ROM1 contributes to phenotypic heterogeneity in PRPH2-associated retinal disease

Abstract

Peripherin 2 (PRPH2) is a retina-specific tetraspanin protein essential for the formation of rod and cone photoreceptor outer segments (OS). Patients with mutations in PRPH2 exhibit severe retinal degeneration characterized by vast inter- and intra-familial phenotypic heterogeneity. To help understand contributors to this within-mutation disease variability, we asked whether the PRPH2 binding partner rod outer segment membrane protein 1 (ROM1) could serve as a phenotypic modifier. We utilized knockin and transgenic mouse models to evaluate the structural, functional, and biochemical effects of eliminating one allele of Rom1 (Rom1+/−) in three different Prph2 models which mimic human disease: C213Y Prph2 (Prph2C/+), K153Del Prph2 (Prph2K/+) and R172W (Prph2R172W). Reducing Rom1 in the absence of Prph2 mutations (Rom1+/−) had no effect on retinal structure or function. However, the effects of reducing Rom1 in the presence of Prph2 mutations were highly variable. Prph2K/+/Rom1+/− mice had improved rod and cone function compared to Prph2K/+ as well as amelioration of K153Del-associated defects in PRPH2/ROM1 oligomerization. In contrast, Prph2R172W/Rom1+/− animals had worsened rod and cone function and exacerbated retinal degeneration compared to Prph2R172W animals. Removing one allele of Rom1 had no effect in Prph2C/+. Combined, our findings support a role for non-pathogenic ROM1 null variants in contributing to phenotypic variability in mutant PRPH2-associated retinal degeneration. Since the effects of Rom1 reduction are variable, our data suggest that this contribution is specific to the type of Prph2 mutation.

Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation

“…This results in a strong heterogeneity of phenotypes, even within a family that shares the same mutation, with clinical manifestations ranging from retinitis pigmentosa to various forms of macular dystrophy [ 50 , 51 ]. The presence of ROM1 variants [ 52 ], the existence of different PRPH2 haplotypes [ 53 ], and/or interactions with other genes/proteins [ 54 ] can modulate the patient phenotype. This intriguing pattern highlights the intricate relationship between specific genetic alterations and the resulting phenotypic expression.…”

Downregulation of rhodopsin is an effective therapeutic strategy in ameliorating peripherin-2-associated inherited retinal disorders

“…The knockin mouse models, Prph2 K153∆/K153Δ and Prph2 Y141C/Y141C , were generated and characterized previously 13 , 14 . Additionally, an in-house WT mouse strain was generated as described previously 67 . The homozygous Rho knockout mouse line ( Rho −/− ) was originally obtained as a generous gift from Dr. Janis Lem (Tufts University, Boston, MA, USA) and has been previously described 34 .…”

“…Histology and morphometric analyses were performed as previously described 67 . Briefly, eyes were enucleated from euthanized mice and fixed in modified Davidson’s fixative 71 (12% formaldehyde, 15% ethanol, and 5% glacial acetic acid) overnight at 4 °C.…”

Prph2 mutant knock-in mice recapitulate all features of human central areolar choroidal dystrophy and reveals an aberrant synaptic remodelling and microglial activation

“…This results in a strong heterogeneity of phenotypes, even within a family that shares the same mutation, with clinical manifestations ranging from retinitis pigmentosa to various forms of macular dystrophy (Antonelli et al, 2022;Bianco et al, 2023). It was described that the presence of ROM1 variants (Strayve et al, 2020), the existence of different PRPH2 haplotypes (Shankar et al, 2016), and/or the interactions with other genes/proteins (Xiao et al, 2022) can modulate the patient phenotype. This intriguing pattern highlights the intricate relationship between speci c genetic alterations and the resulting phenotypic expression.…”