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. 2024 Feb 18;33(5):448-464. doi: 10.1093/hmg/ddad199. Erratum In: Hum Mol Genet. 2024 Feb 18;33(5):475-476. doi: 10.1093/hmg/ddae004. 2024 Jan 13;: PMID 37975905

Journal: Human Molecular Genetics, Volume 33, Issue 5, Feb 2024

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.