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

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 (per(WT)), mutant peripherin-2 (per(MT)), 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 per(WT) and Rom-1. Furthermore, both mutants are preferentially forming non-covalent per(MT)-per(MT), per(WT)-per(MT), and Rom-1-per(MT) dimers. However, only per(WT)-per(MT), but not per(MT)-per(MT) or Rom-1-per(MT) complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent per(WT)-per(MT) dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of per(WT) and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals

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

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 (per$^{WT}$), mutant peripherin-2 (per$^{MT}$), 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 per$^{WT}$ and Rom-1. Furthermore, both mutants are preferentially forming non-covalent per$^{MT}$-per$^{MT}$, per$^{WT}$-per$^{MT}$, and Rom-1-per$^{MT}$ dimers. However, only per$^{WT}$-per$^{MT}$, but not per$^{MT}$-per$^{MT}$ or Rom-1-per$^{MT}$ complexes could be targeted to murine rod OS. Our study provides first evidence that non-covalent per$^{WT}$-per$^{MT}$ dimers can be targeted to rod OS. Finally, our study unravels unexpected opposing roles of per$^{WT}$ and Rom-1 in rod OS targeting of adRP-linked peripherin-2 mutants and suggests a new treatment strategy for the affected individuals