ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy

Müllenbach, Roman; Linton, K J; Wiltshire, Steven; Elias, ER; McCarthy, Michele; Williamson, C

doi:10.1016/s0168-8278(03)80114-9

Cited by 36 publications

(44 citation statements)

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“…Affected women have genetic variation in the biliary transporters (ABCB4 and ABCB11) and nuclear receptors that influence bile acid (BA) homeostasis (10,11,(13)(14)(15)(16). The phenotype of ICP is likely to be caused by pathologically elevated levels of reproductive hormone metabolites in genetically predisposed women (12,(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Papacleovoulou¹,

Abu‐Hayyeh²,

Nikolopoulou³

et al. 2013

J. Clin. Invest.

107

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The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.

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Section: Introductionmentioning

confidence: 99%

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Papacleovoulou¹,

Abu‐Hayyeh²,

Nikolopoulou³

et al. 2013

J. Clin. Invest.

107

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“…Mutations in BSEP, MDR3 and FIC1 have been identified in children with congenital cholestasis, [6][7][8] and MDR3 mutations have been identified in mothers with obstetric cholestasis. [9][10][11] Other genes of interest include the hepatic sinusoidal transporters ( Ursodeoxycholic acid (UDCA) and dexamethasone are clinically useful in OC, and we have shown that they protect neonatal rat cardiomyocytes from the arrhythmogenic effects of taurocholate. 12 UDCA induces hepatic expression of MRP2, which encodes an active transporter of anionic conjugates including bile acids.…”

Section: Introductionmentioning

confidence: 99%

Basic science: Genes encoding bile acid, phospholipid and anion transporters are expressed in a human fetal cardiomyocyte culture

Gorelik

Patel

Ng'andwe

et al. 2006

BJOG

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Objectives To establish a human fetal cardiomyocyte culture and to investigate whether the genes that encode transporters that may influence influx or efflux of bile acids are expressed in human fetal cardiomyocytes. Design Laboratory study. Setting Imperial College London. Sample Six fetal hearts were obtained at the time of termination of pregnancy at 12–13 weeks of gestation and used to generate primary human cardiomyocyte cultures. Methods To confirm the presence of cardiomyocytes, the cells were incubated with monoclonal antibodies to sarcomeric α‐actinin and anticardiac myosin heavy chain. Real‐time reverse transcription polymerase chain reaction was used to establish whether transcripts of genes that may influence bile acid transport are present in the culture (NTCP, BSEP, MDR3, FIC1, MRP2, MRP3, OATP‐A, OATP‐C, OATP‐D, OATP‐E) and whether taurocholate administration alters messenger RNA (mRNA) expression. Main outcome measures Relative mRNA expression of genes of interest. Results Real‐time polymerase chain reaction demonstrated the presence of mRNA for BSEP, MDR3, FIC1, OATP‐C, OATP‐D and OATP‐E in fetal heart. Four transcripts remained in the cardiomyocyte culture (BSEP, MDR3, FIC1 and OATP‐D), and we demonstrated the influence of taurocholate on gene expression. Conclusions We have developed an in vitro model of the fetal heart that may be used for studies of the cardiac effect of endobiotics, e.g. bile acids, or of specific agents that may be used to treat the mother or fetus in pregnancy.

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“…Heterozygous ABCB4 mutations were also identified in up to 15% of women suffering from ICP. 12,20,[21][22][23][24][25][26][27][28][29][30][31] ICP is a reversible form of cholestasis that may develop in the third trimester of pregnancy, usually rapidly resolves after delivery and recurs in 45-70% of subsequent pregnancies. 27 The main symptoms are pruritus and, to a lesser extent, jaundice.…”

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confidence: 99%

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

et al. 2011

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The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptivesinduced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of the LPAC patients and in 27% (16/59) of the ICP/CIC patients. High-resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of the LPAC patients, and in 2% (1/59) of the ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.

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ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy

Cited by 36 publications

References 0 publications

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Maternal cholestasis during pregnancy programs metabolic disease in offspring

Basic science: Genes encoding bile acid, phospholipid and anion transporters are expressed in a human fetal cardiomyocyte culture

First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis

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