Clinical information of an infantile liver failure syndrome type 1 patient with biallelic LARS1 variants. A Pedigree of the family. B Abdominal computed tomography image at eight months old. C Changes in serum levels of AST and ALT. D Developmental curve

Leucine-tRNA synthetase (LARS) mutations. A LARS domains and pathogenic variants found in infantile liver failure syndrome type 1 patients. Variants in our patients are shown in bold. Variants in another reported case with severe manifestation in the neonatal period are in red. B Conservations of the missense variant in LARS

Larsb-knockin larvae display liver abnormality during the liver developmental stage. A Diagram showing the larsb genomic locus and larsb-knockin (larsb-I451F) zebrafish mutant genotype. B In the genomic sequencing analysis chromatograms, the mutation site in the larsb-I451F zebrafish is shown in red. C Morphological abnormality at 4 to 7 dpf in the livers of larsb-I451F larvae with a Tg[fabp10:mcherry] background. White arrows indicate the loss of liver edges in larsb-I451F larvae. Scale bar: 200 μm. D Relative liver area in larsb-WT (n = 15 fish) and larsb-I451F (n = 9 fish) larvae with a Tg[fabp10:mcherry] background (4 to 7 dpf). *P < 0.05. E Circularity of liver in larsb-WT (n = 15 fish) and larsb-I451F (n = 9 fish) larvae with a Tg[fabp10:mcherry] background (4 to 7 dpf). Error bars indicate SEM. *P < 0.05, **P < 0.01

Histopathology and lipids staining of the liver in larsb-knockin larvae. A Hematoxylin and eosin staining of the liver in larsb-knockin (larsb-I451F) larvae at 5 dpf. Scale bar: 20 μm. B Quantification of the vesicle number in larsb-WT (n = 7 sections) and larsb-I451F (n = 12 sections) liver at 5 dpf. Error bars indicate SEM. *P < 0.05. C Lipids staining of the liver in larsb-I451F larvae at 5 dpf. Scale bar: 20 μm. D Quantification of the lipid area in larsb-WT (n = 6 sections) and larsb-I451F (n = 6 sections) larvae liver at 5 dpf. Error bars indicate SEM. **P < 0.01. Dpf: days post fertilization

Enhanced autophagy in the liver of larsb-knockin larvae. A Immunostaining of LC-3 in the liver of larsb-knockin (larsb-I451F) larvae at 5 dpf. Scale bar: 20 μm. White arrowheads indicate LC3-positive dots. B Quantification of the number of LC-3 dots in larsb-WT (n = 10 sections) and larsb-I451F (n = 9 sections) larvae liver at 5 dpf. Error bars indicate SEM. **P < 0.01. C Morphological abnormality in the livers of larsb-I451F larvae at 5 dpf with a Tg[fabp10:mcherry] background treated with DMSO or bafilomycin. Scale bar: 200 μm. D Liver area in larsb-I451F larvae at 5 dpf with a Tg[fabp10:mcherry] background treated with DMSO (larsb-WT n = 11 sections, larsb-I451F n = 9 sections) or bafilomycin (larsb-WT n = 10 sections, larsb-I451F n = 14 sections). Error bars indicate SEM. *P < 0.05. E Circularity of the liver in larsb-I451F larvae at 5 dpf with a Tg[fabp10:mcherry] background treated with DMSO (larsb-WT n = 11 sections, larsb-I451F n = 9 sections) or bafilomycin (larsb-WT n = 10 sections, larsb-I451F n = 14 sections). Error bars indicate SEM. *P < 0.05. F Lipids staining of the liver in larsb-I451F larvae at 5 dpf treated with DMSO or bafilomycin. Scale bar: 20 μm. G Quantification of the lipid area in larsb-I451F larvae liver at 5 dpf treated with DMSO (larsb-WT n = 10 sections, larsb-I451F n = 11 sections) or bafilomycin (larsb-WT n = 14 sections, larsb-I451F n = 9 sections). Error bars indicate SEM. **P < 0.01. Dpf: days post fertilization