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A Mouse Model with Ablated Asparaginase and Isoaspartyl Peptidase 1 (Asrgl1) Develops Early Onset Retinal Degeneration (RD) Recapitulating the Human Phenotype
- Source :
- Genes; Volume 13; Issue 8; Pages: 1461, Genes, vol 13, iss 8
- Publication Year :
- 2022
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2022.
-
Abstract
- We previously identified a homozygous G178R mutation in human ASRGL1 (hASRGL1) through whole-exome analysis responsible for early onset retinal degeneration (RD) in patients with coneārod dystrophy. The mutant G178R ASRGL1 expressed in Cos-7 cells showed altered localization, while the mutant ASRGL1 in E. coli lacked the autocatalytic activity needed to generate the active protein. To evaluate the effect of impaired ASRGL1 function on the retina in vivo, we generated a mouse model with c.578_579insAGAAA (NM_001083926.2) mutation (Asrgl1mut/mut) through the CRISPR/Cas9 methodology. The expression of ASGRL1 and its asparaginase activity were undetectable in the retina of Asrgl1mut/mut mice. The ophthalmic evaluation of Asrgl1mut/mut mice showed a significant and progressive decrease in scotopic electroretinographic (ERG) response observed at an early age of 3 months followed by a decrease in photopic response around 5 months compared with age-matched wildtype mice. Immunostaining and RT-PCR analyses with rod and cone cell markers revealed a loss of cone outer segments and a significant decrease in the expression of Rhodopsin, Opn1sw, and Opn1mw at 3 months in Asrgl1mut/mut mice compared with age-matched wildtype mice. Importantly, the retinal phenotype of Asrgl1mut/mut mice is consistent with the phenotype observed in patients harboring the G178R mutation in ASRGL1 confirming a critical role of ASRGL1 in the retina and the contribution of ASRGL1 mutations in retinal degeneration.
- Subjects :
- early onset degeneration
Neurodegenerative
Inbred C57BL
Eye
Autoantigens
Mice
Rare Diseases
Escherichia coli
Genetics
Animals
Humans
Asparaginase
2.1 Biological and endogenous factors
Aetiology
Cas9
CRISPR/Cas9
Eye Disease and Disorders of Vision
Genetics (clinical)
Animal
animal model
Retinal Degeneration
Neurosciences
Infant
ASRGL1
Phenotype
CRISPR
Disease Models
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 20734425
- Database :
- OpenAIRE
- Journal :
- Genes; Volume 13; Issue 8; Pages: 1461
- Accession number :
- edsair.doi.dedup.....f79d195e52b8ab7038ca322ef33136b1
- Full Text :
- https://doi.org/10.3390/genes13081461