PUBLICATION
Retinopathy-associated inosine monophosphate dehydrogenase 1 mutations cause metabolic and filament defects in cones
- Authors
- Rutter, K.M., Giarmarco, M.M., Truong, V., Wang, Y., Eminhizer, M., Xiang, Y., Cleghorn, W.M., Sanchez, G., Burrell, A.L., Kollman, J.M., Du, J., Brockerhoff, S.E.
- ID
- ZDB-PUB-250818-6
- Date
- 2025
- Source
- Disease models & mechanisms : (Journal)
- Registered Authors
- Brockerhoff, Susan
- Keywords
- IMPDH1, Purine metabolism, Retina, Retinitis pigmentosa, Zebrafish
- MeSH Terms
-
- Retinal Cone Photoreceptor Cells*/enzymology
- Retinal Cone Photoreceptor Cells*/metabolism
- Retinal Cone Photoreceptor Cells*/pathology
- Animals
- IMP Dehydrogenase*/genetics
- IMP Dehydrogenase*/metabolism
- Cyclic GMP/metabolism
- Retinal Diseases*/enzymology
- Retinal Diseases*/genetics
- Retinal Diseases*/pathology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Mutation*/genetics
- PubMed
- 40820815 Full text @ Dis. Model. Mech.
Citation
Rutter, K.M., Giarmarco, M.M., Truong, V., Wang, Y., Eminhizer, M., Xiang, Y., Cleghorn, W.M., Sanchez, G., Burrell, A.L., Kollman, J.M., Du, J., Brockerhoff, S.E. (2025) Retinopathy-associated inosine monophosphate dehydrogenase 1 mutations cause metabolic and filament defects in cones. Disease models & mechanisms. :.
Abstract
Dominant mutations in inosine monophosphate dehydrogenase I (IMPDH1), a key enzyme in the de novo synthesis of purine bases, cause progressive photoreceptor death leading to blindness. To investigate the cause of degeneration, we generated the first mutant IMPDH1 animal models and expressed mutant forms of impdh1a in zebrafish cone photoreceptors. Unlike cones expressing exogenous normal impdh1a, cones containing impdh1a with the K238E mutation degenerated. Cones expressing the D226N mutation did not show significant cone loss by 2 years. Steady-state and flux metabolomics in zebrafish retina revealed no difference in glucose shunting to the pentose phosphate pathway, no change in AMP or GMP due to D226N expression, but reduced AMP/IMP and GMP/IMP in K238E expressing cones. cGMP levels were normal in both mutant retinas. Further pde6cw59; impdh1asa23234 double mutant cones were not rescued from degeneration. Both K238E and D226N mutant containing proteins formed abnormally large mis-localized filaments, which could disrupt normal dynamic protein-protein interactions. Our work disproves the model of a hyperactive enzyme leading to elevated cGMP causing cell death, and reveals new defects associated with IMPDH1 mutant expression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping