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Zhao C, Shi X, Zhang Y, Huang H. Case Report: Three novel pathogenic ABCC2 mutations identified in two patients with Dubin–Johnson syndrome. Front Genet 2022; 13:895247. [PMID: 36092886 PMCID: PMC9452728 DOI: 10.3389/fgene.2022.895247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
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.
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Affiliation(s)
- Chenyu Zhao
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoliu Shi
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yonghong Zhang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hui Huang
- Department of Medical Genetics, The Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Hui Huang,
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Wu H, Zhao XK, Zhu JJ. Clinical characteristics and ABCC2 genotype in Dubin-Johnson syndrome: A case report and review of the literature. World J Clin Cases 2021; 9:878-885. [PMID: 33585635 PMCID: PMC7852649 DOI: 10.12998/wjcc.v9.i4.878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/20/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dubin-Johnson syndrome (DJS) is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene. It is characterized by chronic or intermittent conjugated hyperbilirubinemia, with chronic idiopathic jaundice as the main clinical manifestation. Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS; however, the causative ABCC2 point mutation in Chinese patients remains unknown. Research on ABCC2 mutations in Chinese DJS patients is extremely rare, and the diagnosis of DJS remains limited. The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS. Here, we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient. This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.
CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses. ABCC2 mutations were identified by next-generation sequencing (NGS). The patient showed intermittent jaundice and conjugated hyper-bilirubinemia. Histopathological examinations were consistent with the typical phenotype of DJS. Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant, namely c.2443C>T (p.Arg815*), which has not been reported previously in the domestic or foreign literature.
CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS, especially in patients with atypical presentations. Currently, NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.
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Affiliation(s)
- Huan Wu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
| | - Xue-Ke Zhao
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
| | - Juan-Juan Zhu
- Department of Infectious Diseases, The Affiliated Hospital of Guizhou Medical University, Guiyang 550001, Guizhou Province, China
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Kim KY, Kim TH, Seong MW, Park SS, Moon JS, Ko JS. Mutation spectrum and biochemical features in infants with neonatal Dubin-Johnson syndrome. BMC Pediatr 2020; 20:369. [PMID: 32758197 PMCID: PMC7404915 DOI: 10.1186/s12887-020-02260-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 07/27/2020] [Indexed: 01/06/2023] Open
Abstract
Background Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder presenting as isolated direct hyperbilirubinemia.DJS is rarely diagnosed in the neonatal period. The purpose of this study was to clarify the clinical features of neonatal DJS and to analyze the genetic mutation of adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2). Methods From 2013 to 2018, 135 infants with neonatal cholestasis at Seoul National University Hospital were enrolled. Genetic analysis was performed by neonatal cholestasis gene panel. To clarify the characteristics of neonatal DJS, the clinical and laboratory results of 6 DJS infants and 129 infants with neonatal cholestasis from other causes were compared. Results A total of 8 different ABCC2 variants were identified among the 12 alleles of DJS. The most common variant was p.Arg768Trp (33.4%), followed by p.Arg100Ter (16.8%). Three novel variants were identified (p.Gly693Glu, p.Thr394Arg, and p.Asn718Ser). Aspartate transaminase (AST) and alanine transaminase (ALT) levels were significantly lower in infants with DJS than in infants with neonatal cholestasis from other causes. Direct bilirubin and total bilirubin were significantly higher in the infants with DJS. Conclusions We found three novel variants in 6 Korean infants with DJS. When AST and ALT levels are normal in infants with neonatal cholestasis, genetic analysis of ABCC2 permits an accurate diagnosis.
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Affiliation(s)
- Kwang Yeon Kim
- Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-Gu, 110-769, Seoul, Korea
| | - Tae Hyeong Kim
- Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-Gu, 110-769, Seoul, Korea
| | - Moon-Woo Seong
- Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Sup Park
- Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-Gu, 110-769, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-Gu, 110-769, Seoul, Korea.
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Huang WG, Wang J, Liu YJ, Wang HX, Zhou SZ, Chen H, Yang FW, Li Y, Yi Y, He YH. Endoplasmic Reticulum Stress Increases Multidrug-resistance Protein 2 Expression and Mitigates Acute Liver Injury. Curr Mol Med 2020; 20:548-557. [PMID: 31976833 DOI: 10.2174/1566524020666200124102411] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 12/30/2019] [Accepted: 01/12/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Multidrug-resistance protein (MRP) 2 is a key membrane transporter that is expressed on hepatocytes and regulated by nuclear factor kappa B (NF-κB). Interestingly, endoplasmic reticulum (ER) stress is closely associated with liver injury and the activation of NF-κB signaling. OBJECTIVE Here, we investigated the impact of ER stress on MRP2 expression and the functional involvement of MRP2 in acute liver injury. METHODS ER stress, MRP2 expression, and hepatocyte injury were analyzed in a carbon tetrachloride (CCl4)-induced mouse model of acute liver injury and in a thapsigargin (TG)-induced model of ER stress. RESULTS CCl4 and TG induced significant ER stress, MRP2 protein expression and NF- κB activation in mice and LO2 cells (P < 0.05). Pretreatment with ER stress inhibitor 4- phenyl butyric acid (PBA) significantly mitigated CCl4 and TG-induced ER stress and MRP2 protein expression (P < 0.05). Moreover, pretreatment with pyrrolidine dithiocarbamic acid (PDTC; NF-κB inhibitor) significantly inhibited CCl4-induced NF-κB activation and reduced MRP2 protein expression (1±0.097 vs. 0.623±0.054; P < 0.05). Furthermore, hepatic downregulation of MRP2 expression significantly increased CCl4- induced ER stress, apoptosis, and liver injury. CONCLUSION ER stress enhances intrahepatic MRP2 protein expression by activating NF-κB. This increase in MRP2 expression mitigates ER stress and acute liver injury.
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Affiliation(s)
- Wen-Ge Huang
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Jun Wang
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Yu-Juan Liu
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Hong-Xia Wang
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Si-Zhen Zhou
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Huan Chen
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Fang-Wan Yang
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Ying Li
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Yu Yi
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Yi-Huai He
- Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
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Wu L, Li Y, Song Y, Zhou D, Jia S, Xu A, Zhang W, You H, Jia J, Huang J, Ou X. A recurrent ABCC2 p.G693R mutation resulting in loss of function of MRP2 and hyperbilirubinemia in Dubin-Johnson syndrome in China. Orphanet J Rare Dis 2020; 15:74. [PMID: 32183854 PMCID: PMC7079413 DOI: 10.1186/s13023-020-1346-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/02/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Dubin-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. METHODS Clinical 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. RESULTS The 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. CONCLUSIONS The 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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Affiliation(s)
- Lina Wu
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Yanmeng Li
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Yi Song
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Donghu Zhou
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Siyu Jia
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Anjian Xu
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Wei Zhang
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Hong You
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China
| | - Jidong Jia
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China.
| | - Jian Huang
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China.
| | - Xiaojuan Ou
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-An Road, Beijing, 100050, China.
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