ArticleGastroenterology2021
Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms.
Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 22 citations in OpenAlex.
- Genetic testing in liver diseases: Clinical applications.JHEP reports : innovation in hepatology · 2026Review
- Challenges in the diagnosis and treatment of genetic cholestasis in adults.JHEP reports : innovation in hepatology · 2026Review
- Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System.Cells · 2024Review
- Prenatal opioid exposure significantly impacts placental protein kinase C (PKC) and drug transporters, leading to drug resistance and neonatal opioid withdrawal syndrome.Frontiers in neuroscience · 2024Article
- Review
- Update on Hepatobiliary Plasticity.Seminars in liver disease · 2023Article
- Genetic alterations and molecular mechanisms underlying hereditary intrahepatic cholestasis.Frontiers in pharmacology · 2023Review
- Isolation and Culturing Primary Chaolangiocytes from Mouse Liver.Bio-protocol · 2021Article
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsThe etiology of cholestasis remains unknown in many children. We surveyed the genome of children with chronic cholestasis for variants in genes not previously associated with liver disease and validated their biological relevance in zebrafish and murine models.
methodWhole-exome (n = 4) and candidate gene sequencing (n = 89) was completed on 93 children with cholestasis and normal serum γ-glutamyl transferase (GGT) levels without pathogenic variants in genes known to cause low GGT cholestasis such as ABCB11 or ATP8B1. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing was used to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice.
resultsIn a 1-year-old female patient with normal GGT cholestasis and bile duct paucity, we identified a homozygous truncating pathogenic variant (c.198delA, p.Gly67Alafs∗6) in the ABCC12 gene (NM_033226). Five additional rare ABCC12 variants, including a pathogenic one, were detected in our cohort. ABCC12 encodes multidrug resistance-associated protein 9 (MRP9) that belongs to the adenosine 5'-triphosphate-binding cassette transporter C family with unknown function and no previous implication in liver disease. Immunohistochemistry and Western blotting revealed conserved MRP9 protein expression in the bile ducts in human, mouse, and zebrafish. Zebrafish abcc12-null mutants were prone to cholangiocyte apoptosis, which caused progressive bile duct loss during the juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared with wild-type mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge.
conclusionsOur work connects MRP9 with bile duct homeostasis and cholestatic liver disease for the first time. It identifies a potential therapeutic target to attenuate bile acid-induced cholangiocyte injury.
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