Identification of a Causal Gene Variant Prom1 for Photoreceptor Degeneration in BXD83 Mice

Abstract

Purpose : Progressive loss of photoreceptors is a common cause of many retinal diseases leading to irreversible visual impairment. The purpose of this study is to identify the causal factor that is responsible for photoreceptor degeneration in BXD83 mice which was predicted with inherited photoreceptor degeneration.

Methods : The BXD mouse family consists of ~150 fully sequenced inbred strains and is currently the largest phenotyped murine family. Using systems genetics approach, BXD83 mice was predicted to develop photoreceptor degeneration. Retinal histology, retinography (ERG), and visual function assessment by optomotor response (OMR) were compared in C57BL/6 (WT) and BXD83 mice over time. Retinal structural and retinal pigment epithelium (RPE) barrier function of WT and BXD83 were also examined. A mouse line knocked with a mutated form of Prom1 found in BXD83 mice was also generated. Retinal morphology was characterized through histology and optical coherence topography (OCT) imaging. Functional analysis of retinal function, visual function, and RPE barrier function of Prom1^m/m mice were investigated alongside with WT mice.

Results : Deep sequencing data predicted Prom1 as a causal factor for photoreceptor degeneration in BXD83 mouse line. Morphological and functional analysis of BXD83 mice demonstrated progressive photoreceptor loss, as well as abnormities in the RPE. A significant reduction of ERG scotopic and flicker responses was also detected in BXD83 mice starting by 6-weeks of age. By characterizing the causal gene(s) responsible for retinal degeneration, we found a stop-gain mutation of Prom1 may have a high impact among the variants in BXD83 mice. Mice carrying this specific Prom1 mutation (Prom1^m/m) exhibited thinning of the outer nuclear layer (ONL), outer segment (OS), inner plexiform layer (IPL), and RPE as measured by OCT. By 6 weeks of age, significant reduction of visual function and barrier function of primary RPE cells were also detected in Prom1^m/m mice.

Conclusions : Characterization of the morphological and functional changes in the BXD83 and Prom1^m/m mice supports the mutation in Prom1 as a pivotal factor contributing to photoreceptor degeneration. The study sheds light on potential pathways for targeted interventions aimed at preventing retinal degeneration and visual function deterioration in photoreceptor degeneration in the future.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.