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

Pham, D.H., Kudira, R., Xu, L., Valencia, C.A., Ellis, J.L., Shi, T., Evason, K.J., Osuji, I., Matuschek, N., Pfuher, L., Mullen, M., Mohanty, S.K., Husami, A., Bull, L.N., Zhang, K., Wali, S., Yin, C., Miethke, A.
Gastroenterology   161(1): 287-300.e16 (Journal)
Registered Authors
Yin, Chunyue
Progressive familial intrahepatic cholestasis, bile duct paucity, mouse, zebrafish
MeSH Terms
  • ATP-Binding Cassette Transporters/genetics*
  • ATP-Binding Cassette Transporters/metabolism
  • Animals
  • Apoptosis
  • Bile Ducts, Intrahepatic/metabolism
  • Bile Ducts, Intrahepatic/pathology*
  • Case-Control Studies
  • Cholestasis, Intrahepatic/genetics*
  • Cholestasis, Intrahepatic/metabolism
  • Cholestasis, Intrahepatic/pathology*
  • Chronic Disease
  • Exome Sequencing
  • Female
  • Gene Editing
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Phenotype
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
33771553 Full text @ Gastroenterology
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.
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.
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.
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes