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Case Report: Three novel pathogenic ABCC2 mutations identified in two patients with Dubin-Johnson syndrome.

ABSTRACT: Background: Dubin-Johnson syndrome (DJS) is a rare autosomal recessive genetic disease which is caused by mutations in the ABCC2 gene; it is characterized by chronic hyperbilirubinemia. Here, we report two pedigrees affected with DJS which were caused by three novel pathogenic ABCC2 mutations. Case summary: The two patients exhibited intermittent low-grade, predominantly conjugated hyperbilirubinemia and showed no other abnormalities. They were diagnosed clinically with DJS. Three novel pathogenic ABCC2 mutations-c.2980delA, c.1834C>T, and c.4465_4473delinsGGCCCACAG-were identified by whole-exome sequencing. These mutations could be responsible for DJS in the two pedigrees. The genetic test confirmed the diagnosis of DJS. Conclusion: These results contributed to the genetic diagnosis of the two patients with DJS and expanded the variant database for the ABCC2 gene.

SUBMITTER: Zhao C

PROVIDER: S-EPMC9452728 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case Report: Three novel pathogenic ABCC2 mutations identified in two patients with Dubin-Johnson syndrome.

Zhao Chenyu C Shi Xiaoliu X Zhang Yonghong Y Huang Hui H

Frontiers in genetics 20220825

Background: Dubin-Johnson syndrome (DJS) is a rare autosomal recessive genetic disease which is caused by mutations in the ABCC2 gene; it is characterized by chronic hyperbilirubinemia. Here, we report two pedigrees affected with DJS which were caused by three novel pathogenic ABCC2 mutations. Case summary: The two patients exhibited intermittent low-grade, predominantly conjugated hyperbilirubinemia and showed no other abnormalities. They were diagnosed clinically wi ...[more]

PMID: 36092886

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ABCC2 p.R393W variant contributes to Dubin-Johnson syndrome by targeting MRP2 to proteasome degradation.

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Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome: A case report and review of the literature.

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Mutation analysis of the ABCC2 gene in Chinese patients with Dubin-Johnson syndrome.

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A recurrent ABCC2 p.G693R mutation resulting in loss of function of MRP2 and hyperbilirubinemia in Dubin-Johnson syndrome in China.

Project description:BackgroundDubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations in the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) gene, which encodes multidrug resistance-associated protein 2 (MRP2). However, little is known about the causative mutation of DJS in China. Recently, we have reported ABCC2 p.G693R mutation in two unrelated cases. In the present study, we investigated the pathogenicity of the ABCC2 p.G693R mutation in DJS in China.MethodsClinical and genetic analysis was conducted for the two patients with the ABCC2 p.G693R mutation. Whole exome sequencing for mutations in other known hyperbilirubinemia-related genes was conducted for the cases with ABCC2 p.G693R. Expression and cellular localization of the mutant MRP2 p.G693R were analyzed by Western blotting and immunofluorescence assay, respectively. Organic anion transport activity was evaluated by the analysis of glutathione-conjugated-monochlorobimane.ResultsThe two DJS patients with ABCC2 p.G693R mutation, which was conserved among different species, showed typical hyperbilirubinemia phenotype. No pathogenic mutation was identified in the other known hyperbilirubinemia related genes. Functional studies in three cell lines showed that the expression, localization and the organic anion transport activity were significantly compromised by MRP2 p.G693R mutation compared with wild-type MRP2.ConclusionsThe recurrent ABCC2 p.G693R mutation is associated with loss of function of the MRP2 protein and may result in hyperbilirubinemia in DJS in China.

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Dubin-Johnson syndrome coinciding with colon cancer and atherosclerosis.

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Neonatal Dubin-Johnson Syndrome and its Differentiation from Biliary Atresia.

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