ABCMdb

PMID: 19584064

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., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCB4 p.Arg590Gln ABCB4 p.Thr775Met ABCB4 p.Ser320Phe 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 ABCB4 p.Arg590Gln 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 8 ABCB4 p.Arg652Gly The chromosomal frequency of the p.Arg652Gly variant did not differ between the ICP and control group (p = 0.40). Login to comment 48 ABCB4 p.Arg590Gln ABCB4 p.Ser320Phe 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 ABCB4 p.Arg590Gln 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 ABCB4 p.Arg590Gln 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 51 ABCB4 p.Thr775Met A missense mutation (c.2324C.T, p.Thr775Met) was detected in exon 19 in one heterozygous patient and was absent in controls. Login to comment 55 ABCB4 p.Arg652Gly The sequence variant c.1954A.G, p.Arg652Gly was detected in three heterozygous patients with ICP, and in nine heterozygous and one homozygous control women. Login to comment 56 ABCB4 p.Arg652Gly The distribution of the p.Arg652Gly alleles was not significantly different between the ICP and control group. Login to comment 66 ABCB4 p.Arg590Gln ABCB4 p.Thr775Met ABCB4 p.Ser320Phe 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 68 ABCB4 p.Ser320Phe The p.Ser320Phe mutation has been described in homozygous patients with ICP16 21 and was absent in our control group. Login to comment 70 ABCB4 p.Arg590Gln The allele distribution of p.Arg590Gln detected in exon 15 was significantly different between patients with ICP and controls. Login to comment 71 ABCB4 p.Arg590Gln We found two women homozygous for p.Arg590Gln in the ICP group and none in the control group. Login to comment 72 ABCB4 p.Arg590Gln 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 ABCB4 p.Arg590Gln This haplotype reveals a probable founder effect for this p.Arg590Gln mutation. Login to comment 74 ABCB4 p.Arg590Gln ABCB4 p.Arg590Gln ABCB4 p.Thr775Met ABCB4 p.Ser320Phe ABCB4 p.Arg652Gly Furthermore, Arg590 is well conserved during evolution (fig 1), and the missense mutation p.Arg590Gln is localised in the first ATP-binding domain of the ABCB4 protein, where it substitutes a basic amino acid for a Table 3 Allele frequencies of ABCB4 genomic variants in 50 patients with intrahepatic cholestasis of pregnancy (100 chromosomes) and 107 controls (214 chromosomes) Genomic variant Exon Allele identification ICP (n (%)) Controls (n (%)) p Value Deduced effect Protein domain c.175 C.T 4 C 86 (86) 180 (84.1) 0.66 Silent T 14 (14) 34 (15.9) c.462 C.T 6 C 99 (99) 214 (100) 0.14 p.Arg144Stop (nonsense) Intracytoplasmic first loopT 1 (1) 0 (0) c.504 T.C 6 T 68 (68) 115 (53.7) 0.017 Silent C 32 (32) 99 (46.3) c.711 A.T 8 A 86 (86) 176 (82.2) 0.40 Silent T 14 (14) 38 (17.8) c.959 C.T 9 C 99 (99) 214 (100) 0.14 p.Ser320Phe (missense) TM5 T 1 (1) 0 (0) c.1769 G.A 15 G 93 (93) 213 (99.5) 0.0017 p.Arg590Gln (missense) NBD1 A 7 (7) 1 (0.5) c.1954 A.G 16 A 97 (97) 202 (94.4) 0.40 p.Arg652Gly (missense) NBD1 G 3 (3) 12 (5.6) c.2324 C.T 19 C 99 (99) 214 (100) 0.32 p.Thr775Met (missense) TM8 T 1 (1) 0 (0) ICP, intrahepatic cholestasis of pregnancy; NBD, nucleotide-binding domain; TM, transmembrane domain; n, number of chromosomes. Login to comment 77 ABCB4 p.Thr775Met ABCB4 p.Thr775Met The heterozygous status for the missense p.Thr775Met mutation that we found in one patient with ICP has been reported in a woman in a control group.16 A deleterious effect of the p.Thr775Met allele may, however, be possible because of its localisation in a transmembrane domain, which is important for substrate specificity.9 Thr775 is conserved in mammals, and a cysteine is present in fish (fig 1). Login to comment 78 ABCB4 p.Thr775Met The p.Thr775Met mutation leads to substitution of a small polar amino acid for a large non-polar one. Login to comment 79 ABCB4 p.Arg652Gly The chromosomal frequency of the p.Arg652Gly variant was not significantly different between patients with ICP and controls. Login to comment 90 ABCB4 p.Arg652Gly No ABCB4 mutation was found in these three patients, except the p.Arg652Gly variant, considered to be a neutral polymorphism, which was found in one of them. Login to comment 94 ABCB4 p.Arg590Gln ABCB4 p.Arg590Gln ABCB4 p.Arg590Gln ABCB4 p.Arg590Gln ABCB4 p.Arg590Gln ABCB4 p.Thr775Met ABCB4 p.Ser320Phe 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