- Title
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Genetic therapy in a mitochondrial disease model suggests a critical role for liver dysfunction in mortality
- Authors
- Sabharwal, A., Wishman, M.D., Cervera, R.L., Serres, M.R., Anderson, J.L., Holmberg, S.R., Kar, B., Treichel, A.J., Ichino, N., Liu, W., Yang, J., Ding, Y., Deng, Y., Lacey, J.M., Laxen, W.J., Loken, P.R., Oglesbee, D., Farber, S.A., Clark, K.J., Xu, X., Ekker, S.C.
- Source
- Full text @ Elife
GBT mutagenesis generates a novel zebrafish model of LSFC. |
Overall predicted structure of human and zebrafish LRPPRC and its C-terminus comparison with human LRPPRC. |
Domain organization of human LRPPRC predicted from structural and sequence analysis. |
Domain organization of zebrafish Lrpprc predicted from structural and sequence analysis. |
Sequence alignment of SEC1 domain of LRPPRC from different model organisms. |
Spatiotemporal expression of Lrpprc-mRFP in GBT0235 mutants. |
Lrpprc-mRFP localizes to the mitochondria in the zebrafish mutants. |
rpprcGBT0235/GBT0235 mutants recapitulate the hallmarks of LSFC. |
Relative mtDNA copy number in lrpprc homozygous mutants: No significant change was observed in the homozygous mutants as compared to wild-type siblings (lrpprc+/+ vs lrpprcGBT0235/GBT0235; p-value = 0.8263). |
lrpprcGBT0235/GBT0235 mutants display decreased birefringence. |
lrpprcGBT0235/GBT0235 and Tg(fabp10:Cre)lrpprcGBT0235/GBT0235 mutants display decreased birefringence at 4 dpf. |
lrpprc homozygous mutants do not display neuronal necrosis. |
RNAseq of lrpprcGBT0235/GBT0235 homozygous mutants. |
The liver plays an important role in the pathology of LSFC and genetic liver-specific rescue rescues the lipid defect and mortality in lrpprc homozygous mutant larvae. |
Irreversible liver-specific Cre recombinase-mediated rescue. |
Genetic liver-specific rescue of altered dietary lipid metabolism in lrpprc homozygous mutant larvae. |