Related Experiment Video
Updated: Jul 11, 2025
A Protocol to Evaluate and Quantify Retinal Pigmented Epithelium Pathologies in Mouse Models of Age-Related Macular Degeneration
Published on: March 10, 2023
Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations
Brittany N Williams1,2,3, Adam Draper1,2, Patrick F Lang1,2
1Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, United States.
Abstract:
Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.
Insights
Mouse models reveal that specific interphotoreceptor matrix proteoglycan 2 (IMPG2) mutations cause distinct retinitis pigmentosa (RP) pathologies. Understanding mutation type is crucial for developing effective IMPG2-RP treatments.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Biallelic mutations in IMPG2 cause retinitis pigmentosa (RP), a condition affecting vision.
- Disease progression in IMPG2-RP varies significantly due to genetic factors and mutation type.
- Currently, no treatments exist for IMPG2-RP, necessitating better understanding through animal models.
Purpose of the Study:
- To develop and characterize mouse models that mimic human IMPG2-RP.
- To investigate the impact of different IMPG2 mutation types on retinal pathology progression.
- To provide preclinical data for the development of future therapeutic strategies.
Main Methods:
- Generation of mouse models with homozygous frameshift (T807Ter, Q244Ter) or missense (Y250C) Impg2 mutations.
- Longitudinal characterization of retinal pathologies from postnatal development to late adulthood.
- Histological and functional assessments of retinal integrity and photoreceptor health.
Main Results:
- Mice with frameshift mutations (Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter) showed early gliosis, photoreceptor dysfunction, subretinal deposits, and retinal detachment.
- Mice with the missense mutation (Impg2Y250C/Y250C) exhibited minimal retinal pathology.
- Mutation type significantly influences the severity and progression of retinal disease in IMPG2-RP models.
Conclusions:
- The type of IMPG2 mutation is a critical determinant of disease phenotype in retinitis pigmentosa.
- Developed mouse models offer valuable tools for studying IMPG2-RP pathogenesis.
- Preclinical data from these models can guide the advancement of therapeutic interventions for IMPG2-RP.
