Anubha Seth, PhD

Travel Award
$1,500

Yale University

KIF12 Deficiency Unraveled in Cholestatic Liver Disease: Linking Organelle Mispositioning to Hepatic Pathology

Mentor: Silvia Vilarinho, MD, PhD

Recent studies have identified that mutations in the KIF12 gene can result in rare severe cholestatic liver

disease in children, with some individuals requiring liver transplantation for survival. Our research centers on KIF12, a protein from a family of molecular “motors” responsible for transporting essential organelles within cells.

Our first goal was to localize KIF12 in the liver. We identified its dominant presence in biliary cells - the cells that line the ducts that drain the bile out of the liver—in healthy human livers. This link emphasizes the need to understand how KIF12 affects liver health, especially in a condition called cholestasis, where the flow of bile is hindered, potentially leading to liver damage. To investigate how KIF12 malfunction leads to disease, we developed a model using inducible pluripotent stem cells (iPSC) to grow biliary cells. In healthy cells, KIF12 travels along microtubule tracks and helps position key cell organelles like mitochondria (energy producers), lysosomes (waste processors), and cilia (antenna-like structures that help cells sense their surroundings). When KIF12 is defective, these organelles are mispositioned, likely contributing to cell dysfunction. Remarkably, we managed to correct these defects by introducing a healthy version of KIF12. We uncovered the crucial connection between defects in the KIF12 motor protein and abnormalities in liver cells.

This discovery highlights for the first time that KIF12 plays a crucial role in liver health. Our findings advance our understanding of how this disease develops and offer a potential pathway toward developing targeted genetic medicines.