PUBLICATION

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

Authors
Bao, W., Wang, X., Luo, L., Ni, R.
ID
ZDB-PUB-210429-6
Date
2021
Source
Zebrafish   18(3): 175-183 (Journal)
Registered Authors
Luo, Lingfei
Keywords
fig4a, hepatocyte vacuolation, liver, lysosomal storage, pikfyve, zebrafish
MeSH Terms
  • Animals
  • Liver
  • Lysosomes
  • Mutation
  • Phosphoric Monoester Hydrolases*/genetics
  • Zebrafish*/genetics
PubMed
33909505 Full text @ Zebrafish
Abstract
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes