Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy

Floreani, Annarosa; Carderi, I.; Paternoster, Delia Maria; Soardo, Giorgio; Azzaroli, Francesco; Esposito, W.; Montagnani, Marco; Marchesoni, D.; Variola, Angela; Rizzotto, E. Rosa; Braghin, C.; Mazzella, Giuseppe

doi:10.1016/j.dld.2007.10.016

Cited by 66 publications

(47 citation statements)

References 25 publications

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“…77 Multiple mutations in MDR3 (multidrug resistance protein 3) gene have been demonstrated in a minority of these patients. 78 Increased risk of cholestasis in these patients when exposed to female sex hormones, suggest a hormonal influence to the pathogenesis. 79,80 Liver dysfunction is usually mild, and typical presentation in 2nd half of pregnancy does not require an extensive evaluation, except USG abdomen to rule out an obstructed biliary system, prior to a presumptive diagnosis.…”

Section: Intrahepatic Cholestasis Of Pregnancy (Icp)mentioning

confidence: 99%

Pregnancy-Related Liver Disorders

Goel

Jamwal

Ramachandran

et al. 2014

Journal of Clinical and Experimental Hepatology

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Pregnancy-related liver disorders accounted for 8% of all maternal deaths at our center from 1999 to 2011. Of the three pregnancy-related liver disorders (acute fatty liver of pregnancy (AFLP), HELLP (Hemolysis, elevated liver enzymes, low platelets) syndrome and pre-eclamptic liver dysfunction, which can lead to adverse maternal and fetal outcome, AFLP is most typically under -diagnosed. Risk of maternal death can be minimised by timely recognition and early/aggressive multi-specialty management of these conditions. Urgent termination of pregnancy remains the cornerstone of therapy for some of these life threatening disorders, but recent advancements in our understanding help us in better overall management of these patients. This review focuses on various aspects of pregnancy-related liver disorders. ( J CLIN EXP HEPATOL 2014;4:151-162) A ny liver disorder can occur co-incidentally in pregnancy. Pregnancy can also occur in a patient with pre-existent chronic liver disorder/portal hypertension. In addition, liver dysfunction in pregnancy can also be secondary to pregnancy (i.e. pregnancy-related liver disorders). The 5 pregnancy-related liver disorders-acute fatty liver of pregnancy (AFLP), HELLP syndrome (hemolysis, elevated liver enzymes and low platelets), pre-eclamptic liver dysfunction, intrahepatic cholestasis of pregnancy (ICP) and hyperemesis gravidarum-occur in different gestational time periods.

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Section: Intrahepatic Cholestasis Of Pregnancy (Icp)mentioning

confidence: 99%

Pregnancy-Related Liver Disorders

Goel

Jamwal

Ramachandran

et al. 2014

Journal of Clinical and Experimental Hepatology

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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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“…Since the identification of ABCB4-associated diseases, a growing number of mutations have been reported. [16][17][18] However, it remains unclear how mutations identified from genetics studies affect ABCB4 expression. If it is clear that frame-shift mutations introduce premature stop codons and lead to nonfunctional truncated mutants, missense mutations may affect the protein in different ways.…”

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confidence: 99%

A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature

et al. 2008

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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease characterized by early onset of cholestasis that leads to cirrhosis and liver failure before adulthood. PFIC3 may be improved by chronic administration of ursodeoxycholic acid, although in many cases liver transplantation is the only therapy. The disease is caused by mutations of the adenosine triphosphate (ATP)-binding cassette, sub-family B, member 4 (ABCB4) [multidrug resistance 3 (MDR3)] gene encoding a specific hepatocellular canalicular transporter involved in biliary phosphatidylcholine secretion. Several mutations have been reported; however, the effect of individual mutations has not been investigated. ABCB4 is highly homologous to ATP-binding cassette, sub-family B, member 1 (ABCB1) (MDR1), the multidrug transporter responsible for drug resistance of cancer cells. We have studied the effect of mutation I541F localized to the first nucleotide-binding domain, which is highly conserved between ABCB4 and ABCB1. Plasmids encoding the wild-type human ABCB4 or rat ABCB1-green fluorescing protein (GFP) construct, and corresponding I541F-mutants, were expressed in hepatocellular carcinoma, human (HepG2) and Madin-Darby canine kidney (MDCK) cells. Expression studies showed that ABCB4 was localized at the bile canalicular membrane in HepG2 cells and at the apical surface in MDCK cells, whereas the I541F mutant was intracellular. In MDCK cells, ABCB1-I541F also accumulated intracellularly in compartments, which were identified as the endoplasmic reticulum and cis-Golgi, and remained partially endoH-sensitive. After shifting cells to 27°C, ABCB1-I541F was expressed at the apical cell surface in a mature and active form. Similarly, ABCB4 was significantly trafficked to the membrane of bile canaliculi in HepG2 cells. Conclusion: Mutation I541F causes mislocalization of both ABCB4 and ABCB1. Intracellular retention of ABCB4-I541F can explain the disease in PFIC3 patients bearing this mutation. The observation that plasma membrane expression and activity can be rescued by low temperature opens perspectives to develop novel therapies for the treatment of PFIC3. (HEPATOLOGY 2009;49:1218-1227

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Hepatobiliary phospholipid transporter ABCB4, MDR3 gene variants in a large cohort of Italian women with intrahepatic cholestasis of pregnancy

Cited by 66 publications

References 25 publications

Pregnancy-Related Liver Disorders

Pregnancy-Related Liver Disorders

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

A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature

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