Novel Genes in Inherited Chronic Cholestasis

Cholestatic disease is responsible for the majority of liver transplant in children. Study of genetics is key to gaining an accurate understanding of the pathophysiology of these diseases. Genetic testing is now used early in the diagnostic pathway, but in ~ 1/3 of patients with isolated or “primary” cholestasis, a definitive diagnosis is not obtained. The lack of accurate diagnosis hinders our ability to assess disease prognosis and tailor treatment. To improve diagnosis, we team up with clinician, human geneticist, and pathologist to establish a pipeline for discoveries of candidate mutations and nucleotide variants from patients, direct testing for biological relevance in cell culture and animal models, and validation in patients’ tissues.

ABCC12

Through whole-exome sequencing, we identified a bi-allelic truncating loss-of-function variant in ABCC12 in a patient with chronic intrahepatic cholestasis. ABCC12 encodes the largely uncharacterized ATP-binding cassette transporter, MRP9. We showed that MRP9 is expressed in cholangiocytes in human, mouse, and zebrafish and it is required for the integrity and long-term survival of these cells. Currently, we are investigating the function of MRP9 in mitochondrial metabolism, aiming to discover druggable targets to rescue cholangiocyte injury caused by MRP9 loss.

Based on the experiences with building various zebrafish models of cholestatic diseases and the toolbox we generated to study hepatobiliary morphology and function, we established an innovative pipeline enables rapid functional validation of novel causative genes in cholestatic liver diseases using zebrafish.