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

Williams, Brittany N ; Draper, Adam ; Lang, Patrick F ; Lewis, Tylor R ; Smith, Audrey L ; Mayerl, Steven J ; Rougié, Marie ; Simon, Jeremy M ; Arshavsky, Vadim Y ; Greenwald, Scott H ; Gamm, David M ; Pinilla, Isabel (Universidad de Zaragoza) ; Philpot, Benjamin D

Resumen: 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.

Idioma: Inglés

DOI: 10.1093/hmg/ddad199

Año: 2023

Publicado en: HUMAN MOLECULAR GENETICS 33, 5 (2023), 448–464
ISSN: 0964-6906

Factor impacto JCR: 3.1 (2023)

Categ. JCR: GENETICS & HEREDITY rank: 73 / 191 = 0.382 (2023) - Q2 - T2
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 168 / 313 = 0.537 (2023) - Q3 - T2

Factor impacto CITESCORE: 6.9 - Genetics (Q2) - Molecular Biology (Q2) - Genetics (clinical) (Q2)

Tipo y forma: Article (Published version)

Área (Departamento): Área Oftalmología (Dpto. Cirugía)