Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations.

PubMed ID: 37975905

Author(s): Williams BN, Draper A, Lang PF, Lewis TR, Smith AL, Mayerl SJ, Rougie M, Simon JM, Arshavsky VY, Greenwald SH, Gamm DM, Pinilla I, Philpot BD. Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations. Hum Mol Genet. 2023 Nov 17:ddad199. doi: 10.1093/hmg/ddad199. Online ahead of print. PMID 37975905

Journal: Human Molecular Genetics, Nov 2023

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. Towards this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with homozygous frameshift mutations (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 round white deposits surrounding the optic nerve, and disruptions of the outer retina layers and neurosensorial detachment, while 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.