Role of subunit assembly in autosomal dominant retinitis pigmentosa linked to mutations in peripherin 2.

Peripherin 2 is a photoreceptor-specific membrane protein implicated in outer segment disk morphogenesis and linked to various retinopathies including autosomal dominant retinitis pigmentosa (ADRP). Peripherin 2 and ROM1 assemble as a mixture of core noncovalent homomeric and heteromeric tetramers that further link together through disulfide bonds to form higher order oligomers. These complexes are critical for disk rim formation and outer segment structure through interaction with the cGMP-gated channel and other photoreceptor proteins. We have examined the role of subunit assembly in peripherin 2 targeting to disks, outer segment structure, and photoreceptor degeneration by examining molecular and cellular properties of peripherin 2 mutants in COS-1 cells and transgenic Xenopus laevis rod photoreceptors. Wild-type (WT) and the ADRP-linked P216L mutant were transported and incorporated into newly formed outer segment disks of transgenic X. laevis. The P216L mutant, however, induced progressive outer segment instability and photoreceptor degeneration possibly through the introduction of a new N-linked oligosaccharide chain. In contrast, the C214S and L185P disease-linked, tetramerization-defective mutants, were retained in the inner segment, but did not affect outer segment structure or induce photoreceptor degeneration. Together, these results indicate that peripherin 2 mutations can cause ADRP either through a deficiency in WT peripherin 2 (C214S, 1.185P) or by a dominant negative effect on disk stability (P216L).