Rom1 converts Y141C-Prph2-associated pattern dystrophy to retinitis pigmentosa

Abstract

Mutations in peripherin 2 ( PRPH2), also known as retinal degeneration slow/ RDS, lead to various retinal degenerations including retinitis pigmentosa (RP) and macular/pattern dystrophy (MD/PD). PRPH2-associated disease is often characterized by a phenotypic variability even within families carrying the same mutation, raising interest in potential modifiers. PRPH2 oligomerizes with its homologue rod outer segment (OS) membrane protein 1 (ROM1), and non-pathogenic PRPH2/ROM1 mutations, when present together, lead to digenic RP. We asked whether ROM1 could modify the phenotype of a PRPH2 mutation associated with a high degree of intrafamilial phenotypic heterogeneity: Y141C. In vitro, Y141C-Prph2 showed signs of retention in the endoplasmic reticulum (ER), however co-expression with Rom1 rescued this phenotype. In the heterozygous Y141C knockin mouse model ( Prph2 ^Y/+ ), Y141C-Prph2 and Rom1 formed abnormal complexes but were present at normal levels. Abnormal complexes were eliminated in the absence of Rom1 ( Prph2 ^Y/+/Rom1 ^-/- ) and total Prph2 levels were reduced to those found in the haploinsufficient Prph2 ^+/- RP model. The biochemical changes had functional and structural consequences; while Prph2 ^Y/+ animals exhibited a cone-rod electroretinogram defect, Prph2 ^Y/+/Rom1 ^-/- animals displayed a rod-dominant phenotype and OSs similar to those seen in the Prph2 ^+/- . These data show that ablation of Rom1 results in the conversion of an MD/PD phenotype characterized by cone functional defects and the formation of abnormal Prph2/Rom1 complexes to an RP phenotype characterized by rod-dominant functional defects and reductions in total Prph2 protein. Thus one method by which ROM1 may act as a disease modifier is by contributing to the large variability in PRPH2-associated disease phenotypes.