Liver Disease Reveals KIF12 as a Critical Regulator of Organelle Localization

ABSTRACT: Kinesin family member 12 (KIF12) has been implicated in liver disease requiring transplantation in pediatric patients. Single cell RNA-sequencing shows KIF12 expression selectively in biliary cells in healthy human liver. Here, we generated a human KIF12-disease model by introducing a homozygous KIF12 p.Arg219* mutation in induced pluripotent stem cells. These cells were differentiated into 2D cholangiocyte-like cells (iCCs) and 3D biliary organoids. Pioneering single-molecule fluorescence microscopy in live iCCs, we observed wild-type KIF12 co-localizing with microtubules, consistent with prediction of being a microtubule associated motor protein. KIF12 deficiency causes perinuclear clustering of mitochondria and lysosomes, along with aberrant cilia localization. These defects were rescued by viral delivery of wild-type KIF12. Collectively, these findings uncovered a mechanistic link between KIF12 dysfunction, mitochondria, lysosomes, and cilia mispositioning, and biliary pathology. Our study expands the knowledge of kinesins beyond neuronal function and provides a foundation for development of targeted genetic therapies for kinesinopathies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278954 | GEO | 2026/09/23

REPOSITORIES: GEO