Peripherin-2 and Rom-1 have opposing effects on rod outer segment targeting of retinitis pigmentosa-linked peripherin-2 mutants

Sci Rep. 2017 May 24;7(1):2321. doi: 10.1038/s41598-017-02514-5.

Abstract

Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations in the peripherin-2 homolog Rom-1 cause digenic RP in combination with certain heterozygous mutations in peripherin-2. The mechanisms underlying the differential role of peripherin-2 and Rom-1 in RP pathophysiology remained elusive so far. Here, focusing on two adRP-linked peripherin-2 mutants, P210L and C214S, we analyzed the binding characteristics, protein assembly, and rod OS targeting of wild type (perWT), mutant peripherin-2 (perMT), or Rom-1 complexes, which can be formed in patients heterozygous for peripherin-2 mutations. Both mutants are misfolded and lead to decreased binding to perWT and Rom-1. Furthermore, both mutants are preferentially forming non-covalent perMT-perMT, perWT-perMT, and Rom-1-perMT dimers. However, only perWT-perMT, but not perMT-perMT or Rom-1-perMT complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent perWT-perMT dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of perWT and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Eye Proteins
  • Humans
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism
  • Mice
  • Mutation
  • Peripherins / genetics*
  • Peripherins / metabolism
  • Protein Binding
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / metabolism
  • Retinitis Pigmentosa / pathology
  • Rod Cell Outer Segment / metabolism*
  • Rod Cell Outer Segment / pathology
  • Tetraspanins / genetics*
  • Tetraspanins / metabolism

Substances

  • Eye Proteins
  • Intermediate Filament Proteins
  • Peripherins
  • ROM1 protein, human
  • Tetraspanins