the 33 ICP patients screened, 22 of whom did not present any mutation on ABCB4 or ABCB11. Login to comment 157 ABCB11 p.Val444Ala Anyway, considering the V444A polymorphism, we cannot exclude it could represent a susceptibility factor for ICP, as it was associated with 9 of the 11 mutations identified and it was found in 30 of the 33 ICP patients screened, 22 of whom did not present any mutation on ABCB4 or ABCB11. Login to comment 163 ABCB11 p.Val444Ala ABCB4 p.Arg652Gly However, the absence of any disease-causing mutation in 22/33 patients, apart from the presence of the p.V444A and p.R652G polymorphisms (data not shown), suggest that other genes or other factors (comorbility) may play a role in the aetiology of ICP. Login to comment 164 ABCB11 p.Val444Ala ABCB4 p.Arg652Gly However, the absence of any disease-causing mutation in 22/33 patients, apart from the presence of the p.V444A and p.R652G polymorphisms (data not shown), suggest that other genes or other factors (comorbility) may play a role in the aetiology of ICP. Login to comment