title: 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 (Prph2Y/+), Y141C-Prph2 and Rom1 formed abnormal complexes but were present at normal levels. Abnormal complexes were eliminated in the absence of Rom1 (Prph2Y/+/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 Prph2Y/+ animals exhibited a cone-rod electroretinogram defect, Prph2Y/+/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.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Conley
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Stuck
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Watson
authors.affiliation: Department of Biomedical Engineering, University of Houston, Houston, TX, USA.
authors.forename: Muna I
authors.initials: MI
authors.lastname: Naash
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology; D005136:Eye Proteins; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000473:pathology; D051379:Mice; D046912:Multiprotein Complexes / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D064531:Peripherins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D059470:Tetraspanins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*
chemical_list: D005136:Eye Proteins; D046912:Multiprotein Complexes; C578997:PRPH2 protein, human; D064531:Peripherins; C513106:ROM1 protein, human; D059470:Tetraspanins