Article

ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy.

CHRU de Tours, France.
Journal of Medical Genetics (Impact Factor: 5.7). 08/2009; 46(10):711-5. DOI: 10.1136/jmg.2009.067397
Source: PubMed

ABSTRACT 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).
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.
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).
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.

0 Bookmarks
 · 
110 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Liver disorders occurring during pregnancy may be specifically pregnancy-related, or may be due to an intercurrent or chronic liver disease, which may present in anyone, pregnant or not. This review focuses on the liver diseases unique to pregnancy. Hyperemesis gravidarum, which occurs during early pregnancy, may be associated with liver dysfunction. Intrahepatic cholestasis of pregnancy typically occurs during the second or third trimester. Pruritus and the associated biological signs of cholestasis improve rapidly after delivery. Mutations in gene encoding biliary transporters, especially ABCB4 encoding the multidrug resistance 3 protein, have been found to be associated with this complex disease. Ursodeoxycholic acid is currently the most effective medical treatment in improving pruritus and liver tests. Pre-eclampsia, which presents in late pregnancy frequently involves the liver, and HELLP syndrome (Hemolysis-Elevated Liver enzymes-Low Platelets) is a life-threatening complication. Prognosis of acute fatty liver of pregnancy has been radically transformed by early delivery, and clinicians must have a high index of suspicion for this condition when a woman presents nausea or vomiting, epigastric pain, jaundice, or polyuria-polydipsia during the third trimester. Acute fatty liver of pregnancy has been found to be associated with a defect of long-chain 3-hydroxyacyl coenzyme A dehydrogenase in the fetus, and mothers and their offspring should undergo DNA testing at least for the main associated genetic mutation (c.1528G>C).
    Gastroentérologie Clinique et Biologique 02/2011; 35(3):182-93. · 0.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Genetic alterations in the ATP-binding cassette subfamily B member 4 (ABCB4) and ATP-binding cassette subfamily B member 11 (ABCB11) have been associated to the onset of intrahepatic cholestasis of pregnancy (ICP) in predisposed women. AIMS: To identify new and/or frequent ABCB4 and ABCB11 genes variants in a cohort of Italian patients with ICP and to evaluate the possible pathogenetic role for the novel mutations identified. METHODS: DNA of 33 unrelated Italian women with obstetric cholestasis were screened for mutations in the entire coding sequence of ABCB4 and ABCB11 genes. Polymerase chain reaction and automated sequencing was performed on the 27 coding exons of both genes. 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). The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient. CONCLUSIONS: Our data support the hypothesis of a significant involvement of ABCB4 mutations in the onset of ICP, but also confirm an important role for ABCB11 mutations in increasing the susceptibility to cholestasis of pregnancy.
    Digestive and Liver Disease 09/2012; · 3.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abnormalities of liver function (notably rise in alkaline phosphatase and fall in serum albumin) are common in normal pregnancy, whereas rise in serum bilirubin and aminotransferase suggest either exacerbation of underlying pre-existing liver disease, liver disease related to pregnancy or liver disease unrelated to pregnancy. Pregnant women appear to have a worse outcome when infected with Hepatitis E virus. Liver diseases associated with pregnancy include abnormalities associated hyperemesis gravidarum, acute fatty liver disease, pre-eclampsia, cholestasis of pregnancy and HELLP syndrome. Prompt investigation and diagnosis is important in ensuring a successful maternal and foetal outcome. In general, prompt delivery is the treatment of choice for acute fatty liver, pre-eclampsia and HELLP syndrome and ursodeoxycholic acid is used for cholestasis of pregnancy although it is not licenced for this indication.
    Best practice & research. Clinical gastroenterology 08/2013; 27(4):565-575. · 2.48 Impact Factor