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

CHRU de Tours, France.
Journal of Medical Genetics (Impact Factor: 6.34). 08/2009; 46(10):711-5. DOI: 10.1136/jmg.2009.067397
Source: PubMed


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.

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    • "The MDR3 mutation is located on chromosome 7q21.1 and has been identified in 15% of causes of ICP [10]. 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 [15]. Abnormal placental transport of bile acid from the fetal to maternal circulation, increased maternal levels of bile acid and immaturity of fetal transport systems may all contribute to increased fetal levels of bile acid in ICP [3]. "
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    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.
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    • "Carriers of α-1-antitrypsin (AAT) deficiency can also be susceptible to COPD (Hersh et al., 2004; Poller et al., 1990). Interestingly, even such common traits as age-related macular degeneration (AMD) and carpal tunnel syndrome are associated with heterozygous carrier status for mutations in ABCA4, the gene responsible for Stargardt macular dystrophy (Bacq et al., 2009), and Charcot-Marie-Tooth neuropathy genes (Lupski et al., 2010), respectively (Figures 2C and 2D). In the latter case, haploinsufficiency due to either heterozygous SNV (Lupski et al., 2010) or heterozygous CNV (Del Colle et al., 2003) can convey the trait. "
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