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Abstract Details
Deleterious variants in ABCC12 are detected in idiopathic chronic cholestasis and cause intrahepatic bile duct loss in model organisms: ABCC12 pathogenic variants lead to cholestasis
Gastroenterology. 2021 Mar 18;S0016-5085(21)00535-7. doi: 10.1053/j.gastro.2021.03.026.Online ahead of print.
Duc-Hung Pham1, Ramesh Kudira1, Lingfen Xu2, C Alexander Valencia3, Jillian L Ellis1, Tiffany Shi1, Kimberley J Evason4, Immaculeta Osuji1, Nelson Matuschek1, Liva Pfuher1, Mary Mullen1, Sujit K Mohanty5, Ammar Husami6, Laura N Bull7, Kejian Zhang8, Sami Wali9, Chunyue Yin10, Alexander Miethke11
Author information
1Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
2Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Shengjing Hospital of China Medical University, Pediatric Gastroenterology, Shenyang, China.
3Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; Lake Erie College of Osteopathic Medicine, Erie, Pennsylvania, USA; Aperiomics, Inc., Sterling, Virginia, USA.
4Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.
5Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
6Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
7Liver Center Laboratory, Department of Medicine and Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
8Mount Sinai Genomics, New York, New York, USA.
9Prince Sultan Military Medical City, Pediatric Gastroenterology, Riyadh, Saudi Arabia.
10Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. Electronic address: chunyue.yin@cchmc.org.
11Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Abstract
Background and aims: The 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.
Method: Whole-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/Cas9 genome editing was employed to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice.
Results: In a one-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 MRP9 that belongs to the ATP-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 juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared to WT mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge.
Conclusion: Our 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.