The Lysosomal Storage Disorder Due to fig4a Mutation Causes Robust Liver Vacuolation in Zebrafish.

The phospholipid phosphatase FIG4/Fig4 is a subunit of PIKFYVE/Pikfyve kinase complex that synthesizes phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a key regulator of endolysosomal trafficking and function. Loss of FIG4/Fig4 leads to intracellular deficiency of PI(3,5)P2 signaling and multiple endolysosomal defects. Previous works were focused on the effects of FIG4/Fig4 mutations in the nervous and musculoskeletal systems in human clinical and animal studies. In this study, we describe a zebrafish recessive mutant cq35 showing robust liver vacuolation and lethality, with a predicted truncating mutation in fig4a gene. The liver vacuolation progress in fig4a mutant was reversible after regaining normal fig4a transcripts. The hepatic vacuolation pathology was identified as abnormal lysosomal storage with numerous accumulated cargoes, including autophagy intermediates, and caused progressive degeneration of bile canaliculi in mutant liver. These hepatic pathological details of fig4a mutant were repeated in zebrafish pikfyve mutant. Thus, zebrafish possess the conserved structural and functional mechanisms in Pikfyve kinase complex, based on which, pikfyve mutant phenotype covered fig4a mutant phenotype in their double mutant. Our findings represent the first description of the in vivo defects caused by FIG4/Fig4 mutation or PI(3,5)P2 deficiency in liver, and reveal the conserved complex mechanisms associated with FIG4/Fig4-deficient disorders in zebrafish.