Novel compound heterozygous <i>ABCC2</i> variants in patients with Dubin‐Johnson syndrome and intrahepatic cholestasis of pregnancy

Huynh, Minh Tuan; Chrétien, Yves; Grison, S.; Delaunay, Jean; Lascols, Olivier; Tran, Cong Toai; Goria, Odile; Ramond, Marie-José; Barbu, Véronique

doi:10.1111/cge.13420

Cited by 6 publications

(1 citation statement)

References 5 publications

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“…To date, individual BAs in individuals with Mrp2 mutations have not been analyzed. Moreover, several studies have provided evidence that ABCC2 variants are associated with an increased risk of ICP and cholestasis induced by estrogen contraceptives ( Sookoian et al, 2008 ; Dixon et al, 2017 ; Kularatnam et al, 2017 ; Huynh et al, 2018 ; Corpechot et al, 2020 ), albeit a contradictory report also exists ( Meier et al, 2008 ). The exact mechanisms whereby Mrp2 deficiency modifies BA metabolomics and its relationship to ICP have been poorly studied.…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

et al. 2022

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Multidrug resistance-associated protein 2 (Mrp2) mediates biliary secretion of anionic endobiotics and xenobiotics. Genetic alteration of Mrp2 leads to conjugated hyperbilirubinemia and predisposes to the development of intrahepatic cholestasis of pregnancy (ICP), characterized by increased plasma bile acids (BAs) due to mechanisms that are incompletely understood. Therefore, this study aimed to characterize BA metabolomics during experimental Mrp2 deficiency and ICP. ICP was modeled by ethinylestradiol (EE) administration to Mrp2-deficient (TR) rats and their wild-type (WT) controls. Spectra of BAs were analyzed in plasma, bile, and stool using an advanced liquid chromatography–mass spectrometry (LC–MS) method. Changes in BA-related genes and proteins were analyzed in the liver and intestine. Vehicle-administered TR rats demonstrated higher plasma BA concentrations consistent with reduced BA biliary secretion and increased BA efflux from hepatocytes to blood via upregulated multidrug resistance-associated protein 3 (Mrp3) and multidrug resistance-associated protein 4 (Mrp4) transporters. TR rats also showed a decrease in intestinal BA reabsorption due to reduced ileal sodium/bile acid cotransporter (Asbt) expression. Analysis of regulatory mechanisms indicated that activation of the hepatic constitutive androstane receptor (CAR)-Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by accumulating bilirubin may be responsible for changes in BA metabolomics in TR rats. Ethinylestradiol administration to TR rats further increased plasma BA concentrations as a result of reduced BA uptake and increased efflux via reduced Slco1a1 and upregulated Mrp4 transporters. These results demonstrate that Mrp2-deficient organism is more sensitive to estrogen-induced cholestasis. Inherited deficiency in Mrp2 is associated with activation of Mrp3 and Mrp4 proteins, which is further accentuated by increased estrogen. Bile acid monitoring is therefore highly desirable in pregnant women with conjugated hyperbilirubinemia for early detection of intrahepatic cholestasis.

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Section: Introductionmentioning

confidence: 99%

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

et al. 2022

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ABCC2 participates in the resistance of Plutella xylostella to chemical insecticides

Wang

et al. 2020

Pesticide Biochemistry and Physiology

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Genetic contribution of ABCC2 to Dubin‐Johnson syndrome and inherited cholestatic disorders

Corpechot

Barbu

Chazouillères

et al. 2019

Liver International

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Background and AimsThe ABCC2 gene is implicated in Dubin‐Johnson syndrome (DJS), a rare autosomal recessive liver disorder. The primary aim of this study was to determine the diagnostic value of ABCC2 genetic testing in the largest cohort of DJS reported to date. The high number of patients with cholestatic manifestations in this series prompted us to evaluate the genetic contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.MethodsThe cohort study included 32 patients with clinical DJS diagnosis, and 372 patients referred for the following disorders: low phospholipid‐associated cholelithiasis (LPAC) syndrome, intrahepatic cholestasis of pregnancy (ICP) and benign recurrent intrahepatic cholestasis (BRIC). ABCC2 was screened by next‐generation sequencing.ResultsMost patients with clinical DJS had positive genetic diagnosis (n = 30; 94%), with a great diversity of point mutations and copy number variations in ABCC2. Strikingly, eight (27%) of these patients showed transient cholestatic features at presentation: four neonatal cholestasis, two ICP, one contraceptive‐induced cholestasis and one sporadic cholestasis. Conversely, the frequency of rare, heterozygous, potentially pathogenic ABCC2 variants in patients with LPAC, ICP or BRIC did not differ significantly from that of the general population.ConclusionsThis large series reveals that DJS is a highly homogeneous Mendelian disorder involving a large spectrum of ABCC2 variants. Genetic testing is crucial to establish early DJS diagnosis in patients with atypical presentations, such as neonatal cholestasis. This study also provides no evidence for the contribution of rare, potentially pathogenic ABCC2 variants to other inherited cholestatic disorders.

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Novel compound heterozygous ABCC2 variants in patients with Dubin‐Johnson syndrome and intrahepatic cholestasis of pregnancy

Cited by 6 publications

References 5 publications

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

Multidrug Resistance-Associated Protein 2 Deficiency Aggravates Estrogen-Induced Impairment of Bile Acid Metabolomics in Rats

ABCC2 participates in the resistance of Plutella xylostella to chemical insecticides

Genetic contribution of ABCC2 to Dubin‐Johnson syndrome and inherited cholestatic disorders

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