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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