ABCMdb

PMID: 18083082

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., [PubMed]

Sentences

No. Mutations Sentence Comment

10 ABCB4 p.Arg590Gln ABCB4 p.Glu528Asp ABCB4 p.Arg652Gly ABCB4 p.Gly536Ala ABCB4 p.Arg549His 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 ABCB4 p.Arg590Gln ABCB4 p.Arg652Gly ABCB4 p.Gly536Arg ABCB4 p.Thr667Ile 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 55 ABCB4 p.Arg590Gln ABCB4 p.Arg652Gly ABCB4 p.Gly536Arg ABCB4 p.Thr667Ile 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 56 ABCB4 p.Gly536Arg Sequence analysis of exon 14 revealed the three heterozygous mutations previously described: (1) the GAG-GAC mutation in codon 528, resulting in the substitution of the wild-type glutamic acid with a mutant aspartic acid (E528D); (2) a CGC-CAC mutation in codon 549, resulting in the substitution of the wild-type arginine with mutant histidine (R549H); (3) the GGG-AGG mutation in codon 536 resulting in the substitution of the wild-type glycine with mutant arginine (G536R) (Table 3). Login to comment 57 ABCB4 p.Arg590Gln ABCB4 p.Gly536Arg 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 ABCB4 p.Arg590Gln ABCB4 p.Arg652Gly ABCB4 p.Thr667Ile 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 59 ABCB4 p.Arg652Gly ABCB4 p.Arg652Gly ABCB4 p.Thr667Ile R652G variant in exon 16 occurred in two patients. Login to comment 60 ABCB4 p.Arg652Gly R652G variant in exon 16 occurred in two patients. Login to comment 80 ABCB4 p.Arg590Gln ABCB4 p.Glu528Asp ABCB4 p.Arg652Gly ABCB4 p.Arg652Gly ABCB4 p.Arg549His ABCB4 p.Gly536Arg ABCB4 p.Thr667Ile 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 81 ABCB4 p.Arg590Gln ABCB4 p.Glu528Asp ABCB4 p.Arg652Gly ABCB4 p.Arg652Gly ABCB4 p.Arg549His ABCB4 p.Gly536Arg ABCB4 p.Thr667Ile 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 90 ABCB4 p.Ser320Phe In a recent reported case of severe ICP in a woman of Moroccan descent [21], gene sequencing revealed a homozygous MDR3 mutation (S320F). Login to comment 91 ABCB11 p.Val444Ala ABCB4 p.Ser320Phe The patient was also homozygous for the common BSEP polymorphism V444A. Login to comment 92 ABCB11 p.Val444Ala The patient was also homozygous for the common BSEP polymorphism V444A. Login to comment