PUBLICATION

Loss of Leucyl-tRNA synthetase b leads to ILFS1-like symptoms in zebrafish

Authors
Wang, Z., Song, J., Luo, L., Ma, J.
ID
ZDB-PUB-180929-2
Date
2018
Source
Biochemical and Biophysical Research Communications   505(2): 378-384 (Journal)
Registered Authors
Luo, Lingfei
Keywords
ILFS1, Leucyl-tRNA synthetase b, Liver, Zebrafish, mTORC1
MeSH Terms
  • Amino Acyl-tRNA Synthetases/deficiency*
  • Amino Acyl-tRNA Synthetases/genetics
  • Animals
  • Cell Proliferation
  • DNA Damage
  • Liver Failure/drug therapy
  • Liver Failure/enzymology*
  • Liver Failure/genetics
  • Liver Failure/pathology
  • Mutant Proteins
  • Mutation
  • Signal Transduction
  • Sirolimus/therapeutic use
  • Transcription Factors/physiology
  • Zebrafish
  • Zebrafish Proteins/physiology
PubMed
30262142 Full text @ Biochem. Biophys. Res. Commun.
Abstract
Leucyl-tRNA synthetase (LARS) is a kind of aminoacyl-tRNA synthetases (aaRSs), which is important for protein synthesis. Following the discovery of three clinical cases which carry LARS mutations, it has been designated as the infantile liver failure syndrome type 1 (ILFS1) gene. ILFS1 is a kind of infantile hepatopathy, which is difficult to diagnose and manage. As the mechanism underlying this disease is poorly understood and LARS is conserved among vertebrates, we obtained zebrafish larsbcq68 mutant via CRISPR/Cas9 technology to investigate the role of larsb in vivo. In mutant, the proliferation ability of liver was drastically decreased at later stages accompanied with severe DNA damage. Further studies demonstrated that the mTORC1 signaling was hyperactivated in larsbcq68 mutant. Inhibition of mTORC1 signaling pathway by Rapamycin or mTORC1 morpholino can partially rescue the liver failure of the mutants. These data revealed that larsb mutation caused ILFS1-like phenotype in zebrafish, and indicated this mutant may serve as a potential model for ILFS1. Furthermore, we demonstrated that rapamycin treatment can partially rescue the liver defect in mutants, thus providing a practicable therapeutic plan for ILFS1.
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