Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms

Pham, Duc-Hung; Kudira, Ramesh; Xu, Liangliang; Valencia, C. Alexander; Ellis, Jillian L.; Shi, Tiffany; Evason, Kimberley; Osuji, Immaculeta; Matuschek, Nelson; Pfuhler, Liva; Mullen, Mary M.; Mohanty, Sujit K.; Husami, Ammar; Bull, Laura N.; Zhang, Kejian; Wali, Sami; Yin, Chunyue; Miethke, Alexander

doi:10.1053/j.gastro.2021.03.026

Cited by 19 publications

(20 citation statements)

References 60 publications

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“…[37] A harmful mutation of ABCC12 (MRP9) can cause cholestasis. [38] ABCC13 (MRP10), a pseudogene, is highly expressed in human fetal liver. [39,40] Nonetheless, little is known about the role of ABCCs in LIHC.…”

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Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

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Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

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“…The article published by Pham et al 8 in this issue of Gastroenterology reports the use of exome sequencing in 4 patients with unexplained neonatal cholestasis and is a significant contribution to our understanding of this disorder. Three of the 4 patients analyzed were found to be homozygous for recessive pathogenic variants in 2 established PFIC genes, TJP2 and ABCB11.…”

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“…The presence of 2 pathogenic mutations in this patient cohort, one of which was biallelic (homozygous), argued in favor of causality despite little understanding of the ABCC12/ MRP9 function. To gain additional insight into causality, Pham et al 8 studied the hepatic expression of MRP9 via immunohistochemistry, documenting its presence in large and small intrahepatic bile ducts and zone 1 hepatocytes. Interestingly, a liver biopsy specimen from the index patient showed bile duct paucity, thus suggesting a role for MRP9 in cholangiocytes.…”

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“…Having generated elegant data in the zebrafish model supporting a role for ABCC12 in the index patient's cholestasis syndrome, Pham et al 8 established a mouse model that enabled them to study MRP9 function in mammalian cholangiocytes. Mice homozygous for an Mrp9 truncating mutation had biochemical evidence of liver injury and cholestasis along with histologic evidence of intrahepatic bile duct paucity.…”

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“…13 Also to be considered in future studies is whether cholestasis induced by ABCC12/ MRP9 mutation arises from a nonhepatic function of MRP9, as was recently proposed for ABCC7/CFTR in cystic fibrosis cholangiopathy, 15 and whether loss of MRP9 affects cholangiocyte heterogeneity. 16,17 From a clinical perspective, the most important unanswered question raised by the work of Pham et al 8 is whether the heterozygous ABCC12 missense variants they report are pathogenic. These genotype-phenotype correlations will be clarified over time as more variants are identified.…”

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Cholestatic liver diseases of genetic etiology: Advances and controversies

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With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.

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Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms

Cited by 19 publications

References 60 publications

Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

Model Organisms Help Define the ABCs of Neonatal Cholestasis

Cholestatic liver diseases of genetic etiology: Advances and controversies

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