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

Hum Mol Genet. 2017 Feb 1;26(3):509-518. doi: 10.1093/hmg/ddw408.

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.

MeSH terms

  • Animals
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / pathology
  • Eye Proteins
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Humans
  • Macular Degeneration / genetics
  • Macular Degeneration / pathology
  • Mice
  • Multiprotein Complexes / biosynthesis
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Mutation
  • Pedigree
  • Peripherins / biosynthesis
  • Peripherins / chemistry
  • Peripherins / genetics*
  • Phenotype
  • Photoreceptor Cells, Vertebrate / chemistry
  • Photoreceptor Cells, Vertebrate / metabolism
  • Protein Multimerization
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / pathology
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / pathology
  • Tetraspanins / biosynthesis
  • Tetraspanins / chemistry
  • Tetraspanins / genetics*

Substances

  • Eye Proteins
  • Multiprotein Complexes
  • PRPH2 protein, human
  • Peripherins
  • ROM1 protein, human
  • Tetraspanins